Cancer stem cells (CSCs) are highly resistant to conventional chemo- and radiotherapeutic regimes. Therefore, the multiple drug resistance (MDR) of cancer is most likely due to the resistance of CSCs. Such resistance can be attributed to some bypassing pathways including detoxification mechanisms of reactive oxygen and nitrogen species (RO/NS) formation or enhanced autophagy. Unlike in normal cells, where RO/NS concentration is maintained at certain threshold required for signal transduction or immune response mechanisms, CSCs may develop alternative pathways to diminish RO/NS levels leading to cancer survival. In this minireview, we will focus on elaborated mechanisms developed by CSCs to attenuate high RO/NS levels. Gaining a better insight into the mechanisms of stem cell resistance to chemo- or radiotherapy may lead to new therapeutic targets thus serving for better anticancer strategies.

International Clinical Research Center St Anne's University Hospital Masaryk University Kamenice 5 A7 625 00 Brno Czech Republic ; Institute of Molecular Biology and Biophysics Novosibirsk Russia

Oncology and Pathology Group Institut de Recerca Hospital Vall d'Hebron Passeig Vall d'Hebron 119 129 08035 Barcelona Spain

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Plaks V., Kong N., Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell. 2015;16(3):225–238. doi: 10.1016/j.stem.2015.02.015. PubMed DOI PMC

Leal J. A., Feliciano A., Lleonart M. E. Stem cell MicroRNAs in senescence and immortalization: novel players in cancer therapy. Medicinal Research Reviews. 2013;33(1):112–138. doi: 10.1002/med.20246. PubMed DOI

Mitra A., Mishra L., Li S. EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget. 2015;6(13):10697–10711. PubMed PMC

Hassan H. T. c-Kit expression in human normal and malignant stem cells prognostic and therapeutic implications. Leukemia Research. 2009;33(1):5–10. doi: 10.1016/j.leukres.2008.06.011. PubMed DOI

Studer L., Vera E., Cornacchia D. Programming and reprogramming cellular age in the era of induced pluripotency. Cell Stem Cell. 2015;16(6):591–600. doi: 10.1016/j.stem.2015.05.004. PubMed DOI PMC

Mertins S. D. Cancer stem cells: a systems biology view of their role in prognosis and therapy. Anti-Cancer Drugs. 2014;25(4):353–367. doi: 10.1097/cad.0000000000000075. PubMed DOI PMC

Moulder S. Intrinsic resistance to chemotherapy in breast cancer. Women's Health. 2010;6(6):821–830. doi: 10.2217/whe.10.60. PubMed DOI

Cojoc M., Mäbert K., Muders M. H., Dubrovska A. A role for cancer stem cells in therapy resistance: cellular and molecular mechanisms. Seminars in Cancer Biology. 2015;31:16–27. doi: 10.1016/j.semcancer.2014.06.004. PubMed DOI

Ding S., Li C., Cheng N., Cui X., Xu X., Zhou G. Redox regulation in cancer stem cells. Oxidative Medicine and Cellular Longevity. 2015;2015:11. doi: 10.1155/2015/750798.750798 PubMed DOI PMC

Sosa V., Moliné T., Somoza R., Paciucci R., Kondoh H., LLeonart M. E. Oxidative stress and cancer: an overview. Ageing Research Reviews. 2013;12(1):376–390. doi: 10.1016/j.arr.2012.10.004. PubMed DOI

Benz C. C., Yau C. Ageing, oxidative stress and cancer: paradigms in parallax. Nature Reviews Cancer. 2008;8(11):875–879. doi: 10.1038/nrc2522. PubMed DOI PMC

Wang J., Yi J. Cancer cell killing via ROS: to increase or decrease, that is a question. Cancer Biology and Therapy. 2008;7(12):1875–1884. doi: 10.4161/cbt.7.12.7067. PubMed DOI

