Oral Oncology 50 (2014) e13–e14
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Letter to the Editor Therapeutic aspects of the inflammation mediated oral carcinogenesis
Chronic persistent inflammation mediated activation of oncogenes and inactivation of tumor-suppressor genes may result in genetic instability with an increased risk of cancer [1]. Hence, in our classification of potentially malignant disorder, we have included a separate category for such lesions called ‘Group II: Morphologically altered tissue in which chronic persistent inflammation is responsible for malignant transformation (chronic inflammation mediated carcinogenesis)’ [2]. COX-2 inhibition has been shown to result in cell growth inhibition in oral squamous cell carcinoma (OSCC) cell lines [3]. The dysplastic mucosa displayed expression of COX-2 at different stages of carcinogenesis and not in normal mucosa [4]. This suggests a possible role of COX-2 inhibition in OSCC chemoprevention. Studies using the COX-2 inhibitor as a single agent in oral premalignant lesions revealed evidence of regression in the grades of dysplasia [5]. A number of chemoprevention and therapeutic trials in OSCC using COX-2 inhibitors are underway [6,7]. OSCC is characterized by over activation of the Akt signaling pathway [8]. Apoptosis induced by COX-2 inhibitors is linked not only with the attenuation of Akt and its subsequent effectors such as BAD and pro-caspase-9, but also with decreased levels of the anti-apoptotic protein MCL-1 and the phosphorylated SAP-kinase. A new celecoxib analog potentially inhibited tumor growth [9] while inhibiting pAkt signaling and inactivating breast cancer cells that overexpress EGFR [10]. The literature also suggests the link between COX-2 and EGFR [1]. Therapeutically targeting these two pathways can synergistically or additively block progression of OSCC growth [3,11–13]. The combination of erlotinib and celecoxib has been shown to synergistically inhibit OSCC cancer cell growth in preclinical studies [3,11]. Saba et al. [13] reported the results of a phase I clinical trial and pharmacokinetic studies of this combination in oral premalignant lesions with encouraging results. Chuang et al. [14] reported connective tissue growth factor (CTGF) mediated down regulation of COX-2 and reduction in migration of OSCC cells. CTGF inhibits COX-2 expression by binding to the avb5 integrin receptor and reduction of FAK, PI3 K, Akt which inhibits binding of c-Jun to AP-1 site, resulting in the reduction tumor migration [14]. The p38a MAP kinase pathway is also involved in inflammation. Gill et al. [15] have designed a tetrapeptide, VWCS as p38a inhibitor on the basis of structural information of the ATP binding site by molecular modeling. It potentially inhibited the cell growth and induced apoptosis in OSCC cells [15]. Vander Broek et al. [16] reviewed several agents that inhibit the inflammation associated NF-kB pathway in OSCC. These agents are Retinoids, PI3K-mTOR inhibitors, curcumin, Vitamin E, antidiabetic 1368-8375/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.12.026
