Familial Cancer DOI 10.1007/s10689-014-9757-9
REVIEW
Mitochondrial membrane potential and reactive oxygen species in cancer stem cells Bei-bei Zhang • Dao-gang Wang • Fen-fen Guo Chao Xuan
•
Ó Springer Science+Business Media Dordrecht 2014
Abstract Cancer stem cells (CSCs) are believed as the initiators of the occurrence, development and recurrence of malignant tumors. Targeting this unique cell population would provide a less toxic approach than regular chemotherapeutic agents that kill bulk rapid proliferating tumor cells and also normal cells which divide rapidly. To date, major research effort has been aimed at identifying and eradicating CSC population. The metabolism heterogeneity of mitochondria in CSCs shows a big promise for cancer research. Of them, mitochondrial membrane potential (Dwm), reflecting the functional status of the mitochondrion is proved to be highly related to cancer malignancy. Reactive oxygen species, mainly produced from mitochondria, are also increased in many types of cancer cells. However, their statuses in CSCs remain poorly understood. Here we shall review the mitochondrial membrane
Bei-bei Zhang and Dao-gang Wang have contributed equally to this work. B. Zhang Graduate School of Medicine, Mie University, Tsu, Mie, Japan D. Wang (&) Department of Gastroenterology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, People’s Republic of China e-mail: [email protected] F. Guo Department of Clinical Laboratory, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of China C. Xuan Department of Clinical Laboratory, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China
potential and reactive oxygen species of CSCs and propose the novel potential targets for cancer therapy. Keywords Mitochondrial membrane potential Reactive oxygen species Cancer stem cells
Introduction After chemotherapy or radiotherapy, cancer recurrence is initiated by a subpopulation of residual malignant cells termed cancer stem cells (CSCs), which are highly resistant to therapeutics [1, 2]. These cells have many characters such as self-renewal, tumorigenic potential, unique profiles of surface markers, etc. [3]. To date, much effort has been devoted to the identification and characterization of CSCs [4–7]. For example, high expression of aldehyde dehydrogenase (ALDH) has successfully been applied to identify leukemia stem cells (LSCs) in clinical samples recently [8, 9]. Due to the central role of CSCs in the tumorigenesis, progression and recurrence, there is no doubt that targeting CSCs will provide a promising future for cancer therapy. For a better understanding of CSC biology, we must know further unique properties of these cells. Mitochondria exert both vital and lethal functions in physiological and pathological scenarios [10]. They are important organelles in eukaryotic cells not only do they integrate death signals but also provide energy to sustain the metabolic needs of cells [11]. Owing to their roles in the regulation of fundamental cellular functions, it is not surprising that mitochondria have been implicated in multiple aspects of tumorigenesis and tumor progression [12]. Cancer cell mitochondria are structurally and functionally different from their normal counterparts [12, 13]. However, the mitochondrial phenotypes of CSCs remain
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unknown. Recently, several studies indicated that some mitochondrial features showed differences in CSCs, including the mitochondria membrane potential (Dwm) and reactive oxygen species (ROS) [14, 15]. Some researchers have even suggested that the percentage of cells with a perinuclear mitochondrial arrangement might serve as an indicator of the stem cells [16, 17]. This review will focus on the discussion of the mitochondria membrane potential and ROS status in CSCs, and propose the potential therapeutic implication targeting mitochondria to elimination this unique cell population.