Colak S., Medema J. P. Cancer stem cells—important players in tumor therapy resistance. FEBS Journal. 2014;281(21):4779–4791. doi: 10.1111/febs.13023. PubMed DOI

Dean M. ABC transporters, drug resistance, and cancer stem cells. Journal of Mammary Gland Biology and Neoplasia. 2009;14(1):3–9. doi: 10.1007/s10911-009-9109-9. PubMed DOI

Cui H., Zhang A. J., Chen M., Liu J. J. ABC transporter inhibitors in reversing multidrug resistance to chemotherapy. Current Drug Targets. 2015;16(14) doi: 10.2174/1389450116666150330113506. PubMed DOI

Shervington A., Lu C. Expression of multidrug resistance genes in normal and cancer stem cells. Cancer Investigation. 2008;26(5):535–542. doi: 10.1080/07357900801904140. PubMed DOI

Dean M., Fojo T., Bates S. Tumour stem cells and drug resistance. Nature Reviews Cancer. 2005;5(4):275–284. doi: 10.1038/nrc1590. PubMed DOI

Liesa M., Qiu W., Shirihai O. S. Mitochondrial ABC transporters function: the role of ABCB10 (ABC-me) as a novel player in cellular handling of reactive oxygen species. Biochimica et Biophysica Acta. 2012;1823(10):1945–1957. doi: 10.1016/j.bbamcr.2012.07.013. PubMed DOI PMC

López-Erauskin J., Galino J., Ruiz M., et al. Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. Human Molecular Genetics. 2013;22(16):3296–3305. doi: 10.1093/hmg/ddt186. PubMed DOI

Fahrenbach J. P., Stoller D., Kim G., et al. Abcc9 is required for the transition to oxidative metabolism in the newborn heart. The FASEB Journal. 2014;28(7):2804–2815. doi: 10.1096/fj.13-244459. PubMed DOI PMC

Yang X., Yang J., Li L., et al. PAAT, a novel ATPase and trans-regulator of mitochondrial ABC transporters, is critically involved in the maintenance of mitochondrial homeostasis. The FASEB Journal. 2014;28(11):4821–4834. doi: 10.1096/fj.14-254045. PubMed DOI

Lou D., Zhu L., Ding H., Dai H.-Y., Zou G.-M. Aberrant expression of redox protein Ape1 in colon cancer stem cells. Oncology Letters. 2014;7(4):1078–1082. doi: 10.3892/ol.2014.1864. PubMed DOI PMC

Riganti C., Rolando B., Kopecka J., et al. Mitochondrial-targeting nitrooxy-doxorubicin: a new approach to overcome drug resistance. Molecular Pharmaceutics. 2013;10(1):161–174. doi: 10.1021/mp300311b. PubMed DOI

Wang Z., Li Y., Sarkar F. H. Signaling mechanism(S) of reactive oxygen species in epithelial-mesenchymal transition reminiscent of cancer stem cells in tumor progression. Current Stem Cell Research & Therapy. 2010;5(1):74–80. doi: 10.2174/157488810790442813. PubMed DOI PMC

Bao B., Azmi A. S., Li Y., et al. Targeting CSCs in tumor microenvironment: the potential role of ROS-associated miRNAs in tumor aggressiveness. Current Stem Cell Research and Therapy. 2014;9(1):22–35. doi: 10.2174/1574888x113089990053. PubMed DOI PMC

Zhou J.-N., Zeng Q., Wang H.-Y., et al. MicroRNA-125b attenuates epithelial-mesenchymal transitions and targets stem-like liver cancer cells through small mothers against decapentaplegic 2 and 4. Hepatology. 2015;62(3):801–815. doi: 10.1002/hep.27887. PubMed DOI

Kirshner J. R., He S., Balasubramanyam V., et al. Elesclomol induces cancer cell apoptosis through oxidative stress. Molecular Cancer Therapeutics. 2008;7(8):2319–2327. doi: 10.1158/1535-7163.mct-08-0298. PubMed DOI

