G Model
ARTICLE IN PRESS
YDRUP-542; No. of Pages 17
Drug Resistance Updates xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Drug Resistance Updates journal homepage: www.elsevier.com/locate/drup
Review
The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade Rishil J. Kathawala, Pranav Gupta, Charles R. Ashby Jr. ∗∗ , Zhe-Sheng Chen ∗ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA
a r t i c l e
i n f o
Article history: Received 24 August 2014 Received in revised form 17 November 2014 Accepted 20 November 2014 Keywords: Multidrug resistance ABC transporters Modulators Tyrosine kinase inhibitors Phosphodiesterase inhibitors Marine sponges Natural products
a b s t r a c t ATP-binding cassette (ABC) transporters represent one of the largest and oldest families of membrane proteins in all extant phyla from prokaryotes to humans, which couple the energy derived from ATP hydrolysis essentially to translocate, among various substrates, toxic compounds across the membrane. The fundamental functions of these multiple transporter proteins include: (1) conserved mechanisms related to nutrition and pathogenesis in bacteria, (2) spore formation in fungi, and (3) signal transduction, protein secretion and antigen presentation in eukaryotes. Moreover, one of the major causes of multidrug resistance (MDR) and chemotherapeutic failure in cancer therapy is believed to be the ABC transportermediated active efflux of a multitude of structurally and mechanistically distinct cytotoxic compounds across membranes. It has been postulated that ABC transporter inhibitors known as chemosensitizers may be used in combination with standard chemotherapeutic agents to enhance their therapeutic efficacy. The current paper reviews the advance in the past decade in this important domain of cancer chemoresistance and summarizes the development of new compounds and the re-evaluation of compounds originally designed for other targets as transport inhibitors of ATP-dependent drug efflux pumps. © 2014 Elsevier Ltd. All rights reserved.
Contents 1.
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Multidrug resistance and ABC transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. ABCB1/MDR1/P-gp transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. ABCC1/MRP1 transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. ABCC10/MRP7 transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. ABCG2/BCRP/MXR transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Modulators of ABC transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Breakpoint cluster region-abelson (BCR-ABL) TKIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Imatinib (STI571) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Nilotinib (AMN107) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Ponatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Epidermal growth factor receptor (EGFR) TKIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Icotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Lapatinib (GW-572016) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Erlotinib (OSI-774) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. AST1306 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.5. WHI-P154 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.6. Gefitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.7. Canertinib (CI-1033) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Department of Pharmaceutical Sciences, St. John’s University, Queens, NY 11439, USA. Tel.: +1 718 990 1432; fax: +1 718 990 1877. ∗∗ Corresponding author at: Department of Pharmaceutical Sciences, St. John’s University, Queens, NY 11439, USA. Tel.: +1 631 509 1269. E-mail addresses: [email protected] (C.R. Ashby Jr.), [email protected] (Z.-S. Chen). http://dx.doi.org/10.1016/j.drup.2014.11.002 1368-7646/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kathawala, R.J., et al., The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist. Updat. (2014), http://dx.doi.org/10.1016/j.drup.2014.11.002
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2.3.
3.
4. 5.
Vascular endothelial growth factor receptor (VEGFR) TKIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Telatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Motesanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Vandetanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4. Sunitinib (SU11248) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5. Sorafenib (BAY43-9006) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Miscellaneous TKIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Masitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2. Linsitinib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.3. Crizotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.4. Vemurafenib (PLX4032) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Marine compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.1. Agosterol A (AG-A) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2. Ecteinascidin 743 (ET- 743) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.3. Sipholane triterpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.4. Bryostatin 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.5. Welwitindolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Natural compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1. (−)-Epigallocatechin gallate (EGCG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. Curcumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.3. Capsaicin and gingerol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.4. Rosemary phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.5. Citrus phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.6. Miscellaneous natural compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. PDE-5 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.1. Sildenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.2. Vardenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical relevance of ABC transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. ABCB1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. ABCC10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. ABCG2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure of potential conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Multidrug resistance and ABC transporters The resistance of cancer cells to structurally and mechanistically unrelated classes of anticancer drugs is known as multidrug resistance (MDR) (Gottesman et al., 2002). This pervasive and insidious clinical problem eventually leads to cancer relapse and death (Fig. 1). The mechanisms of MDR have been intensively studied,
Fig. 1. MDR v/s sensitivity. MDR occurs as the cell loses sensitivity to anticancer drugs.
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although not all mechanisms that result in MDR have been elucidated. The mechanisms that cancer cells utilize or develop to evade chemotherapy are complex and have been described in detail in several recent reviews (Gillet and Gottesman, 2010; Gottesman et al., 2002; Szakacs et al., 2006). One of the most prominent mechanisms underlying MDR is overexpression of ATP-binding cassette (ABC) transporters. ABC transporters are a group of active transporter proteins that have diverse functions and are present in both prokaryotes and eukaryotes (Glavinas et al., 2004; Higgins, 1992; Shukla et al., 2008; Wu et al., 2011). These transporters use energy derived from the hydrolysis of ATP to adenosine di-phosphate (ADP) to transport their substrates across the membrane against a concentration gradient (Borths et al., 2002; Locher, 2004; Locher and Borths, 2004). Currently, 49 members of the ABC transporter family have been isolated and identified. The ABC transporter family is divided into seven subfamilies, ABCA through ABCG. Structurally, ABC transporter proteins have two nucleotide-binding domains (NBDs) and two transmembrane binding domains (TMDs) (Tiwari et al., 2011; Wu et al., 2011). ABC transporters can be topologically classified based on the sequence of the NBDs, also known as ABC domains (Dean and Allikmets, 1995; Dean et al., 2001; Deeley et al., 2006). The NBDs are proteins consisting of conserved ABC (necessary for cellular function) that is responsible for binding and extruding physiological and xenobiotic substrates out of the cell. The NBDs, in addition to containing Walker A and B motifs, also contain an additional element, the signature (C) motif, found upstream to Walker B motif joining the Walker A and B motifs. These Walker A and B motifs play a role in hydrolysis of ATP to ADP + P and energy coupling (Higgins et al., 1985; Walker et al., 1982). The NBD hydrolyzes
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Fig. 2. Important MDR-ABC transporters. ABCB1(MDR1/P-gp), ABCC1(MRP1), ABCC10(MRP7) and ABCG2(BCRP/MXR) are major mediators of efflux of anticancer drugs from the cells.