Mitochondria membrane potential (Dwm) in CSCs Mitochondria membrane potential (Dwm), which reflects the mitochondria functional status, is thought to correlate with the cell differentiation status, tumorigenicity and malignancy [14]. Ye et al. [14] found that some lung cancer cell lines (A549, H446, SPC) possessed a higher Dwm than HBE cells, a normal bronchial epithelial cell type. In another important study, Bonnet et al. [18] compared lung cancer A549 cells, glioblastoma M059K cells, and breast cancer MCF-7 cells to that of healthy, noncancerous, small airway epithelial cells, fibroblasts, and pulmonary artery smooth muscle cells, and they found these cancer cells exhibited higher Dwm. Many studies reported that the carcinoma (such as breast cancer, prostate cancer, melanomas, etc.) derived cells possess a higher Dwm than normal epithelial cells at least above 60 mV [19–21]. In contrary, a human mtDNA-deficient breast cancer cell line, T47D rho(0), exhibiting a marked decrease in Dwm, showed a slower proliferation rate, and a severe impairment of tumorigenicity [22]. Schieke et al. [23] detected that the cells with higher Dwm were more prone to continue dividing and form tumors, while lower Dwm cells were more efficient at differentiating into other cell types by transplanting subpopulations of embryonic stem cells into mice. After the Dwm inhibitor rapamycin was administered to those high Dwm stem cells, their tumorigenicity decreased significantly. Heerdt et al. [24] subcloned and established two isogenic cell lines from the SW620 human colonic carcinoma cells that display significant and stable differences in the intrinsic Dwm, and they found the high Dwm is linked to important tumorigenic properties of these cells. For several years, the identification and isolation of CSCs by fluorescence activated cells sorting (FACS) from many cancer cell types were performed using the side population (SP) method [25–28]. By this method, the SP population of lung CSCs from the A549 lung cancer cell line was also proved to possess a higher Dwm, compared with the nonSP population [14]. Moreover, the CSC biomarker CD133
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expression could be detected in these higher Dwm cells, while it is nearly absent in the other cells [14]. Mitochondrial uncoupling proteins (UCPs) may be related to cancer initiation. Derdak et al. [29] observed that UCP2-/mice developed more colon tumors than UCP2?/? littermates. Claire et al. also showed that UCP2-/- cells displayed enhanced colony formation and hypoxia resistance, increased oxygen consumption, and low ATP content [30], which were all valid indicators of stem cell competence [17]. Therefore, the UCP low expression might be one molecular candidate for the high Dwm in CSCs. In recent years, it has been reported that the enhanced tolerance of CSCs to the chemotherapeutics and radiation correlated well with the changes of Dwm [31]. The Dwm is related to apoptosis due to the fact that dissipation of Dwm is a critical event in apoptosis process [11]. It is convincing that the high Dwm cell population possesses a stronger resistance to apoptotic inducers than low Dwm cell population in cultured hMSCs (human mesenchymal stem cells) [32]. The stronger apoptotic resistance of CSCs compared to the non-CSCs in human oral squamous cell carcinoma cell line Ho-1-N-1 was also related to Dwm [33]. In contrast, cells of MEFs with a deficiency in mitochondrial fusion showing a loss of Dwm were more susceptible to apoptotic stimuli [34]. From the previous studies, we would speculate that the CSCs take a higher Dwm than other cell populations.
Reactive oxygen species (ROS) in CSCs Mitochondria are the most prominent source of intracellular ROS, which is an important signaling molecule. The straight connection between ROS and Dwm is absent. However, some sporadic results suggest that ROS is an important contributor to the decrease of Dwm [35]. ROS, acting on thiols in the permeability transition pore complex (PTPC), can facilitate opening of the PTPC and shifting the Dwm [36]. ROS regulation is involved in many signal pathways, especially for the stem cells. Shi et al. previously showed the related signal pathways involved in ROS modulation in hematopoietic stem cells (HSCs) (Fig. 1), which included modulations from the ataxia telangiectasia mutated (ATM) kinase, phosphoinositide 3-kinase (PI3K)/ Akt, phosphorylates FoxO transcription factor 3 (FoxO3a), phosphatase and tensin homolog (PTEN), p53, PR domaincontaining 16 (Prdm16), hypoxia inducible factor (HIF)-1a, p38 mitogen-activated protein kinase (MAPK), and nuclear factor erythroid-2-related factor 2 (Nrf2) [37]. Once the ROS was increased, the expressions of tumor suppressors p16Ink4a and p19Arf will be elevated by activating the p38MAPK, leading to the HSC compartment loss [37]. In fact, cancer cells indeed produce more ROS than normal
Mitochondrial membrane potential and reactive oxygen species
Fig. 1 ROS is related to many signal pathways in hematopoietic stem cells (HSCs) [37]