Qu Y., Wang J., Sim M.-S., et al. Elesclomol, counteracted by Akt survival signaling, enhances the apoptotic effect of chemotherapy drugs in breast cancer cells. Breast Cancer Research and Treatment. 2010;121(2):311–321. doi: 10.1007/s10549-009-0470-6. PubMed DOI

Leskovar A., Wegele H., Werbeck N. D., Buchner J., Reinstein J. The ATPase cycle of the mitochondrial Hsp90 analog trap1. The Journal of Biological Chemistry. 2008;283(17):11677–11688. doi: 10.1074/jbc.m709516200. PubMed DOI

Pridgeon J. W., Olzmann J. A., Chin L.-S., Li L. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biology. 2007;5(7, article e172) doi: 10.1371/journal.pbio.0050172. PubMed DOI PMC

Kang B. H., Altieri D. C. Compartmentalized cancer drug discovery targeting mitochondrial Hsp90 chaperones. Oncogene. 2009;28(42):3681–3688. doi: 10.1038/onc.2009.227. PubMed DOI PMC

Rico-Bautista E., Yang C.-C., Lu L., Roth G. P., Wolf D. A. Chemical genetics approach to restoring p27Kip1 reveals novel compounds with antiproliferative activity in prostate cancer cells. BMC Biology. 2010;8, article 153 doi: 10.1186/1741-7007-8-153. PubMed DOI PMC

Maiuri M. C., Criollo A., Kroemer G. Crosstalk between apoptosis and autophagy within the Beclin 1 interactome. The EMBO Journal. 2010;29(3):515–516. doi: 10.1038/emboj.2009.377. PubMed DOI PMC

Wang Y.-Y., Yang Y.-X., Zhe H., He Z.-X., Zhou S.-F. Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties. Drug Design, Development and Therapy. 2014;8:2075–2088. doi: 10.2147/dddt.s68872. PubMed DOI PMC

Fu Y., Chang H., Peng X., et al. Resveratrol inhibits breast cancer stem-like cells and induces autophagy via suppressing Wnt/β-catenin signaling pathway. PLoS ONE. 2014;9(7) doi: 10.1371/journal.pone.0102535.e102535 PubMed DOI PMC

Kaushik G., Venugopal A., Ramamoorthy P., et al. Honokiol inhibits melanoma stem cells by targeting notch signaling. Molecular Carcinogenesis. 2014 doi: 10.1002/mc.22242. PubMed DOI PMC

Choi D. S., Blanco E., Kim Y.-S., et al. Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells. 2014;32(9):2309–2323. doi: 10.1002/stem.1746. PubMed DOI PMC

Del Bufalo D., Desideri M., De Luca T., et al. Histone deacetylase inhibition synergistically enhances pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer. Molecular Cancer. 2014;13(1, article 230) doi: 10.1186/1476-4598-13-230. PubMed DOI PMC

Zitka O., Skalickova S., Gumulec J., et al. Redox status expressed as GSH:GSSG ratio as a marker for oxidative stress in paediatric tumour patients. Oncology Letters. 2012;4(6):1247–1253. doi: 10.3892/ol.2012.931. PubMed DOI PMC

Jangamreddy J. R., Ghavami S., Grabarek J., et al. Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: differences between primary and cancer cells. Biochimica et Biophysica Acta. 2013;1833(9):2057–2069. doi: 10.1016/j.bbamcr.2013.04.011. PubMed DOI

Tang D. G., Li L., Zhu Z., et al. BMD188, a novel hydroxamic acid compound, demonstrates potent anti- prostate cancer effects in vitro and in vivo by inducing apoptosis: requirements for mitochondria, reactive oxygen species, and proteases. Pathology and Oncology Research. 1998;4(3):179–190. doi: 10.1007/bf02905247. PubMed DOI

Xu R., Tian E., Tang H., Liu C., Wang Q. Proteomic analysis of gossypol induces necrosis in multiple myeloma cells. BioMed Research International. 2014;2014:9. doi: 10.1155/2014/839232.839232 PubMed DOI PMC