ATP via an ATPase and this is crucial in conferring MDR to various chemotherapeutic compounds (Ambudkar et al., 2006; Dean, 2009; Eytan et al., 1996; Gottesman et al., 2002; Higgins, 1992). Numerous studies indicate that ABC transporters are involved in efflux of toxic endogenous molecules and xenobiotics out of the cell (Assaraf, 2007; Assaraf et al., 1994; Holland, 2011; Hooijberg et al., 1999). In addition, they play a role in transporting important substrates across extracellular and intracellular membranes, such as amino acids, cholesterol and its derivatives, sugars, vitamins, peptides, lipids, some important proteins, hydrophobic drugs and antibiotics (Dean and Annilo, 2005; Goldstein et al., 1989; Gottesman and Ambudkar, 2001; Ifergan et al., 2004; Shi et al., 2007b, 2007c). Four important MDR-ABC transporters are discussed here (Fig. 2). 1.1. ABCB1/MDR1/P-gp transporter The human ABCB1, an ABCB1 encoded gene product localized to chromosome 7p21, was the first identified ABC transporter (Juliano and Ling, 1976; Ueda et al., 1986). ABCB1 has a molecular weight of 170-kDa. ABCB1 is an apical membrane transporter that is located in the kidney, placenta, liver, adrenal glands, intestine and blood–brain barrier cells, where it functions to protect against xenobiotics and cellular toxicants (Assaraf and Borgnia, 1993; Gottesman et al., 2002; Sarkadi et al., 2006; Sauna et al., 2001). The overexpression of ABCB1 confers significant resistance to a wide variety of neutral and cationic hydrophobic chemotherapeutic substrates including taxanes (e.g. paclitaxel, docetaxel), epipodophyllotoxins (e.g. etoposide and teniposide), Vinca alkaloids (e.g. vinblastine and vincristine), anthracyclines
(e.g. doxorubicin and daunorubicin) (Fig. 3) (Gottesman et al., 2002; Schinkel and Jonker, 2003; Sodani et al., 2012; Tiwari et al., 2011), antibiotics (e.g. actinomycin D) (Findling-Kagan et al., 2005; Liu et al., 2001; Sauna et al., 2001), breakpoint cluster regionabelson (BCR-ABL) tyrosine kinase inhibitors (TKIs) [e.g. imatinib (Peng et al., 2012), nilotinib (Mahon et al., 2008)], and epidermal growth factor receptor (EGFR) TKIs (e.g. erlotinib) (Marchetti et al., 2008). Paclitaxel accumulates in the gastrointestinal tract and brain of Abcb1 knockout mice, indicating that ABCB1 prevents paclitaxel’s elimination into the bile and its crossing the blood–brain barrier, respectively (Schinkel et al., 1997). The evaluation of ABCB1 expression in the National Cancer Institute (NCI) 60 cancer cell lines anticancer drug screening panel, using quantitative polymerase chain reaction (PCR), indicated a significant negative correlation coefficient (−0.896) of ABCB1 expression with the sensitivity profile of paclitaxel (Alvarez et al., 1995), suggesting that overexpression of the ABCB1 drug efflux pump leads to paclitaxel resistance. ABCB1 mRNA (Schondorf et al., 1999, 2002) or ABCB1 protein (Parekh et al., 1997) is increased in paclitaxel-resistant tumor cell lines. Therefore, it becomes important to identify the mechanisms by which ABCB1 overexpression modulates paclitaxel resistance. It has been suggested that ABCB1 overexpression results from: (1) amplification of the ABCB1 gene (Assaraf et al., 1989; Schondorf et al., 2002); (2) increased transcription of the ABCB1 gene by novel transcription factors such as RGP8.5 (Xu et al., 2001); (3) changes in ABCB1 translational efficiency (Schondorf et al., 2002); (4) mutations in the ABCB1 gene (Choi et al., 1988; Devine et al., 1992; Gros et al., 1991) and (5) chromosomal rearrangements in the ABCB1 gene that produce hybrid genes (Mickley et al., 1997).
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Fig. 3. Anticancer drugs as substrates of MDR-ABC transporters. ABCB1, ABCC1, ABCC10 and ABCG2 are located on the cell surface that extrudes anticancer drug substrates from the cells.
The pharmacogenetics correlation of paclitaxel resistance and the ABCB1 transporter gene sequence has been unequivocal. The systemic elimination of paclitaxel occurs by hepatic metabolism involving the cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 (Walle et al., 1995) and biliary elimination of paclitaxel occurs by ABCB1 (Sparreboom et al., 1997). Several single nucleotide polymorphisms (SNP) in the ABCB1 gene, including G1199T/A and G2677T/A (Ala893Ser/Thr), are positively correlated with progression-free survival after paclitaxel treatment (Green et al., 2006, 2008). In addition, C3435T (Ile1145Ile, wobble) has been positively correlated with paclitaxel-mediated peripheral neuropathy and neutropenia (Sissung et al., 2006). However, in other studies, no significant correlation was found between the pharmacokinetics of paclitaxel and the ABCB1 genotype (Grimm et al., 2010; Henningsson et al., 2005; Nakajima et al., 2005; Sissung et al., 2006). The ABCC2 and ABCG2 genetic variants have also been suggested to play a role in paclitaxel treatment, although no significant correlations to paclitaxel efficacy have been reported (Marsh et al., 2007). 1.2. ABCC1/MRP1 transporter ABCC1 was first found in the anthracycline-resistant cell lines, H69AR and HL60/Adr (Bakos et al., 1998; Cole et al., 1992; Kruh and Belinsky, 2003). This 190-kDa protein is present on the basolateral surface of the epithelial membrane and it effluxes various endogenous and exogenous substances (Bakos et al., 1998; Kruh and Belinsky, 2003). In spite of the relatively low degree of amino acid sequence identity with ABCB1 (15%), there is a significant overlap between ABCB1 and the resistance profile of ABCC1 (Leschziner et al., 2006). The overexpression of the ABCC1 transporter confers
resistance to a wide range of anticancer drugs, such as anthracyclines, Vinca alkaloids, epipodophyllotoxins, camptothecins, methotrexate, saquinavir, and mitoxantrone (Fig. 3) (Anreddy et al., 2014; Assaraf et al., 2003; Sodani et al., 2012; Wang et al., 2014d). However, unlike ABCB1 and ABCC10, ABCC1 does not confer resistance to taxanes, an important component of the ABCB1 resistance profile (Cole et al., 1994; Morrow et al., 2006). Fibroblast cell lines from Abcc1 knockout mice show a similar resistance pattern (Lin et al., 2002), along with sensitization to taxanes and mitoxantrone. ABCC1 also mediates resistance to TKIs, such as imatinib (Czyzewski and Styczynski, 2009). 1.3. ABCC10/MRP7 transporter The human ABCC10 transporter is an ABCC10 encoded gene product localized to chromosome 6p21.1 (Hopper et al., 2001; Kruh et al., 2007). The ABCC10 transporter is a 171-kDa protein containing three membrane-spanning domains (MSD1, MSD2 and MSD3) and two NBDs (Deng et al., 2013; Hopper et al., 2001; Kruh et al., 2007). It belongs to the class of long ABCCs, such as ABCC1, ABCC2, ABCC3 and ABCC6 (Chen et al., 2003a; Hopper et al., 2001; Sodani et al., 2012) and is localized to the basolateral cell surface (Malofeeva et al., 2012). The ABCC10 transcript is expressed in the skin, testes, spleen, stomach, colon, kidney, heart and brain, albeit at low levels (Hopper et al., 2001). Another group reported that the ABCC10 transcript expression was highest in the pancreas, followed by the liver, placenta, lungs, kidneys, brain, ovaries, lymph nodes, spleen, heart, leukocytes and colon (Takayanagi et al., 2004). The ABCC10 is an amphipathic anion transporter whose physiological functions remain to be determined (Malofeeva et al., 2012). The substrates of ABCC10 are restricted
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Fig. 4. Classification modulators of MDR-ABC transporters. MDR-ABC modulators can be pharmacologically classified as breakpoint cluster region-abelson (BCR-ABL) TKIs, epidermal growth factor receptor (EGFR) TKIs, vascular endothelial growth factor receptor (VEGFR) TKIs, miscellaneous TKIs, marine compounds, natural compounds and phosphodiesterase-5 inhibitors.