cells do [38], and the heterogeneity of ROS in cancer cell subpopulation is also existed. ROS are involved in each stage of cancer development, including the initiation, promotion, and progression [39]. Recently, results from Diehn et al. study indicated that, similar to normal tissue stem cells, subsets of CSCs in tumors also contained lower ROS levels and enhanced ROS defenses compared to their non-tumorigenic progeny, contributing to the radio-resistance [15]. This unique cell subpopulation might have a high antioxidant capacity to keep cellular ROS at a moderate level, not like bulk cancer cells and maintain both stemness and cancer forming capabilities [14, 15]. Lower ROS levels in CSCs are found to be associated with increased expression of free radical scavenging systems. In leukemia, CD34? subpopulation in the CML cell line K562 had a higher expression of SOD1 and thus lower ROS level than that in the CD34- cells. Knockdown of SOD1 in CD34? cells had no significant effects on cell survival and growth, while it sensitized the CD34? cells to imatinib therapy [40]. This suggests the antioxidant effects of SOD1 were essential for the resistance of CD34? cells to imatinib therapy and simultaneously increasing the endogenous ROS level could be applied to sensitize the LSCs to imatinib-induced cell death. Further, CD44?/ CD24- breast CSCs from clinical samples have been found to exhibit an enhanced ROS defense system by overexpressing antioxidant enzyme genes and less DNA damage when compared with non-CSCs [15]. Besides, hypoxia in microenvironment has been shown to be a regulator that maintains the stem-like phenotype of CSCs from colorectal
cancer cell lines HT29 and SW1222 and prevents differentiation of enterocytes and goblet cells by regulating CDX1 and Notch1 [41]. Cells with elevated intrinsic Dwm have an enhanced capacity to respond to hypoxia by avoiding apoptosis and initiating angiogenesis. Given that hypoxia is capable of inducing ROS and the stabilization of HIF1a, there seems a linkage between ROS-HIF-1a and CDX1/Notch1 that controls the switch between stemness and differentiation in mature cancer cells [41]. Recently, low production of ROS was reported as one important reason for the radio-resistance of prostate CSCs [42]. Since the association of ROS levels and resistance in CSCs was existed. It is optimistic that selective targeting of CSCs involved ROS with mitochondrial targeted agents is likely to attract great interest. The hypothesis that decreasing or increasing ROS could be as the cancer therapy strategies was proposed several years ago by Kong and Lillehei [43]. The killing of CSCs specifically is important in the war against cancer. A recent report has shown that TDZD-8 could selectively induce the death of LSCs in different leukemia types in a ROS dependent manner [44]. Indeed, as CSCs exhibit unique properties that make them vulnerable to certain classes of mitochondria targeting drugs, including the nature compounds such as parthenolide, at least partially via ROS overproduction [45]. Some other chemicals such as niclosamide and arsenic trioxide also showed the potential to eliminate CSCs in different cancers related to the ROS modulation [46, 47]. The tumor suppressor gene PML (promyelocytic leukemia), which is involved in the t(15;17) chromosomal translocation of acute promyelocytic leukemia, has been demonstrated to be an important factor that maintains the quiescent state of CSCs. Increasing ROS could lead to PML degradation by arsenic trioxide administration [48]. The upregulation of ROS in niches of CSCs at least could trigger differentiation, though the mechanism of killing CSCs by ROS is still elusive [49].
Conclusion A better understanding of the key pathophysiological differences between mitochondria in CSCs and non-CSC cancer cells as well as their counterparts in non-malignant cells will present a promising avenue for further cancer therapy. Here, we propose that the differences of Dwm and ROS in the mitochondria of cancer subpopulations could be as the new potential targets for cancer therapy (Fig. 2). Compared to cancer cells, CSCs would be more dependent on the antioxidant system and more vulnerable to further ROS induced by the ROS generating agents, or compounds that inhibit the antioxidant system, especially due to the more intake of Dwm dependent chemicals. A further
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Fig. 2 The Dwm and ROS in the mitochondria of cancer subpopulations as potential targets
increase of ROS is likely to break the low ROS niches of stemness, induce differentiation and reach the ROS threshold level leading to cell death. Although the status of them may be not accordant due to the differences in the studied cell types and cell cycle stages, the fact that many mitochondria targeted anti-cancer agents such as Dwm dependent lipophilic cations showed great promise in the cancer therapy [50, 51]. Twenty-five years ago, rhodamine 123, a Dwm dependent mitochondrial staining fluorescent dye, exhibited selective cytotoxicity to cancer cell in comparison with normal epithelial cells [52]. Moreover, two delocalized lipophilic cations displayed dose dependent synergy with AZT against three cancer cell lines, but none of the compounds, alone or in combination, affected a control epithelial cell line [53]. Similar observations of selective mitochondrial association were also reported by other study [54]. Recently, we even identified one type of fluorescent dyes exhibiting the CSC selective inhibition, which are related to the ROS production and other CSC metabolic characters (data not shown). Therefore, increasing ROS-induced cytotoxicity by Dwm depedent agents may provide a promising future for achieving complete eradication of CSCs. Conflict of interest declare.