drugs, berry extracts, genistein and resveratrol. The other NF-kBinhibitory compounds currently being tested for their chemopreventive potential are pomegranate juice, luteolin, lycopene and vegetable extracts [15]. Macha et al. [17] reported inhibition of the activation of NF-kB and STAT3 proteins in OSCC cells by guggulsterone. Treatment of OSCC cells with guggulsterone abrogated both smokeless tobacco and nicotine-induced nuclear activation of NF-kB and pSTAT3 proteins and their downstream targets COX-2 and VEGF. Guggulsterone treatment not only inhibited proliferation, but also induced apoptosis by abrogating the effects of smokeless tobacco and nicotine on PI3K/Akt pathway in OSCC cells [18]. Conflict of interest statement None declared. References [1] Feller L, Altini M, Lemmer J. Inflammation in the context of oral cancer. Oral Oncol 2013;49:887–92. [2] Sarode SC, Sarode GS, Karmarkar S, Tupkari JV. A new classification for potentially malignant disorders of the oral cavity. Oral Oncol 2011;47:920–1. [3] Chen Z, Zhang X, Li M, Wang Z, Wieand HS, Grandis JR, et al. Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck. Clin Cancer Res 2004;10:5930–9. [4] Nathan CO, Leskov IL, Lin M, Abreo FW, Shi R, Hartman GH, et al. COX-2 expression in dysplasia of the head and neck: correlation with elF4E. Cancer 2001;92:1888–95. [5] Wirth LJKJ, Li Y, Othus M, Moran AE, Dorfman DM, Norris Jr CM, et al. A pilot surrogate endpoint biomarker study of celecoxib in oral premalignant lesions. Cancer Prev Res (Phila) 2008;1:339–48. [6] Papadimitrakopoulou VA, William Jr WN, Dannenberg AJ, Lippman SM, Lee JJ, Ondrey FG, et al. Pilot randomized phase II study of celecoxib in oral premalignant lesions. Clin Cancer Res 2008;14:2095–101. [7] Ondrey FG, Juhn SK, Adams GL. Inhibition of head and neck tumor cell growth with arachidonic acid metabolism inhibition. Laryngoscope 1996;106:129–34. [8] Moral M, Paramio JM. Akt pathway as a target for therapeutic intervention in HNSCC. Histol Histopathol 2008;23:1269–78. [9] Zhu J, Huang JW, Tseng PH, Yang YT, Fowble J, Shiau CW, et al. From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3phosphoinositidedependent protein kinase-1 inhibitors. Cancer Res 2004;64:4309–18. [10] Kucab JE, Lee C, Chen CS, Zhu J, Gilks CB, Cheang M, et al. Celecoxib analogues disrupt Akt signaling, which is commonly activated in primary breast tumours. Breast Cancer Res 2005;7:R796–807. [11] Zhang X, Chen ZG, Choe MS, Lin Y, Sun SY, Wieand HS, et al. Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model. Clin Cancer Res 2005;11:6261–9. [12] Choe MS, Zhang X, Shin HJ, Shin DM, Chen ZG. Interaction between epidermal growth factor receptor- and cyclooxygenase 2-mediated pathways and its implications for the chemoprevention of head and neck cancer. Mol Cancer Ther 2005;4:1448–55. [13] Saba N, Hurwitz SJ, Kono S, Yang CS, Zhao Y, Chen Z, et al. Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase 1b and pharmacokinetic study. Cancer Prev Res (Phila) 2013. http://dx.doi.org/ 10.1158/1940-6207.CAPR-13-0215.
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Letter to the Editor / Oral Oncology 50 (2014) e13–e14
[14] Chuang JY, Yang WY, Lai CH, Lin CD, Tsai MH, Tang CH. CTGF inhibits cell motility and COX-2 expression in oral cancer cells. Int Immunopharmacol 2011;11:948–54. [15] Gill K, Singh AK, Kapoor V, Nigam L, Kumar R, Holla P, et al. Development of peptide inhibitor as a therapeutic agent against head and neck squamous cell carcinoma (HNSCC) targeting p38a MAP kinase. Biochim Biophys Acta 2013;1830:2763–9. [16] Vander Broek R, Snow GE, Chen Z, Van Waes C. Chemoprevention of head and neck squamous cell carcinoma through inhibition of NF-jB signaling. Oral Oncol 2013. pii:S1368-8375(13)00714-8. [17] Macha MA, Matta A, Chauhan SS, Siu KW, Ralhan R. Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-jB and STAT3 pathways in head and neck cancer cells. Carcinogenesis 2011;32:368–80. [18] Macha MA, Matta A, Chauhan SS, Siu KW, Ralhan R. Guggulsterone targets smokeless tobacco induced PI3K/Akt pathway in head and neck cancer cells. PLoS One 2011;6:e14728.