Hernlund E., Ihrlund L. S., Khan O., et al. Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2-deoxyglucose and etomoxir. International Journal of Cancer. 2008;123(2):476–483. doi: 10.1002/ijc.23525. PubMed DOI

Xing F., Li S., Ge X., et al. The inhibitory effect of a novel organoselenium compound BBSKE on the tongue cancer Tca8113 in vitro and in vivo. Oral Oncology. 2008;44(10):963–969. doi: 10.1016/j.oraloncology.2007.12.001. PubMed DOI

Kim H. M., Haraguchi N., Ishii H., et al. Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon. Annals of Surgical Oncology. 2012;19(3):S539–S548. doi: 10.1245/s10434-011-2040-5. PubMed DOI

Nishikawa S., Ishii H., Haraguchi N., et al. Genotoxic therapy stimulates error-prone DNA repair in dormant hepatocellular cancer stem cells. Experimental and Therapeutic Medicine. 2012;3(6):959–962. doi: 10.3892/etm.2012.522. PubMed DOI PMC

Liu G., Yuan X., Zeng Z., et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Molecular Cancer. 2006;5, article 67 doi: 10.1186/1476-4598-5-67. PubMed DOI PMC

Daniele S., Costa B., Zappelli E., et al. Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells. Scientific Reports. 2015;5, article 9956 doi: 10.1038/srep09956. PubMed DOI PMC

Singh B. N., Kumar D., Shankar S., Srivastava R. K. Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochemical Pharmacology. 2012;84(9):1154–1163. doi: 10.1016/j.bcp.2012.08.007. PubMed DOI

Zhu J., Wang H., Fan Y., et al. Targeting the NF-E2-related factor 2 pathway: a novel strategy for glioblastoma (Review) Oncology Reports. 2014;32(2):443–450. doi: 10.3892/or.2014.3259. PubMed DOI

Murakami S., Motohashi H. Roles of NRF2 in cell proliferation and differentiation. Free Radical Biology & Medicine. 2015 doi: 10.1016/j.freeradbiomed.2015.06.030. PubMed DOI

Ryoo I. G., Choi B. H., Kwak M. K. Activation of NRF2 by p62 and proteasome reduction in sphere-forming breast carcinoma cells. Oncotarget. 2015;6(10):8167–8184. PubMed PMC

Del Vecchio C. A., Feng Y., Sokol E. S., et al. De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling. PLoS Biology. 2014;12(9) doi: 10.1371/journal.pbio.1001945.e1001945 PubMed DOI PMC

Mizushima N., Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728–741. doi: 10.1016/j.cell.2011.10.026. PubMed DOI

Fuchs Y., Steller H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nature Reviews Molecular Cell Biology. 2015;16(6):329–344. doi: 10.1038/nrm3999. PubMed DOI PMC

Lu S. Z., Harrison-Findik D. D. Autophagy and cancer. World Journal of Biological Chemistry. 2013;4(3):64–70. PubMed PMC

Zhu H., Wang D., Liu Y., et al. Role of the Hypoxia-inducible factor-1 alpha induced autophagy in the conversion of non-stem pancreatic cancer cells into CD133+ pancreatic cancer stem-like cells. Cancer Cell International. 2013;13(1, article 119) doi: 10.1186/1475-2867-13-119. PubMed DOI PMC

Martinez-Outschoorn U. E., Trimmer C., Lin Z., et al. Autophagy in cancer associated fibroblasts promotes tumor cell survival: role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle. 2010;9(17):3515–3533. doi: 10.4161/cc.9.17.12928. PubMed DOI PMC

Song Y.-J., Zhang S.-S., Guo X.-L., et al. Autophagy contributes to the survival of CD133+ liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment. Cancer Letters. 2013;339(1):70–81. doi: 10.1016/j.canlet.2013.07.021. PubMed DOI