The authors have no conflict of interests to
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REVIEW
Mitochondrial membrane potential and reactive oxygen species in cancer stem cells Bei-bei Zhang • Dao-gang Wang • Fen-fen Guo Chao Xuan
•
Ó Springer Science+Business Media Dordrecht 2014
Abstract Cancer stem cells (CSCs) are believed as the initiators of the occurrence, development and recurrence of malignant tumors. Targeting this unique cell population would provide a less toxic approach than regular chemotherapeutic agents that kill bulk rapid proliferating tumor cells and also normal cells which divide rapidly. To date, major research effort has been aimed at identifying and eradicating CSC population. The metabolism heterogeneity of mitochondria in CSCs shows a big promise for cancer research. Of them, mitochondrial membrane potential (Dwm), reflecting the functional status of the mitochondrion is proved to be highly related to cancer malignancy. Reactive oxygen species, mainly produced from mitochondria, are also increased in many types of cancer cells. However, their statuses in CSCs remain poorly understood. Here we shall review the mitochondrial membrane
Bei-bei Zhang and Dao-gang Wang have contributed equally to this work. B. Zhang Graduate School of Medicine, Mie University, Tsu, Mie, Japan D. Wang (&) Department of Gastroenterology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, People’s Republic of China e-mail: [email protected] F. Guo Department of Clinical Laboratory, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of China C. Xuan Department of Clinical Laboratory, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China
potential and reactive oxygen species of CSCs and propose the novel potential targets for cancer therapy. Keywords Mitochondrial membrane potential Reactive oxygen species Cancer stem cells
Introduction After chemotherapy or radiotherapy, cancer recurrence is initiated by a subpopulation of residual malignant cells termed cancer stem cells (CSCs), which are highly resistant to therapeutics [1, 2]. These cells have many characters such as self-renewal, tumorigenic potential, unique profiles of surface markers, etc. [3]. To date, much effort has been devoted to the identification and characterization of CSCs [4–7]. For example, high expression of aldehyde dehydrogenase (ALDH) has successfully been applied to identify leukemia stem cells (LSCs) in clinical samples recently [8, 9]. Due to the central role of CSCs in the tumorigenesis, progression and recurrence, there is no doubt that targeting CSCs will provide a promising future for cancer therapy. For a better understanding of CSC biology, we must know further unique properties of these cells. Mitochondria exert both vital and lethal functions in physiological and pathological scenarios [10]. They are important organelles in eukaryotic cells not only do they integrate death signals but also provide energy to sustain the metabolic needs of cells [11]. Owing to their roles in the regulation of fundamental cellular functions, it is not surprising that mitochondria have been implicated in multiple aspects of tumorigenesis and tumor progression [12]. Cancer cell mitochondria are structurally and functionally different from their normal counterparts [12, 13]. However, the mitochondrial phenotypes of CSCs remain
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unknown. Recently, several studies indicated that some mitochondrial features showed differences in CSCs, including the mitochondria membrane potential (Dwm) and reactive oxygen species (ROS) [14, 15]. Some researchers have even suggested that the percentage of cells with a perinuclear mitochondrial arrangement might serve as an indicator of the stem cells [16, 17]. This review will focus on the discussion of the mitochondria membrane potential and ROS status in CSCs, and propose the potential therapeutic implication targeting mitochondria to elimination this unique cell population.