to glucuronides such as 17--d-glucuronide (E2 17G) and the glutathione conjugate of leukotriene C4 (LTC4) (Chen et al., 2003a). The transfection of HEK293 cells with the ABCC10 gene confers resistance to various anticancer drugs including paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, cytarabine, gemcitabine, 2 ,3 dideoxycytidine, 9-(2-phosphonyl methoxyethyl)adenine (PMEA), epothilone B (Fig. 3) (Bessho et al., 2009; Chen et al., 2003a; Hopper-Borge et al., 2004, 2009, 2011; Hopper et al., 2001; Hu et al., 2011; Kruh et al., 2007; Malofeeva et al., 2012; Oguri et al., 2008; Rudin et al., 2011; Sun et al., 2013). Abcc10 knockout mice are more susceptible to the lethal effects of systemic paclitaxel (Hopper-Borge et al., 2011), suggesting that the ABCC10 transporter is critical for viability and protection against xenobiotic toxicity. With the exception of ABCC2, where resistance towards paclitaxel is detectable under conditions in which endogenous ABCB1 activity is suppressed (Huisman et al., 2005), no other ABCC family member has been reported to confer resistance to paclitaxel except ABCC10 (Sodani et al., 2012). ABCC10 is expressed in salivary gland adenocarcinoma and non-small cell lung carcinoma (Bessho et al., 2009; Naramoto et al., 2007; Oguri et al., 2008). In addition, ABCC10 transcript has been detected in the HepG2 liver cancer cell line and two prostate cancer cell lines (CWR22Rv1 and TSU-PR1) (Dabrowska and Sirotnak, 2004), as well as in breast, lung, colon, prostate, ovarian, and pancreatic tumor specimens (Takayanagi et al., 2004). ABCC10 gene expression is increased, along with ABCB1, in chemosensitive and chemoresistant ovarian tumors in mice during intermittent docetaxel treatment (De Souza et al., 2011). This suggests that the chemotherapy-dosing schedule can alter docetaxel resistance (De Souza et al., 2011). 1.4. ABCG2/BCRP/MXR transporter The ABCG2 protein is a 72-kDa protein (Matsuo et al., 2011; Yang et al., 2014; Zhang et al., 2014b). It is the first known half transporter with one TMD and one NBD to mediate MDR (Litman et al., 2000; Rocchi et al., 2000). It is active upon homodimerization or oligomerization with itself or other transporters (Ejendal and Hrycyna, 2002; Goler-Baron and Assaraf, 2011; Mao and Unadkat, 2005; Robey et al., 2007; Shi et al., 2007c). The ABCG2 transporter is widely distributed and is present mainly in the plasma membrane. Furthermore, it is highly expressed in placental syncytiotrophoblasts, the apical surface of small intestines, colon epithelium, liver canalicular membrane, luminal surfaces of microvessel endothelium of human brain and in the veins
and capillaries of blood vessels (Cooray et al., 2002; Doyle et al., 1998; Maliepaard et al., 2001; Rocchi et al., 2000). The substrates of ABCG2 include organic anion conjugates, nucleoside analogs, organic dyes, TKIs, anthracyclines, camptothecin-derived topoisomerase I inhibitors, methotrexate and flavopiridols (Fig. 3) (Mao and Unadkat, 2005; Sun et al., 2012; Wang et al., 2014b). The ABCG2 transporter is a mediator of MDR in breast, colon, gastric, small cell lung, ovarian, gastric and intestinal cancers and melanomas (Ejendal and Hrycyna, 2002; Tiwari et al., 2009, 2011). Mutations in the ABCG2 gene produce distinct substrate preferences for the mutant and wild-type variants. For example, a mutation at position 482 is the most important mutation for the determination of substrate specificity (Chen et al., 2003b). The amino acid arginine (Arg or R) is located on the carboxy terminus of the third transmembrane segment of the membrane spanning domain, where substrate binding occurs probably due to the formation of salt bridges (Mao and Unadkat, 2005). These mutations cause conformational changes and alter the drug binding and efflux capacity of the transporter (Dai et al., 2009; Honjo et al., 2001; Pozza et al., 2006). The replacement of Arg with threonine (Thr or T) or glycine (Gly or G) at position 482 produces changes in the substrate profiles among the variants (Ejendal and Hrycyna, 2002; Mao and Unadkat, 2005). Rhodamine 123, daunorubicin, and lysotracker green are substrates for the mutant Gly and Thr variants, although they are not substrates for the wild type ABCG2 (Bates et al., 2004; Ejendal et al., 2006; Mao and Unadkat, 2005). In contrast, mitoxantrone, boron-dipyrromethene (BODIPY)-prazosin and almost all nucleoside inhibitors are substrates of both the wild type and the mutant ABCG2 (Ejendal and Hrycyna, 2002). The substitution of Thr or Gly for Arg at position 482 produces resistance to doxorubicin, daunorubicin, mitoxantrone, methotrexate and anthracyclines (Abbott et al., 2002; Suvannasankha et al., 2004). The Gly482 mutant has a similar transport capacity for various antibiotics, conjugated steroids and primary bile acids (Abbott et al., 2002; Suvannasankha et al., 2004). Interestingly, ABCG2 is overexpressed only in subpopulations (also known as side population) of acute myelogenous leukemia specimens (Abbott et al., 2002; Suvannasankha et al., 2004). The overexpression of ABCG2 in these subpopulations of stem cells was also found in other tumors including neuroblastomas, Ewing sarcomas, breast cancer, smallcell lung cancer and glioblastomas (Hirschmann-Jax et al., 2004). These stem cells may play an important role in conferring resistance to chemotherapeutic drugs, thereby contributing to relapse. It is important to point out that the role of ABCG2 in stem cell biology remains to be elucidated.
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2. Modulators of ABC transporters Since the discovery that the overexpression of ABC transporters in cancer cells mediates resistance to anticancer drugs, there has been an ongoing effort to develop therapies that could either block or inactivate these transporters to increase the concentration of anti-cancer drugs within the cells. The first ABC transporter modulators to be discovered were the “first-generation” ABCB1 inhibitors (Coley, 2010; Tan et al., 2000). These compounds included verapamil, cyclosporine A (CSA) and quinine (Leonard et al., 2003; Szakacs et al., 2006; Tsuruo et al., 1989). Although these compounds showed efficacy in pre-clinical trials, they were not effective against MDR in clinical trials (Coley, 2010; Kohler and Stein, 2003). Verapamil, at doses used to treat MDR, produced cardiotoxicity (Dalton et al., 1995). In addition, CSA, when used in combination with vincristine, doxorubicin and dexamethasone, lacked significant efficacy in Phase III clinical trials in patients with refractory multiple myeloma (Sonneveld et al., 1994). In order to circumvent the problems associated with the first generation drugs, the compounds valspodar (PSC-833, a CSA analog) and biricodar (VX-710) were designed to target specific MDR transporters. These compounds, subsequently known as “second-generation MDR modulators” (Sonneveld et al., 1994), were more efficacious than the first generation drugs when used in combination with conventional chemotherapeutic drugs (Nobili et al., 2006, 2012). In addition, they had improved bioavailability and produced less toxicity (Goldman, 2003) compared to the first-generation drugs. However, the second-generation MDR modulators lacked significant efficacy in clinical trials (Nobili et al., 2006). In addition, these compounds inhibited hepatic and intestinal cytochrome P450 enzymes, decreasing the metabolism and clearance of the substrate drugs, thereby causing systemic toxicity (Leonard et al., 2003; Lum and Gosland, 1995; Szakacs et al., 2006). The “thirdgeneration MDR modulators” were developed using quantitative structure-activity relationship (QSAR) to overcome the problems associated with the first and second-generation MDR modulators (Hyafil et al., 1993; Nobili et al., 2006; Thomas and Coley, 2003). Third-generation drugs, such as elacridar (GF120918), laniquidar (R101933) zosuquidar (LY335979) and tariquidar (XR9576), significantly inhibited ABCB1 function at nanomolar concentrations (Dantzig et al., 1999; Fracasso et al., 2004; Martin et al., 1999; Mistry et al., 2001). Furthermore, these compounds were less toxic and were also inhibitors of ABCG2 and ABCC1 (Dantzig et al., 1999; Szakacs et al., 2006). Zosuquidar, a TKI in Phase III clinical trials has shown significant efficacy in patients with acute myeloid leukemia (Dantzig et al., 1999; Jemal et al., 2009). Although most of the modulators are inhibitors of ABCB1, only a few can inhibit other ABC transporters. For example, agosterol-A, CSA, leukotriene C4 and D4 receptor antagonist (MK571), raloxifine analogs, isoxazole-derived molecules PAK 104P and agosterol-A significantly reverse ABCC1and ABCC2-mediated MDR (Chen et al., 1999; Morschhauser et al., 2007; Qadir et al., 2005; Sumizawa et al., 1997). In contrast, inhibitors for other transporters such as ABCA5, ABCB4, ABCB5, ABCB11, ABCC4, ABCC5, ABCC6, ABCC10, and ABCC11 have not been developed. Fumitremorgin C (FTC,), a derivative of Ko143 (Rabindran et al., 2000; van Loevezijn et al., 2001), inhibits ABCG2. Several nonspecific ABC transporter inhibitors such as elacridar and biricodar are known to inhibit ABCB1 and ABCC1 (Bates et al., 2002; Szakacs et al., 2006; Thomas and Coley, 2003). Apart from the aforementioned MDR modulators, several studies have reported in the last decade that ABC transporters can be inhibited by TKIs, marine compounds, natural compounds and phosphodiesterase5 (PDE-5) inhibitors (Fig. 4), which are mechanistically and structurally distinct from the 3 generations of ABC transporters discussed above. The last 10 years were filled with plethora of drugs that modulate MDR-ABC transporters (Table 1), which not