Yu L., Gu C., Zhong D., et al. Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance. Cancer Letters. 2014;355(1):34–45. doi: 10.1016/j.canlet.2014.09.020. PubMed DOI

Yu L., Gu C., Zhong D., et al. Autophagy contributes to the enrichment and survival of colorectal cancer stem cells under oxaliplatin treatment. Cancer Letters. 2015;361:128–136. PubMed

Zhou J., Xi C., Wang W., et al. Autophagy plays an important role in triptolide-induced apoptosis in cardiomyocytes. Toxicology Letters. 2015;236:168–183. PubMed

Viale A., Pettazzoni P., Lyssiotis C. A., et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014;514(7524):628–632. doi: 10.1038/nature13611. PubMed DOI PMC

Zhang H.-M., Zhang Y. Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. Journal of Pineal Research. 2014;57(2):131–146. doi: 10.1111/jpi.12162. PubMed DOI

Martín V., Sanchez-Sanchez A. M., Puente-Moncada N., et al. Involvement of autophagy in melatonin-induced cytotoxicity in glioma-initiating cells. Journal of Pineal Research. 2014;57:308–316. doi: 10.1111/jpi.12170. PubMed DOI

Ojha R., Jha V., Singh S. K., Bhattacharyya S. Autophagy inhibition suppresses the tumorigenic potential of cancer stem cell enriched side population in bladder cancer. Biochimica et Biophysica Acta—Molecular Basis of Disease. 2014;1842(11):2073–2086. doi: 10.1016/j.bbadis.2014.07.007. PubMed DOI

Gupta P. B., Onder T. T., Jiang G., et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645–659. doi: 10.1016/j.cell.2009.06.034. PubMed DOI PMC

Jangamreddy J. R., Jain M. V., Hallbeck A. L., et al. Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death. Oncotarget. 2015;6(12):10134–10145. PubMed PMC

Zhu L.-Q., Zhen Y.-F., Zhang Y., Guo Z.-X., Dai J., Wang X.-D. Salinomycin activates AMP-activated protein kinase-dependent autophagy in cultured osteoblastoma cells: a negative regulator against cell apoptosis. PLoS ONE. 2013;8(12) doi: 10.1371/journal.pone.0084175.e84175 PubMed DOI PMC

Cheong J.-H., Park E. S., Liang J., et al. Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Molecular Cancer Therapeutics. 2011;10(12):2350–2362. doi: 10.1158/1535-7163.mct-11-0497. PubMed DOI PMC

Wang Z., Liu P., Chen Q., et al. Targeting AMPK signaling pathway to overcome drug resistance for cancer therapy. Current Drug Targets. 2015;16(14):1–16. doi: 10.2174/1389450116666150316223655. PubMed DOI

Dorn G. W., Kitsis R. N. The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circulation Research. 2015;116(1):167–182. doi: 10.1161/circresaha.116.303554. PubMed DOI PMC

Frank M., Duvezin-Caubet S., Koob S., et al. Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochimica et Biophysica Acta: Molecular Cell Research. 2012;1823(12):2297–2310. doi: 10.1016/j.bbamcr.2012.08.007. PubMed DOI

Tanida I. Autophagosome formation and molecular mechanism of autophagy. Antioxidants & Redox Signaling. 2011;14(11):2201–2214. doi: 10.1089/ars.2010.3482. PubMed DOI

Houten S. M., Denis S., Te Brinke H., et al. Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia. Human Molecular Genetics. 2014;23(18):5009–5016. doi: 10.1093/hmg/ddu218. PubMed DOI

Marino M. L., Fais S., Djavaheri-Mergny M., et al. Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells. Cell Death and Disease. 2010;1(10, article e87) doi: 10.1038/cddis.2010.67. PubMed DOI PMC

Lin G., Hill D. K., Andrejeva G., et al. Dichloroacetate induces autophagy in colorectal cancer cells and tumours. British Journal of Cancer. 2014;111(2):375–385. doi: 10.1038/bjc.2014.281. PubMed DOI PMC