Mitochondria membrane potential (Dwm) in CSCs Mitochondria membrane potential (Dwm), which reflects the mitochondria functional status, is thought to correlate with the cell differentiation status, tumorigenicity and malignancy [14]. Ye et al. [14] found that some lung cancer cell lines (A549, H446, SPC) possessed a higher Dwm than HBE cells, a normal bronchial epithelial cell type. In another important study, Bonnet et al. [18] compared lung cancer A549 cells, glioblastoma M059K cells, and breast cancer MCF-7 cells to that of healthy, noncancerous, small airway epithelial cells, fibroblasts, and pulmonary artery smooth muscle cells, and they found these cancer cells exhibited higher Dwm. Many studies reported that the carcinoma (such as breast cancer, prostate cancer, melanomas, etc.) derived cells possess a higher Dwm than normal epithelial cells at least above 60 mV [19–21]. In contrary, a human mtDNA-deficient breast cancer cell line, T47D rho(0), exhibiting a marked decrease in Dwm, showed a slower proliferation rate, and a severe impairment of tumorigenicity [22]. Schieke et al. [23] detected that the cells with higher Dwm were more prone to continue dividing and form tumors, while lower Dwm cells were more efficient at differentiating into other cell types by transplanting subpopulations of embryonic stem cells into mice. After the Dwm inhibitor rapamycin was administered to those high Dwm stem cells, their tumorigenicity decreased significantly. Heerdt et al. [24] subcloned and established two isogenic cell lines from the SW620 human colonic carcinoma cells that display significant and stable differences in the intrinsic Dwm, and they found the high Dwm is linked to important tumorigenic properties of these cells. For several years, the identification and isolation of CSCs by fluorescence activated cells sorting (FACS) from many cancer cell types were performed using the side population (SP) method [25–28]. By this method, the SP population of lung CSCs from the A549 lung cancer cell line was also proved to possess a higher Dwm, compared with the nonSP population [14]. Moreover, the CSC biomarker CD133
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expression could be detected in these higher Dwm cells, while it is nearly absent in the other cells [14]. Mitochondrial uncoupling proteins (UCPs) may be related to cancer initiation. Derdak et al. [29] observed that UCP2-/mice developed more colon tumors than UCP2?/? littermates. Claire et al. also showed that UCP2-/- cells displayed enhanced colony formation and hypoxia resistance, increased oxygen consumption, and low ATP content [30], which were all valid indicators of stem cell competence [17]. Therefore, the UCP low expression might be one molecular candidate for the high Dwm in CSCs. In recent years, it has been reported that the enhanced tolerance of CSCs to the chemotherapeutics and radiation correlated well with the changes of Dwm [31]. The Dwm is related to apoptosis due to the fact that dissipation of Dwm is a critical event in apoptosis process [11]. It is convincing that the high Dwm cell population possesses a stronger resistance to apoptotic inducers than low Dwm cell population in cultured hMSCs (human mesenchymal stem cells) [32]. The stronger apoptotic resistance of CSCs compared to the non-CSCs in human oral squamous cell carcinoma cell line Ho-1-N-1 was also related to Dwm [33]. In contrast, cells of MEFs with a deficiency in mitochondrial fusion showing a loss of Dwm were more susceptible to apoptotic stimuli [34]. From the previous studies, we would speculate that the CSCs take a higher Dwm than other cell populations.
Reactive oxygen species (ROS) in CSCs Mitochondria are the most prominent source of intracellular ROS, which is an important signaling molecule. The straight connection between ROS and Dwm is absent. However, some sporadic results suggest that ROS is an important contributor to the decrease of Dwm [35]. ROS, acting on thiols in the permeability transition pore complex (PTPC), can facilitate opening of the PTPC and shifting the Dwm [36]. ROS regulation is involved in many signal pathways, especially for the stem cells. Shi et al. previously showed the related signal pathways involved in ROS modulation in hematopoietic stem cells (HSCs) (Fig. 1), which included modulations from the ataxia telangiectasia mutated (ATM) kinase, phosphoinositide 3-kinase (PI3K)/ Akt, phosphorylates FoxO transcription factor 3 (FoxO3a), phosphatase and tensin homolog (PTEN), p53, PR domaincontaining 16 (Prdm16), hypoxia inducible factor (HIF)-1a, p38 mitogen-activated protein kinase (MAPK), and nuclear factor erythroid-2-related factor 2 (Nrf2) [37]. Once the ROS was increased, the expressions of tumor suppressors p16Ink4a and p19Arf will be elevated by activating the p38MAPK, leading to the HSC compartment loss [37]. In fact, cancer cells indeed produce more ROS than normal
Mitochondrial membrane potential and reactive oxygen species
Fig. 1 ROS is related to many signal pathways in hematopoietic stem cells (HSCs) [37]