only showed convincing in vitro and in vivo results but some of them also showed significant efficacy in clinical trials (Kelly et al., 2012; Kunz et al., 2012; O’Brien et al., 2010; Zhang et al., 2014b). 2.1. Breakpoint cluster region-abelson (BCR-ABL) TKIs 2.1.1. Imatinib (STI571) Imatinib, approved by the Food and Drug Administration in 2001, is a first generation BCR-ABL inhibitor that inhibits proliferation of myeloid cells containing the BCR-ABL oncogene and is used in patients with chronic myeloid leukemia (CML) (Goldman and Melo, 2003; Stegmeier et al., 2010). Imatinib also inhibits the c-Kit and PDGFR tyrosine kinases (Hirota et al., 1998). We have reported that in vitro, imatinib (1, 2.5 and 5 M) significantly reverses ABCC10mediated MDR and enhances the efficacy of ABCC10 substrates (paclitaxel and vincristine) in ABCC10-transfected HEK293 cells (Shen et al., 2009). Gao et al. reported that in vitro, imatinib (1 M) increases the intracellular concentration of vincristine and mitoxantrone in cells overexpressing ABCB1 and ABCG2, respectively (Gao et al., 2006). 2.1.2. Nilotinib (AMN107) Nilotinib, a second-generation TKI, was developed to surmount imatinib-resistant CML (Kantarjian et al., 2006). We have reported that in vitro, nilotinib (2.5 and 5 M) inhibits the efflux function of ABCB1 and ABCG2 (Tiwari et al., 2009). In vitro, nilotinib (1, 2.5 and 5 M) reverses ABCC10-mediated MDR and increases the intracellular accumulation of paclitaxel and vincristine in ABCC10transfected HEK293 cells (Shen et al., 2009). In vivo studies from our lab have shown that nilotinib (75 mg/kg, p.o., q3d × 6), in combination with paclitaxel (18 mg/kg, i.p., q3d × 6) or doxorubicin (1.8 mg/kg, i.p., q3d × 6), significantly decreased the size of tumors overexpressing the ABCB1 and ABCC10, or ABCG2 transporter, respectively (Tiwari et al., 2013). 2.1.3. Ponatinib Ponatinib, an inhibitor of BCR-ABL, FMS-related tyrosine kinase 3 (FLT3), vascular endothelial growth factor receptor (VEGFR) and angiopoietin, has been reported to surmount the imatinib-resistant T315I mutant in Ph+ CML patients (Huang et al., 2010; O’Hare et al., 2011). Ponatinib, in vitro, reverses the ABCB1-, ABCG2- and ABCC10-mediated MDR (Sen et al., 2012; Sun et al., 2014). It increases the uptake of the substrates for ABCB1 and ABCG2 in cells overexpressing these transporters and inhibits [125 I]-IAAP binding to ABCB1 and ABCG2, with IC50 values of 0.63 and 0.04 M, respectively (Sen et al., 2012). Furthermore, in vitro, ponatinib increases the sensitivity to substrates of ABCC10, in cells overexpressing the ABCC10 transporter, and it increases the intracellular accumulation of [3 H]-paclitaxel, at 0.1, 0.25 and 0.5 M (Sun et al., 2014). Moreover, it inhibits the efflux of [3 H]-paclitaxel at 0.5 M and downregulates the expression of the ABCC10 protein in a concentration-dependent manner (Sun et al., 2014). 2.2. Epidermal growth factor receptor (EGFR) TKIs 2.2.1. Icotinib Icotinib, a small molecule EGFR TKI, is efficacious in patients with non-small cell lung cancer (Gao et al., 2013). Wang et al. reported that icotinib reverses the MDR mediated by the ABCG2 transporter (Wang et al., 2014a). In vitro, icotinib, at 1 and 5 M, increases the intracellular accumulation of [3 H]-mitoxantrone and inhibits the efflux of [3 H]-mitoxantrone at 5 M in ABCG2 overexpressing cells (Wang et al., 2014a). Furthermore, icotinib stimulates ATPase activity in a concentration-dependent manner (Wang et al., 2014a). However, expression levels of Akt (i.e. protein kinase B)
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and ABCG2 were not significantly altered in ABCG2 overexpressing NCI-H460/MX20 cells incubated for 72 h with 5 M, of icotinib (Wang et al., 2014a). In vivo studies from our lab have shown that icotinib (60 mg/kg, p.o., q3d × 6), in combination with topotecan (3.0 mg/kg, i.p., q3d × 6), significantly decreased the size of tumors overexpressing the ABCG2 transporter (Wang et al., 2014a). 2.2.2. Lapatinib (GW-572016) Lapatinib is a non-selective EGFR inhibitor that inhibits both ErbB1 and ErbB2 (Nelson and Dolder, 2006; Wood et al., 2004). Lapatinib (0.625, 1.25 and 2.5 M), in vitro, increases the accumulation of doxorubicin or mitoxantrone in cells overexpressing ABCB1 or ABCG2, respectively and it increases the ATPase activity of both ABCB1 and ABCG2 (Dai et al., 2008). Furthermore, lapatinib (0.625, 1.25 and 2.5 M) significantly reduces ABCC10-mediated MDR and increase the sensitivity of ABCC10-transfected HEK293 cells to docetaxel, paclitaxel, vinblastine, and vinorelbine (Kuang et al., 2010). Thus, lapatinib reverses the MDR mediated by the overexpression of ABCB1, ABCG2, and ABCC10 by inhibiting their transport function. The mouse xenograft studies from our lab have shown that, in vivo, lapatinib (100 mg/kg, p.o., q3d × 4), in combination with paclitaxel (18 mg/kg, i.p., q3d × 4), significantly decreased the size of tumors overexpressing the ABCB1 transporter (Dai et al., 2008). 2.2.3. Erlotinib (OSI-774) Erlotinib is a selective ErbB1 inhibitor that inhibits EGFRdependent cellular proliferation and causes cell cycle arrest at G1 phase (Moyer et al., 1997). Erlotinib (2.5 and 10 M), in vitro, reverses ABCB1- and ABCG2-mediated MDR. Erlotinib (0.625, 1.25 and 2.5 M) also increases the accumulation of [3 H]-paclitaxel in HEK293/ABCC10 cells and reverses ABCC10-mediated MDR (Kuang et al., 2010; Shi et al., 2007c). 2.2.4. AST1306 AST1306, an inhibitor of EGFR and ErB2, has been tested for its effect on MDR induced by ABCG2. AST1306 (0.25 and 1 M), in vitro, increases the (1) cytotoxicity of mitoxantrone and SN-38 in cells overexpressing the ABCG2 transporter and (2) intracellular accumulation of [3 H]-mitoxantrone in both wild type and mutant cells expressing ABCG2 (Zhang et al., 2014c). AST1306 also stimulates the ATPase activity of ABCG2 and its reversal of ABCG2-mediated MDR is more potent than that of lapatinib and erlotinib (Zhang et al., 2014c). 2.2.5. WHI-P154 WHI-P154 is an irreversible inhibitor of EGFR and janus kinase-3 (Changelian et al., 2008). Zhang et al. reported that in vitro, WHIP154 (1 and 4 M) increases the sensitivity of ABCG2 substrates in MDR cells due to ABCG2 overexpression (Zhang et al., 2014d). WHI-P154 (1 and 4 M) increases the intracellular accumulation of [3 H]-mitoxantrone in ABCG2-overexpressing cells and stimulates the ATPase activity of ABCG2 at concentrations
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Contents lists available at ScienceDirect
Drug Resistance Updates journal homepage: www.elsevier.com/locate/drup
Review
The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade Rishil J. Kathawala, Pranav Gupta, Charles R. Ashby Jr. ∗∗ , Zhe-Sheng Chen ∗ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA
a r t i c l e
i n f o
Article history: Received 24 August 2014 Received in revised form 17 November 2014 Accepted 20 November 2014 Keywords: Multidrug resistance ABC transporters Modulators Tyrosine kinase inhibitors Phosphodiesterase inhibitors Marine sponges Natural products
a b s t r a c t ATP-binding cassette (ABC) transporters represent one of the largest and oldest families of membrane proteins in all extant phyla from prokaryotes to humans, which couple the energy derived from ATP hydrolysis essentially to translocate, among various substrates, toxic compounds across the membrane. The fundamental functions of these multiple transporter proteins include: (1) conserved mechanisms related to nutrition and pathogenesis in bacteria, (2) spore formation in fungi, and (3) signal transduction, protein secretion and antigen presentation in eukaryotes. Moreover, one of the major causes of multidrug resistance (MDR) and chemotherapeutic failure in cancer therapy is believed to be the ABC transportermediated active efflux of a multitude of structurally and mechanistically distinct cytotoxic compounds across membranes. It has been postulated that ABC transporter inhibitors known as chemosensitizers may be used in combination with standard chemotherapeutic agents to enhance their therapeutic efficacy. The current paper reviews the advance in the past decade in this important domain of cancer chemoresistance and summarizes the development of new compounds and the re-evaluation of compounds originally designed for other targets as transport inhibitors of ATP-dependent drug efflux pumps. © 2014 Elsevier Ltd. All rights reserved.