Sawa T., Ihara H., Ida T., Fujii S., Nishida M., Akaike T. Formation, signaling functions, and metabolisms of nitrated cyclic nucleotide. Nitric Oxide. 2013;34:10–18. doi: 10.1016/j.niox.2013.04.004. PubMed DOI

Saeidnia S., Abdollahi M. Toxicological and pharmacological concerns on oxidative stress and related diseases. Toxicology and Applied Pharmacology. 2013;273(3):442–455. doi: 10.1016/j.taap.2013.09.031. PubMed DOI

Wang X., Peralta S., Moraes C. T. Mitochondrial alterations during carcinogenesis: a review of metabolic transformation and targets for anticancer treatments. Advances in Cancer Research. 2013;119:127–160. doi: 10.1016/b978-0-12-407190-2.00004-6. PubMed DOI

Lyakhovich A., Graifer D. Mitochondria-mediated oxidative stress: old target for new drugs. Current Medicinal Chemistry. 2015;22(26):3040–3053. doi: 10.2174/0929867322666150729114036. PubMed DOI

Pagano G., Shyamsunder P., Verma R. S., Lyakhovich A. Damaged mitochondria in Fanconi anemia—an isolated event or a general phenomenon? Oncoscience. 2014;1(4):287–295. PubMed PMC

Colak S., Zimberlin C. D., Fessler E., et al. Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells. Cell Death and Differentiation. 2014;21(7):1170–1177. doi: 10.1038/cdd.2014.37. PubMed DOI PMC

Janiszewska M., Suvà M. L., Riggi N., et al. Imp2 controls oxidative phosphorylation and is crucial for preservin glioblastoma cancer stem cells. Genes & Development. 2012;26(17):1926–1944. doi: 10.1101/gad.188292.112. PubMed DOI PMC

Tokarz P., Kaarniranta K., Blasiak J. Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD) Biogerontology. 2013;14(5):461–482. doi: 10.1007/s10522-013-9463-2. PubMed DOI PMC

Lu J., Holmgren A. The thioredoxin antioxidant system. Free Radical Biology and Medicine. 2014;66:75–87. doi: 10.1016/j.freeradbiomed.2013.07.036. PubMed DOI

Yee C., Yang W., Hekimi S. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C elegans. Cell. 2014;157(4):897–909. doi: 10.1016/j.cell.2014.02.055. PubMed DOI PMC

Abdal Dayem A., Choi H.-Y., Kim J.-H., Cho S.-G. Role of oxidative stress in stem, cancer, and cancer stem cells. Cancers. 2010;2(2):859–884. doi: 10.3390/cancers2020859. PubMed DOI PMC

Wang K., Zhang T., Dong Q., Nice E. C., Huang C., Wei Y. Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Cell Death & Disease. 2013;4(3, article e537) doi: 10.1038/cddis.2013.50. PubMed DOI PMC

Shi X., Zhang Y., Zheng J., Pan J. Reactive oxygen species in cancer stem cells. Antioxidants and Redox Signaling. 2012;16(11):1215–1228. doi: 10.1089/ars.2012.4529. PubMed DOI PMC

Ye X.-Q., Li Q., Wang G.-H., et al. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. International Journal of Cancer. 2011;129(4):820–831. doi: 10.1002/ijc.25944. PubMed DOI

Shen Y.-A., Wang C.-Y., Hsieh Y.-T., Chen Y.-J., Wei Y.-H. Metabolic reprogramming orchestrates cancer stem cell properties in nasopharyngeal carcinoma. Cell Cycle. 2015;14(1):86–98. doi: 10.4161/15384101.2014.974419. PubMed DOI PMC

Moreb J. S. Aldehyde dehydrogenase as a marker for stem cells. Current Stem Cell Research and Therapy. 2008;3(4):237–246. doi: 10.2174/157488808786734006. PubMed DOI