Sachin C. Sarode Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Maheshnagar, Pimpri, Pune 411018, Maharashtra, India Fulbright Doctoral and Research scholar, The Ohio State University, College of Dentistry, Oral Pathology, Columbus, OH, USA Tel.: +91 9922491465 E-mail address: [email protected] Gargi S. Sarode Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Maheshnagar, Pimpri, Pune 411018, Maharashtra, India Tel.: +91 9823871462 E-mail address: [email protected] Anuprita Patil 355-B Block, EK 2 Emirates Building, Muhaisnah 4, Dubai, United Arab Emirates Tel.: +91 9823871462. Available online 24 January 2014
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Letter to the Editor Therapeutic aspects of the inflammation mediated oral carcinogenesis
Chronic persistent inflammation mediated activation of oncogenes and inactivation of tumor-suppressor genes may result in genetic instability with an increased risk of cancer [1]. Hence, in our classification of potentially malignant disorder, we have included a separate category for such lesions called ‘Group II: Morphologically altered tissue in which chronic persistent inflammation is responsible for malignant transformation (chronic inflammation mediated carcinogenesis)’ [2]. COX-2 inhibition has been shown to result in cell growth inhibition in oral squamous cell carcinoma (OSCC) cell lines [3]. The dysplastic mucosa displayed expression of COX-2 at different stages of carcinogenesis and not in normal mucosa [4]. This suggests a possible role of COX-2 inhibition in OSCC chemoprevention. Studies using the COX-2 inhibitor as a single agent in oral premalignant lesions revealed evidence of regression in the grades of dysplasia [5]. A number of chemoprevention and therapeutic trials in OSCC using COX-2 inhibitors are underway [6,7]. OSCC is characterized by over activation of the Akt signaling pathway [8]. Apoptosis induced by COX-2 inhibitors is linked not only with the attenuation of Akt and its subsequent effectors such as BAD and pro-caspase-9, but also with decreased levels of the anti-apoptotic protein MCL-1 and the phosphorylated SAP-kinase. A new celecoxib analog potentially inhibited tumor growth [9] while inhibiting pAkt signaling and inactivating breast cancer cells that overexpress EGFR [10]. The literature also suggests the link between COX-2 and EGFR [1]. Therapeutically targeting these two pathways can synergistically or additively block progression of OSCC growth [3,11–13]. The combination of erlotinib and celecoxib has been shown to synergistically inhibit OSCC cancer cell growth in preclinical studies [3,11]. Saba et al. [13] reported the results of a phase I clinical trial and pharmacokinetic studies of this combination in oral premalignant lesions with encouraging results. Chuang et al. [14] reported connective tissue growth factor (CTGF) mediated down regulation of COX-2 and reduction in migration of OSCC cells. CTGF inhibits COX-2 expression by binding to the avb5 integrin receptor and reduction of FAK, PI3 K, Akt which inhibits binding of c-Jun to AP-1 site, resulting in the reduction tumor migration [14]. The p38a MAP kinase pathway is also involved in inflammation. Gill et al. [15] have designed a tetrapeptide, VWCS as p38a inhibitor on the basis of structural information of the ATP binding site by molecular modeling. It potentially inhibited the cell growth and induced apoptosis in OSCC cells [15]. Vander Broek et al. [16] reviewed several agents that inhibit the inflammation associated NF-kB pathway in OSCC. These agents are Retinoids, PI3K-mTOR inhibitors, curcumin, Vitamin E, antidiabetic 1368-8375/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.12.026