Contents 1.
2.
Multidrug resistance and ABC transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. ABCB1/MDR1/P-gp transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. ABCC1/MRP1 transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. ABCC10/MRP7 transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. ABCG2/BCRP/MXR transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Modulators of ABC transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Breakpoint cluster region-abelson (BCR-ABL) TKIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Imatinib (STI571) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Nilotinib (AMN107) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Ponatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Epidermal growth factor receptor (EGFR) TKIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Icotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Lapatinib (GW-572016) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Erlotinib (OSI-774) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. AST1306 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.5. WHI-P154 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.6. Gefitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.7. Canertinib (CI-1033) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Department of Pharmaceutical Sciences, St. John’s University, Queens, NY 11439, USA. Tel.: +1 718 990 1432; fax: +1 718 990 1877. ∗∗ Corresponding author at: Department of Pharmaceutical Sciences, St. John’s University, Queens, NY 11439, USA. Tel.: +1 631 509 1269. E-mail addresses: [email protected] (C.R. Ashby Jr.), [email protected] (Z.-S. Chen). http://dx.doi.org/10.1016/j.drup.2014.11.002 1368-7646/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kathawala, R.J., et al., The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist. Updat. (2014), http://dx.doi.org/10.1016/j.drup.2014.11.002
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2.3.
3.
4. 5.
Vascular endothelial growth factor receptor (VEGFR) TKIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Telatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Motesanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Vandetanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4. Sunitinib (SU11248) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5. Sorafenib (BAY43-9006) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Miscellaneous TKIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Masitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2. Linsitinib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.3. Crizotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.4. Vemurafenib (PLX4032) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Marine compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.1. Agosterol A (AG-A) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2. Ecteinascidin 743 (ET- 743) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.3. Sipholane triterpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.4. Bryostatin 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.5. Welwitindolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Natural compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1. (−)-Epigallocatechin gallate (EGCG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. Curcumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.3. Capsaicin and gingerol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.4. Rosemary phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.5. Citrus phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.6. Miscellaneous natural compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. PDE-5 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.1. Sildenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7.2. Vardenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical relevance of ABC transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. ABCB1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. ABCC10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. ABCG2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure of potential conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Multidrug resistance and ABC transporters The resistance of cancer cells to structurally and mechanistically unrelated classes of anticancer drugs is known as multidrug resistance (MDR) (Gottesman et al., 2002). This pervasive and insidious clinical problem eventually leads to cancer relapse and death (Fig. 1). The mechanisms of MDR have been intensively studied,
Fig. 1. MDR v/s sensitivity. MDR occurs as the cell loses sensitivity to anticancer drugs.
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although not all mechanisms that result in MDR have been elucidated. The mechanisms that cancer cells utilize or develop to evade chemotherapy are complex and have been described in detail in several recent reviews (Gillet and Gottesman, 2010; Gottesman et al., 2002; Szakacs et al., 2006). One of the most prominent mechanisms underlying MDR is overexpression of ATP-binding cassette (ABC) transporters. ABC transporters are a group of active transporter proteins that have diverse functions and are present in both prokaryotes and eukaryotes (Glavinas et al., 2004; Higgins, 1992; Shukla et al., 2008; Wu et al., 2011). These transporters use energy derived from the hydrolysis of ATP to adenosine di-phosphate (ADP) to transport their substrates across the membrane against a concentration gradient (Borths et al., 2002; Locher, 2004; Locher and Borths, 2004). Currently, 49 members of the ABC transporter family have been isolated and identified. The ABC transporter family is divided into seven subfamilies, ABCA through ABCG. Structurally, ABC transporter proteins have two nucleotide-binding domains (NBDs) and two transmembrane binding domains (TMDs) (Tiwari et al., 2011; Wu et al., 2011). ABC transporters can be topologically classified based on the sequence of the NBDs, also known as ABC domains (Dean and Allikmets, 1995; Dean et al., 2001; Deeley et al., 2006). The NBDs are proteins consisting of conserved ABC (necessary for cellular function) that is responsible for binding and extruding physiological and xenobiotic substrates out of the cell. The NBDs, in addition to containing Walker A and B motifs, also contain an additional element, the signature (C) motif, found upstream to Walker B motif joining the Walker A and B motifs. These Walker A and B motifs play a role in hydrolysis of ATP to ADP + P and energy coupling (Higgins et al., 1985; Walker et al., 1982). The NBD hydrolyzes
Please cite this article in press as: Kathawala, R.J., et al., The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist. Updat. (2014), http://dx.doi.org/10.1016/j.drup.2014.11.002
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Fig. 2. Important MDR-ABC transporters. ABCB1(MDR1/P-gp), ABCC1(MRP1), ABCC10(MRP7) and ABCG2(BCRP/MXR) are major mediators of efflux of anticancer drugs from the cells.