Honoki K., Fujii H., Kubo A., et al. Possible involvement of stem-like populations with elevated ALDH1 in sarcomas for chemotherapeutic drug resistance. Oncology Reports. 2010;24(2):501–505. doi: 10.3892/or-00000885. PubMed DOI

Jiang F., Qi Q., Khanna A., et al. Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Molecular Cancer Research. 2009;7(3):330–338. doi: 10.1158/1541-7786.mcr-08-0393. PubMed DOI PMC

Tanei T., Morimoto K., Shimazu K., et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential paclitaxel and epirubicin-based chemotherapy for breast cancers. Clinical Cancer Research. 2009;15(12):4234–4241. doi: 10.1158/1078-0432.ccr-08-1479. PubMed DOI

Raha D., Wilson T. R., Peng J., et al. The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation. Cancer Research. 2014;74(13):3579–3590. doi: 10.1158/0008-5427. PubMed DOI

Cipolleschi M. G., Marzi I., Santini R., et al. Hypoxia-resistant profile implies vulnerability of cancer stem cells to physiological agents, which suggests new therapeutic targets. Cell Cycle. 2014;13(2):268–278. doi: 10.4161/cc.27031. PubMed DOI PMC

Rhee S. G. Cell signaling: H2O2, a necessary evil for cell signaling. Science. 2006;312(5782):1882–1883. PubMed

Zhao Y., Li R., Xia W., et al. Bid integrates intrinsic and extrinsic signaling in apoptosis induced by α-tocopheryl succinate in human gastric carcinoma cells. Cancer Letters. 2010;288(1):42–49. doi: 10.1016/j.canlet.2009.06.021. PubMed DOI

Dong L.-F., Low P., Dyason J. C., et al. Alpha-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene. 2008;27(31):4324–4335. doi: 10.1038/onc.2008.69. PubMed DOI PMC

Gogvadze V., Norberg E., Orrenius S., Zhivotovsky B. Involvement of Ca2+ and ROS in α-tocopheryl succinate-induced mitochondrial permeabilization. International Journal of Cancer. 2010;127(8):1823–1832. doi: 10.1002/ijc.25204. PubMed DOI

Chandra D., Choy G., Tang D. G. Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3. The Journal of Biological Chemistry. 2007;282(43):31289–31301. doi: 10.1074/jbc.m702777200. PubMed DOI

Hulleman E., Kazemier K. M., Holleman A., et al. Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood. 2009;113(9):2014–2021. doi: 10.1182/blood-2008-05-157842. PubMed DOI PMC

Sadahira K., Sagawa M., Nakazato T., et al. Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway. International Journal of Oncology. 2014;45(6):2278–2286. doi: 10.3892/ijo.2014.2652. PubMed DOI PMC

Ni Z., Dai X., Wang B., et al. Natural Bcl-2 inhibitor (-)-gossypol induces protective autophagy via reactive oxygen species-high mobility group box 1 pathway in Burkitt lymphoma. Leukemia & Lymphoma. 2013;54(10):2263–2268. doi: 10.3109/10428194.2013.775437. PubMed DOI

Cheng P., Ni Z., Dai X., et al. The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma cells. Cell Death and Disease. 2013;4, article e598 doi: 10.1038/cddis.2013.124. PubMed DOI PMC

Legrand-Poels S., Esser N., L'Homme L., Scheen A., Paquot N., Piette J. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochemical Pharmacology. 2014;92(1):131–141. doi: 10.1016/j.bcp.2014.08.013. PubMed DOI

Luo Z., Yu L., Yang F., et al. Ruthenium polypyridyl complexes as inducer of ROS-mediated apoptosis in cancer cells by targeting thioredoxin reductase. Metallomics. 2014;6(8):1480–1490. doi: 10.1039/c4mt00044g. PubMed DOI

Alakhova D. Y., Kabanov A. V. Pluronics and MDR reversal: an update. Molecular Pharmaceutics. 2014;11(8):2566–2578. doi: 10.1021/mp500298q. PubMed DOI PMC

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