drugs, berry extracts, genistein and resveratrol. The other NF-kBinhibitory compounds currently being tested for their chemopreventive potential are pomegranate juice, luteolin, lycopene and vegetable extracts [15]. Macha et al. [17] reported inhibition of the activation of NF-kB and STAT3 proteins in OSCC cells by guggulsterone. Treatment of OSCC cells with guggulsterone abrogated both smokeless tobacco and nicotine-induced nuclear activation of NF-kB and pSTAT3 proteins and their downstream targets COX-2 and VEGF. Guggulsterone treatment not only inhibited proliferation, but also induced apoptosis by abrogating the effects of smokeless tobacco and nicotine on PI3K/Akt pathway in OSCC cells [18]. Conflict of interest statement None declared. References [1] Feller L, Altini M, Lemmer J. Inflammation in the context of oral cancer. Oral Oncol 2013;49:887–92. [2] Sarode SC, Sarode GS, Karmarkar S, Tupkari JV. A new classification for potentially malignant disorders of the oral cavity. Oral Oncol 2011;47:920–1. [3] Chen Z, Zhang X, Li M, Wang Z, Wieand HS, Grandis JR, et al. Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck. Clin Cancer Res 2004;10:5930–9. [4] Nathan CO, Leskov IL, Lin M, Abreo FW, Shi R, Hartman GH, et al. COX-2 expression in dysplasia of the head and neck: correlation with elF4E. Cancer 2001;92:1888–95. [5] Wirth LJKJ, Li Y, Othus M, Moran AE, Dorfman DM, Norris Jr CM, et al. A pilot surrogate endpoint biomarker study of celecoxib in oral premalignant lesions. Cancer Prev Res (Phila) 2008;1:339–48. [6] Papadimitrakopoulou VA, William Jr WN, Dannenberg AJ, Lippman SM, Lee JJ, Ondrey FG, et al. Pilot randomized phase II study of celecoxib in oral premalignant lesions. Clin Cancer Res 2008;14:2095–101. [7] Ondrey FG, Juhn SK, Adams GL. Inhibition of head and neck tumor cell growth with arachidonic acid metabolism inhibition. Laryngoscope 1996;106:129–34. [8] Moral M, Paramio JM. Akt pathway as a target for therapeutic intervention in HNSCC. Histol Histopathol 2008;23:1269–78. [9] Zhu J, Huang JW, Tseng PH, Yang YT, Fowble J, Shiau CW, et al. From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3phosphoinositidedependent protein kinase-1 inhibitors. Cancer Res 2004;64:4309–18. [10] Kucab JE, Lee C, Chen CS, Zhu J, Gilks CB, Cheang M, et al. Celecoxib analogues disrupt Akt signaling, which is commonly activated in primary breast tumours. Breast Cancer Res 2005;7:R796–807. [11] Zhang X, Chen ZG, Choe MS, Lin Y, Sun SY, Wieand HS, et al. Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model. Clin Cancer Res 2005;11:6261–9. [12] Choe MS, Zhang X, Shin HJ, Shin DM, Chen ZG. Interaction between epidermal growth factor receptor- and cyclooxygenase 2-mediated pathways and its implications for the chemoprevention of head and neck cancer. Mol Cancer Ther 2005;4:1448–55. [13] Saba N, Hurwitz SJ, Kono S, Yang CS, Zhao Y, Chen Z, et al. Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase 1b and pharmacokinetic study. Cancer Prev Res (Phila) 2013. http://dx.doi.org/ 10.1158/1940-6207.CAPR-13-0215.
e14
Letter to the Editor / Oral Oncology 50 (2014) e13–e14
[14] Chuang JY, Yang WY, Lai CH, Lin CD, Tsai MH, Tang CH. CTGF inhibits cell motility and COX-2 expression in oral cancer cells. Int Immunopharmacol 2011;11:948–54. [15] Gill K, Singh AK, Kapoor V, Nigam L, Kumar R, Holla P, et al. Development of peptide inhibitor as a therapeutic agent against head and neck squamous cell carcinoma (HNSCC) targeting p38a MAP kinase. Biochim Biophys Acta 2013;1830:2763–9. [16] Vander Broek R, Snow GE, Chen Z, Van Waes C. Chemoprevention of head and neck squamous cell carcinoma through inhibition of NF-jB signaling. Oral Oncol 2013. pii:S1368-8375(13)00714-8. [17] Macha MA, Matta A, Chauhan SS, Siu KW, Ralhan R. Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-jB and STAT3 pathways in head and neck cancer cells. Carcinogenesis 2011;32:368–80. [18] Macha MA, Matta A, Chauhan SS, Siu KW, Ralhan R. Guggulsterone targets smokeless tobacco induced PI3K/Akt pathway in head and neck cancer cells. PLoS One 2011;6:e14728.
Sachin C. Sarode Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Maheshnagar, Pimpri, Pune 411018, Maharashtra, India Fulbright Doctoral and Research scholar, The Ohio State University, College of Dentistry, Oral Pathology, Columbus, OH, USA Tel.: +91 9922491465 E-mail address: [email protected] Gargi S. Sarode Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Maheshnagar, Pimpri, Pune 411018, Maharashtra, India Tel.: +91 9823871462 E-mail address: [email protected] Anuprita Patil 355-B Block, EK 2 Emirates Building, Muhaisnah 4, Dubai, United Arab Emirates Tel.: +91 9823871462. Available online 24 January 2014