ATP via an ATPase and this is crucial in conferring MDR to various chemotherapeutic compounds (Ambudkar et al., 2006; Dean, 2009; Eytan et al., 1996; Gottesman et al., 2002; Higgins, 1992). Numerous studies indicate that ABC transporters are involved in efflux of toxic endogenous molecules and xenobiotics out of the cell (Assaraf, 2007; Assaraf et al., 1994; Holland, 2011; Hooijberg et al., 1999). In addition, they play a role in transporting important substrates across extracellular and intracellular membranes, such as amino acids, cholesterol and its derivatives, sugars, vitamins, peptides, lipids, some important proteins, hydrophobic drugs and antibiotics (Dean and Annilo, 2005; Goldstein et al., 1989; Gottesman and Ambudkar, 2001; Ifergan et al., 2004; Shi et al., 2007b, 2007c). Four important MDR-ABC transporters are discussed here (Fig. 2). 1.1. ABCB1/MDR1/P-gp transporter The human ABCB1, an ABCB1 encoded gene product localized to chromosome 7p21, was the first identified ABC transporter (Juliano and Ling, 1976; Ueda et al., 1986). ABCB1 has a molecular weight of 170-kDa. ABCB1 is an apical membrane transporter that is located in the kidney, placenta, liver, adrenal glands, intestine and blood–brain barrier cells, where it functions to protect against xenobiotics and cellular toxicants (Assaraf and Borgnia, 1993; Gottesman et al., 2002; Sarkadi et al., 2006; Sauna et al., 2001). The overexpression of ABCB1 confers significant resistance to a wide variety of neutral and cationic hydrophobic chemotherapeutic substrates including taxanes (e.g. paclitaxel, docetaxel), epipodophyllotoxins (e.g. etoposide and teniposide), Vinca alkaloids (e.g. vinblastine and vincristine), anthracyclines
(e.g. doxorubicin and daunorubicin) (Fig. 3) (Gottesman et al., 2002; Schinkel and Jonker, 2003; Sodani et al., 2012; Tiwari et al., 2011), antibiotics (e.g. actinomycin D) (Findling-Kagan et al., 2005; Liu et al., 2001; Sauna et al., 2001), breakpoint cluster regionabelson (BCR-ABL) tyrosine kinase inhibitors (TKIs) [e.g. imatinib (Peng et al., 2012), nilotinib (Mahon et al., 2008)], and epidermal growth factor receptor (EGFR) TKIs (e.g. erlotinib) (Marchetti et al., 2008). Paclitaxel accumulates in the gastrointestinal tract and brain of Abcb1 knockout mice, indicating that ABCB1 prevents paclitaxel’s elimination into the bile and its crossing the blood–brain barrier, respectively (Schinkel et al., 1997). The evaluation of ABCB1 expression in the National Cancer Institute (NCI) 60 cancer cell lines anticancer drug screening panel, using quantitative polymerase chain reaction (PCR), indicated a significant negative correlation coefficient (−0.896) of ABCB1 expression with the sensitivity profile of paclitaxel (Alvarez et al., 1995), suggesting that overexpression of the ABCB1 drug efflux pump leads to paclitaxel resistance. ABCB1 mRNA (Schondorf et al., 1999, 2002) or ABCB1 protein (Parekh et al., 1997) is increased in paclitaxel-resistant tumor cell lines. Therefore, it becomes important to identify the mechanisms by which ABCB1 overexpression modulates paclitaxel resistance. It has been suggested that ABCB1 overexpression results from: (1) amplification of the ABCB1 gene (Assaraf et al., 1989; Schondorf et al., 2002); (2) increased transcription of the ABCB1 gene by novel transcription factors such as RGP8.5 (Xu et al., 2001); (3) changes in ABCB1 translational efficiency (Schondorf et al., 2002); (4) mutations in the ABCB1 gene (Choi et al., 1988; Devine et al., 1992; Gros et al., 1991) and (5) chromosomal rearrangements in the ABCB1 gene that produce hybrid genes (Mickley et al., 1997).
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Fig. 3. Anticancer drugs as substrates of MDR-ABC transporters. ABCB1, ABCC1, ABCC10 and ABCG2 are located on the cell surface that extrudes anticancer drug substrates from the cells.
The pharmacogenetics correlation of paclitaxel resistance and the ABCB1 transporter gene sequence has been unequivocal. The systemic elimination of paclitaxel occurs by hepatic metabolism involving the cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 (Walle et al., 1995) and biliary elimination of paclitaxel occurs by ABCB1 (Sparreboom et al., 1997). Several single nucleotide polymorphisms (SNP) in the ABCB1 gene, including G1199T/A and G2677T/A (Ala893Ser/Thr), are positively correlated with progression-free survival after paclitaxel treatment (Green et al., 2006, 2008). In addition, C3435T (Ile1145Ile, wobble) has been positively correlated with paclitaxel-mediated peripheral neuropathy and neutropenia (Sissung et al., 2006). However, in other studies, no significant correlation was found between the pharmacokinetics of paclitaxel and the ABCB1 genotype (Grimm et al., 2010; Henningsson et al., 2005; Nakajima et al., 2005; Sissung et al., 2006). The ABCC2 and ABCG2 genetic variants have also been suggested to play a role in paclitaxel treatment, although no significant correlations to paclitaxel efficacy have been reported (Marsh et al., 2007). 1.2. ABCC1/MRP1 transporter ABCC1 was first found in the anthracycline-resistant cell lines, H69AR and HL60/Adr (Bakos et al., 1998; Cole et al., 1992; Kruh and Belinsky, 2003). This 190-kDa protein is present on the basolateral surface of the epithelial membrane and it effluxes various endogenous and exogenous substances (Bakos et al., 1998; Kruh and Belinsky, 2003). In spite of the relatively low degree of amino acid sequence identity with ABCB1 (15%), there is a significant overlap between ABCB1 and the resistance profile of ABCC1 (Leschziner et al., 2006). The overexpression of the ABCC1 transporter confers
resistance to a wide range of anticancer drugs, such as anthracyclines, Vinca alkaloids, epipodophyllotoxins, camptothecins, methotrexate, saquinavir, and mitoxantrone (Fig. 3) (Anreddy et al., 2014; Assaraf et al., 2003; Sodani et al., 2012; Wang et al., 2014d). However, unlike ABCB1 and ABCC10, ABCC1 does not confer resistance to taxanes, an important component of the ABCB1 resistance profile (Cole et al., 1994; Morrow et al., 2006). Fibroblast cell lines from Abcc1 knockout mice show a similar resistance pattern (Lin et al., 2002), along with sensitization to taxanes and mitoxantrone. ABCC1 also mediates resistance to TKIs, such as imatinib (Czyzewski and Styczynski, 2009). 1.3. ABCC10/MRP7 transporter The human ABCC10 transporter is an ABCC10 encoded gene product localized to chromosome 6p21.1 (Hopper et al., 2001; Kruh et al., 2007). The ABCC10 transporter is a 171-kDa protein containing three membrane-spanning domains (MSD1, MSD2 and MSD3) and two NBDs (Deng et al., 2013; Hopper et al., 2001; Kruh et al., 2007). It belongs to the class of long ABCCs, such as ABCC1, ABCC2, ABCC3 and ABCC6 (Chen et al., 2003a; Hopper et al., 2001; Sodani et al., 2012) and is localized to the basolateral cell surface (Malofeeva et al., 2012). The ABCC10 transcript is expressed in the skin, testes, spleen, stomach, colon, kidney, heart and brain, albeit at low levels (Hopper et al., 2001). Another group reported that the ABCC10 transcript expression was highest in the pancreas, followed by the liver, placenta, lungs, kidneys, brain, ovaries, lymph nodes, spleen, heart, leukocytes and colon (Takayanagi et al., 2004). The ABCC10 is an amphipathic anion transporter whose physiological functions remain to be determined (Malofeeva et al., 2012). The substrates of ABCC10 are restricted
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Fig. 4. Classification modulators of MDR-ABC transporters. MDR-ABC modulators can be pharmacologically classified as breakpoint cluster region-abelson (BCR-ABL) TKIs, epidermal growth factor receptor (EGFR) TKIs, vascular endothelial growth factor receptor (VEGFR) TKIs, miscellaneous TKIs, marine compounds, natural compounds and phosphodiesterase-5 inhibitors.