cells do [38], and the heterogeneity of ROS in cancer cell subpopulation is also existed. ROS are involved in each stage of cancer development, including the initiation, promotion, and progression [39]. Recently, results from Diehn et al. study indicated that, similar to normal tissue stem cells, subsets of CSCs in tumors also contained lower ROS levels and enhanced ROS defenses compared to their non-tumorigenic progeny, contributing to the radio-resistance [15]. This unique cell subpopulation might have a high antioxidant capacity to keep cellular ROS at a moderate level, not like bulk cancer cells and maintain both stemness and cancer forming capabilities [14, 15]. Lower ROS levels in CSCs are found to be associated with increased expression of free radical scavenging systems. In leukemia, CD34? subpopulation in the CML cell line K562 had a higher expression of SOD1 and thus lower ROS level than that in the CD34- cells. Knockdown of SOD1 in CD34? cells had no significant effects on cell survival and growth, while it sensitized the CD34? cells to imatinib therapy [40]. This suggests the antioxidant effects of SOD1 were essential for the resistance of CD34? cells to imatinib therapy and simultaneously increasing the endogenous ROS level could be applied to sensitize the LSCs to imatinib-induced cell death. Further, CD44?/ CD24- breast CSCs from clinical samples have been found to exhibit an enhanced ROS defense system by overexpressing antioxidant enzyme genes and less DNA damage when compared with non-CSCs [15]. Besides, hypoxia in microenvironment has been shown to be a regulator that maintains the stem-like phenotype of CSCs from colorectal
cancer cell lines HT29 and SW1222 and prevents differentiation of enterocytes and goblet cells by regulating CDX1 and Notch1 [41]. Cells with elevated intrinsic Dwm have an enhanced capacity to respond to hypoxia by avoiding apoptosis and initiating angiogenesis. Given that hypoxia is capable of inducing ROS and the stabilization of HIF1a, there seems a linkage between ROS-HIF-1a and CDX1/Notch1 that controls the switch between stemness and differentiation in mature cancer cells [41]. Recently, low production of ROS was reported as one important reason for the radio-resistance of prostate CSCs [42]. Since the association of ROS levels and resistance in CSCs was existed. It is optimistic that selective targeting of CSCs involved ROS with mitochondrial targeted agents is likely to attract great interest. The hypothesis that decreasing or increasing ROS could be as the cancer therapy strategies was proposed several years ago by Kong and Lillehei [43]. The killing of CSCs specifically is important in the war against cancer. A recent report has shown that TDZD-8 could selectively induce the death of LSCs in different leukemia types in a ROS dependent manner [44]. Indeed, as CSCs exhibit unique properties that make them vulnerable to certain classes of mitochondria targeting drugs, including the nature compounds such as parthenolide, at least partially via ROS overproduction [45]. Some other chemicals such as niclosamide and arsenic trioxide also showed the potential to eliminate CSCs in different cancers related to the ROS modulation [46, 47]. The tumor suppressor gene PML (promyelocytic leukemia), which is involved in the t(15;17) chromosomal translocation of acute promyelocytic leukemia, has been demonstrated to be an important factor that maintains the quiescent state of CSCs. Increasing ROS could lead to PML degradation by arsenic trioxide administration [48]. The upregulation of ROS in niches of CSCs at least could trigger differentiation, though the mechanism of killing CSCs by ROS is still elusive [49].
Conclusion A better understanding of the key pathophysiological differences between mitochondria in CSCs and non-CSC cancer cells as well as their counterparts in non-malignant cells will present a promising avenue for further cancer therapy. Here, we propose that the differences of Dwm and ROS in the mitochondria of cancer subpopulations could be as the new potential targets for cancer therapy (Fig. 2). Compared to cancer cells, CSCs would be more dependent on the antioxidant system and more vulnerable to further ROS induced by the ROS generating agents, or compounds that inhibit the antioxidant system, especially due to the more intake of Dwm dependent chemicals. A further
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Fig. 2 The Dwm and ROS in the mitochondria of cancer subpopulations as potential targets
increase of ROS is likely to break the low ROS niches of stemness, induce differentiation and reach the ROS threshold level leading to cell death. Although the status of them may be not accordant due to the differences in the studied cell types and cell cycle stages, the fact that many mitochondria targeted anti-cancer agents such as Dwm dependent lipophilic cations showed great promise in the cancer therapy [50, 51]. Twenty-five years ago, rhodamine 123, a Dwm dependent mitochondrial staining fluorescent dye, exhibited selective cytotoxicity to cancer cell in comparison with normal epithelial cells [52]. Moreover, two delocalized lipophilic cations displayed dose dependent synergy with AZT against three cancer cell lines, but none of the compounds, alone or in combination, affected a control epithelial cell line [53]. Similar observations of selective mitochondrial association were also reported by other study [54]. Recently, we even identified one type of fluorescent dyes exhibiting the CSC selective inhibition, which are related to the ROS production and other CSC metabolic characters (data not shown). Therefore, increasing ROS-induced cytotoxicity by Dwm depedent agents may provide a promising future for achieving complete eradication of CSCs. Conflict of interest declare.
The authors have no conflict of interests to
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