to glucuronides such as 17--d-glucuronide (E2 17G) and the glutathione conjugate of leukotriene C4 (LTC4) (Chen et al., 2003a). The transfection of HEK293 cells with the ABCC10 gene confers resistance to various anticancer drugs including paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, cytarabine, gemcitabine, 2 ,3 dideoxycytidine, 9-(2-phosphonyl methoxyethyl)adenine (PMEA), epothilone B (Fig. 3) (Bessho et al., 2009; Chen et al., 2003a; Hopper-Borge et al., 2004, 2009, 2011; Hopper et al., 2001; Hu et al., 2011; Kruh et al., 2007; Malofeeva et al., 2012; Oguri et al., 2008; Rudin et al., 2011; Sun et al., 2013). Abcc10 knockout mice are more susceptible to the lethal effects of systemic paclitaxel (Hopper-Borge et al., 2011), suggesting that the ABCC10 transporter is critical for viability and protection against xenobiotic toxicity. With the exception of ABCC2, where resistance towards paclitaxel is detectable under conditions in which endogenous ABCB1 activity is suppressed (Huisman et al., 2005), no other ABCC family member has been reported to confer resistance to paclitaxel except ABCC10 (Sodani et al., 2012). ABCC10 is expressed in salivary gland adenocarcinoma and non-small cell lung carcinoma (Bessho et al., 2009; Naramoto et al., 2007; Oguri et al., 2008). In addition, ABCC10 transcript has been detected in the HepG2 liver cancer cell line and two prostate cancer cell lines (CWR22Rv1 and TSU-PR1) (Dabrowska and Sirotnak, 2004), as well as in breast, lung, colon, prostate, ovarian, and pancreatic tumor specimens (Takayanagi et al., 2004). ABCC10 gene expression is increased, along with ABCB1, in chemosensitive and chemoresistant ovarian tumors in mice during intermittent docetaxel treatment (De Souza et al., 2011). This suggests that the chemotherapy-dosing schedule can alter docetaxel resistance (De Souza et al., 2011). 1.4. ABCG2/BCRP/MXR transporter The ABCG2 protein is a 72-kDa protein (Matsuo et al., 2011; Yang et al., 2014; Zhang et al., 2014b). It is the first known half transporter with one TMD and one NBD to mediate MDR (Litman et al., 2000; Rocchi et al., 2000). It is active upon homodimerization or oligomerization with itself or other transporters (Ejendal and Hrycyna, 2002; Goler-Baron and Assaraf, 2011; Mao and Unadkat, 2005; Robey et al., 2007; Shi et al., 2007c). The ABCG2 transporter is widely distributed and is present mainly in the plasma membrane. Furthermore, it is highly expressed in placental syncytiotrophoblasts, the apical surface of small intestines, colon epithelium, liver canalicular membrane, luminal surfaces of microvessel endothelium of human brain and in the veins
and capillaries of blood vessels (Cooray et al., 2002; Doyle et al., 1998; Maliepaard et al., 2001; Rocchi et al., 2000). The substrates of ABCG2 include organic anion conjugates, nucleoside analogs, organic dyes, TKIs, anthracyclines, camptothecin-derived topoisomerase I inhibitors, methotrexate and flavopiridols (Fig. 3) (Mao and Unadkat, 2005; Sun et al., 2012; Wang et al., 2014b). The ABCG2 transporter is a mediator of MDR in breast, colon, gastric, small cell lung, ovarian, gastric and intestinal cancers and melanomas (Ejendal and Hrycyna, 2002; Tiwari et al., 2009, 2011). Mutations in the ABCG2 gene produce distinct substrate preferences for the mutant and wild-type variants. For example, a mutation at position 482 is the most important mutation for the determination of substrate specificity (Chen et al., 2003b). The amino acid arginine (Arg or R) is located on the carboxy terminus of the third transmembrane segment of the membrane spanning domain, where substrate binding occurs probably due to the formation of salt bridges (Mao and Unadkat, 2005). These mutations cause conformational changes and alter the drug binding and efflux capacity of the transporter (Dai et al., 2009; Honjo et al., 2001; Pozza et al., 2006). The replacement of Arg with threonine (Thr or T) or glycine (Gly or G) at position 482 produces changes in the substrate profiles among the variants (Ejendal and Hrycyna, 2002; Mao and Unadkat, 2005). Rhodamine 123, daunorubicin, and lysotracker green are substrates for the mutant Gly and Thr variants, although they are not substrates for the wild type ABCG2 (Bates et al., 2004; Ejendal et al., 2006; Mao and Unadkat, 2005). In contrast, mitoxantrone, boron-dipyrromethene (BODIPY)-prazosin and almost all nucleoside inhibitors are substrates of both the wild type and the mutant ABCG2 (Ejendal and Hrycyna, 2002). The substitution of Thr or Gly for Arg at position 482 produces resistance to doxorubicin, daunorubicin, mitoxantrone, methotrexate and anthracyclines (Abbott et al., 2002; Suvannasankha et al., 2004). The Gly482 mutant has a similar transport capacity for various antibiotics, conjugated steroids and primary bile acids (Abbott et al., 2002; Suvannasankha et al., 2004). Interestingly, ABCG2 is overexpressed only in subpopulations (also known as side population) of acute myelogenous leukemia specimens (Abbott et al., 2002; Suvannasankha et al., 2004). The overexpression of ABCG2 in these subpopulations of stem cells was also found in other tumors including neuroblastomas, Ewing sarcomas, breast cancer, smallcell lung cancer and glioblastomas (Hirschmann-Jax et al., 2004). These stem cells may play an important role in conferring resistance to chemotherapeutic drugs, thereby contributing to relapse. It is important to point out that the role of ABCG2 in stem cell biology remains to be elucidated.
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2. Modulators of ABC transporters Since the discovery that the overexpression of ABC transporters in cancer cells mediates resistance to anticancer drugs, there has been an ongoing effort to develop therapies that could either block or inactivate these transporters to increase the concentration of anti-cancer drugs within the cells. The first ABC transporter modulators to be discovered were the “first-generation” ABCB1 inhibitors (Coley, 2010; Tan et al., 2000). These compounds included verapamil, cyclosporine A (CSA) and quinine (Leonard et al., 2003; Szakacs et al., 2006; Tsuruo et al., 1989). Although these compounds showed efficacy in pre-clinical trials, they were not effective against MDR in clinical trials (Coley, 2010; Kohler and Stein, 2003). Verapamil, at doses used to treat MDR, produced cardiotoxicity (Dalton et al., 1995). In addition, CSA, when used in combination with vincristine, doxorubicin and dexamethasone, lacked significant efficacy in Phase III clinical trials in patients with refractory multiple myeloma (Sonneveld et al., 1994). In order to circumvent the problems associated with the first generation drugs, the compounds valspodar (PSC-833, a CSA analog) and biricodar (VX-710) were designed to target specific MDR transporters. These compounds, subsequently known as “second-generation MDR modulators” (Sonneveld et al., 1994), were more efficacious than the first generation drugs when used in combination with conventional chemotherapeutic drugs (Nobili et al., 2006, 2012). In addition, they had improved bioavailability and produced less toxicity (Goldman, 2003) compared to the first-generation drugs. However, the second-generation MDR modulators lacked significant efficacy in clinical trials (Nobili et al., 2006). In addition, these compounds inhibited hepatic and intestinal cytochrome P450 enzymes, decreasing the metabolism and clearance of the substrate drugs, thereby causing systemic toxicity (Leonard et al., 2003; Lum and Gosland, 1995; Szakacs et al., 2006). The “thirdgeneration MDR modulators” were developed using quantitative structure-activity relationship (QSAR) to overcome the problems associated with the first and second-generation MDR modulators (Hyafil et al., 1993; Nobili et al., 2006; Thomas and Coley, 2003). Third-generation drugs, such as elacridar (GF120918), laniquidar (R101933) zosuquidar (LY335979) and tariquidar (XR9576), significantly inhibited ABCB1 function at nanomolar concentrations (Dantzig et al., 1999; Fracasso et al., 2004; Martin et al., 1999; Mistry et al., 2001). Furthermore, these compounds were less toxic and were also inhibitors of ABCG2 and ABCC1 (Dantzig et al., 1999; Szakacs et al., 2006). Zosuquidar, a TKI in Phase III clinical trials has shown significant efficacy in patients with acute myeloid leukemia (Dantzig et al., 1999; Jemal et al., 2009). Although most of the modulators are inhibitors of ABCB1, only a few can inhibit other ABC transporters. For example, agosterol-A, CSA, leukotriene C4 and D4 receptor antagonist (MK571), raloxifine analogs, isoxazole-derived molecules PAK 104P and agosterol-A significantly reverse ABCC1and ABCC2-mediated MDR (Chen et al., 1999; Morschhauser et al., 2007; Qadir et al., 2005; Sumizawa et al., 1997). In contrast, inhibitors for other transporters such as ABCA5, ABCB4, ABCB5, ABCB11, ABCC4, ABCC5, ABCC6, ABCC10, and ABCC11 have not been developed. Fumitremorgin C (FTC,), a derivative of Ko143 (Rabindran et al., 2000; van Loevezijn et al., 2001), inhibits ABCG2. Several nonspecific ABC transporter inhibitors such as elacridar and biricodar are known to inhibit ABCB1 and ABCC1 (Bates et al., 2002; Szakacs et al., 2006; Thomas and Coley, 2003). Apart from the aforementioned MDR modulators, several studies have reported in the last decade that ABC transporters can be inhibited by TKIs, marine compounds, natural compounds and phosphodiesterase5 (PDE-5) inhibitors (Fig. 4), which are mechanistically and structurally distinct from the 3 generations of ABC transporters discussed above. The last 10 years were filled with plethora of drugs that modulate MDR-ABC transporters (Table 1), which not
only showed convincing in vitro and in vivo results but some of them also showed significant efficacy in clinical trials (Kelly et al., 2012; Kunz et al., 2012; O’Brien et al., 2010; Zhang et al., 2014b). 2.1. Breakpoint cluster region-abelson (BCR-ABL) TKIs 2.1.1. Imatinib (STI571) Imatinib, approved by the Food and Drug Administration in 2001, is a first generation BCR-ABL inhibitor that inhibits proliferation of myeloid cells containing the BCR-ABL oncogene and is used in patients with chronic myeloid leukemia (CML) (Goldman and Melo, 2003; Stegmeier et al., 2010). Imatinib also inhibits the c-Kit and PDGFR tyrosine kinases (Hirota et al., 1998). We have reported that in vitro, imatinib (1, 2.5 and 5 M) significantly reverses ABCC10mediated MDR and enhances the efficacy of ABCC10 substrates (paclitaxel and vincristine) in ABCC10-transfected HEK293 cells (Shen et al., 2009). Gao et al. reported that in vitro, imatinib (1 M) increases the intracellular concentration of vincristine and mitoxantrone in cells overexpressing ABCB1 and ABCG2, respectively (Gao et al., 2006). 2.1.2. Nilotinib (AMN107) Nilotinib, a second-generation TKI, was developed to surmount imatinib-resistant CML (Kantarjian et al., 2006). We have reported that in vitro, nilotinib (2.5 and 5 M) inhibits the efflux function of ABCB1 and ABCG2 (Tiwari et al., 2009). In vitro, nilotinib (1, 2.5 and 5 M) reverses ABCC10-mediated MDR and increases the intracellular accumulation of paclitaxel and vincristine in ABCC10transfected HEK293 cells (Shen et al., 2009). In vivo studies from our lab have shown that nilotinib (75 mg/kg, p.o., q3d × 6), in combination with paclitaxel (18 mg/kg, i.p., q3d × 6) or doxorubicin (1.8 mg/kg, i.p., q3d × 6), significantly decreased the size of tumors overexpressing the ABCB1 and ABCC10, or ABCG2 transporter, respectively (Tiwari et al., 2013). 2.1.3. Ponatinib Ponatinib, an inhibitor of BCR-ABL, FMS-related tyrosine kinase 3 (FLT3), vascular endothelial growth factor receptor (VEGFR) and angiopoietin, has been reported to surmount the imatinib-resistant T315I mutant in Ph+ CML patients (Huang et al., 2010; O’Hare et al., 2011). Ponatinib, in vitro, reverses the ABCB1-, ABCG2- and ABCC10-mediated MDR (Sen et al., 2012; Sun et al., 2014). It increases the uptake of the substrates for ABCB1 and ABCG2 in cells overexpressing these transporters and inhibits [125 I]-IAAP binding to ABCB1 and ABCG2, with IC50 values of 0.63 and 0.04 M, respectively (Sen et al., 2012). Furthermore, in vitro, ponatinib increases the sensitivity to substrates of ABCC10, in cells overexpressing the ABCC10 transporter, and it increases the intracellular accumulation of [3 H]-paclitaxel, at 0.1, 0.25 and 0.5 M (Sun et al., 2014). Moreover, it inhibits the efflux of [3 H]-paclitaxel at 0.5 M and downregulates the expression of the ABCC10 protein in a concentration-dependent manner (Sun et al., 2014). 2.2. Epidermal growth factor receptor (EGFR) TKIs 2.2.1. Icotinib Icotinib, a small molecule EGFR TKI, is efficacious in patients with non-small cell lung cancer (Gao et al., 2013). Wang et al. reported that icotinib reverses the MDR mediated by the ABCG2 transporter (Wang et al., 2014a). In vitro, icotinib, at 1 and 5 M, increases the intracellular accumulation of [3 H]-mitoxantrone and inhibits the efflux of [3 H]-mitoxantrone at 5 M in ABCG2 overexpressing cells (Wang et al., 2014a). Furthermore, icotinib stimulates ATPase activity in a concentration-dependent manner (Wang et al., 2014a). However, expression levels of Akt (i.e. protein kinase B)
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and ABCG2 were not significantly altered in ABCG2 overexpressing NCI-H460/MX20 cells incubated for 72 h with 5 M, of icotinib (Wang et al., 2014a). In vivo studies from our lab have shown that icotinib (60 mg/kg, p.o., q3d × 6), in combination with topotecan (3.0 mg/kg, i.p., q3d × 6), significantly decreased the size of tumors overexpressing the ABCG2 transporter (Wang et al., 2014a). 2.2.2. Lapatinib (GW-572016) Lapatinib is a non-selective EGFR inhibitor that inhibits both ErbB1 and ErbB2 (Nelson and Dolder, 2006; Wood et al., 2004). Lapatinib (0.625, 1.25 and 2.5 M), in vitro, increases the accumulation of doxorubicin or mitoxantrone in cells overexpressing ABCB1 or ABCG2, respectively and it increases the ATPase activity of both ABCB1 and ABCG2 (Dai et al., 2008). Furthermore, lapatinib (0.625, 1.25 and 2.5 M) significantly reduces ABCC10-mediated MDR and increase the sensitivity of ABCC10-transfected HEK293 cells to docetaxel, paclitaxel, vinblastine, and vinorelbine (Kuang et al., 2010). Thus, lapatinib reverses the MDR mediated by the overexpression of ABCB1, ABCG2, and ABCC10 by inhibiting their transport function. The mouse xenograft studies from our lab have shown that, in vivo, lapatinib (100 mg/kg, p.o., q3d × 4), in combination with paclitaxel (18 mg/kg, i.p., q3d × 4), significantly decreased the size of tumors overexpressing the ABCB1 transporter (Dai et al., 2008). 2.2.3. Erlotinib (OSI-774) Erlotinib is a selective ErbB1 inhibitor that inhibits EGFRdependent cellular proliferation and causes cell cycle arrest at G1 phase (Moyer et al., 1997). Erlotinib (2.5 and 10 M), in vitro, reverses ABCB1- and ABCG2-mediated MDR. Erlotinib (0.625, 1.25 and 2.5 M) also increases the accumulation of [3 H]-paclitaxel in HEK293/ABCC10 cells and reverses ABCC10-mediated MDR (Kuang et al., 2010; Shi et al., 2007c). 2.2.4. AST1306 AST1306, an inhibitor of EGFR and ErB2, has been tested for its effect on MDR induced by ABCG2. AST1306 (0.25 and 1 M), in vitro, increases the (1) cytotoxicity of mitoxantrone and SN-38 in cells overexpressing the ABCG2 transporter and (2) intracellular accumulation of [3 H]-mitoxantrone in both wild type and mutant cells expressing ABCG2 (Zhang et al., 2014c). AST1306 also stimulates the ATPase activity of ABCG2 and its reversal of ABCG2-mediated MDR is more potent than that of lapatinib and erlotinib (Zhang et al., 2014c). 2.2.5. WHI-P154 WHI-P154 is an irreversible inhibitor of EGFR and janus kinase-3 (Changelian et al., 2008). Zhang et al. reported that in vitro, WHIP154 (1 and 4 M) increases the sensitivity of ABCG2 substrates in MDR cells due to ABCG2 overexpression (Zhang et al., 2014d). WHI-P154 (1 and 4 M) increases the intracellular accumulation of [3 H]-mitoxantrone in ABCG2-overexpressing cells and stimulates the ATPase activity of ABCG2 at concentrations
