Abstract
CSCs are a population of self-renewing and tumor repopulating cells that have been observed in hematologic and solid tumors and their presence contributes to the development of drug resistance. The failure to eliminate CSCs with conventional therapy is one of major obstacles in the successful treatment of cancer. Several mechanisms have been described to contribute to CSCs chemoresistance properties that include the adoption of drug-efflux pumps, drug detoxification pathways, changes in metabolism, improved DNA repair mechanisms, and deregulated survival and pro-apoptotic pathways. Thus, CSCs are therefore an attractive target to develop new anti-cancer therapies.
Keywords: Cancer stem cells [CSCs], chemoresistance, quiescence, heterogeneity, tumors, hypoxia, autophagy.
[1]
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100(7): 3983-8.
[2]
Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 2007; 11(3): 259-73.
[3]
Tirino V, Desiderio V, Paino F, et al. Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization. FASEB J 2013; 27(1): 13-24.
[4]
Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nat Rev Cancer 2008; 8(10): 755-68.
[5]
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. Clin Cancer Res 2009; 15(12): 4234-41.
[6]
Kim MP, Fleming JB, Wang H, et al. ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. PLoS One 2011; 6(6)e20636
[7]
Addla SK, Brown MD, Hart CA, Ramani VA, Clarke NW. Characterization of the Hoechst 33342 side population from normal and malignant human renal epithelial cells. Am J Physiol Renal Physiol 2008; 295(3): F680-7.
[8]
Tomita H, Tanaka K, Tanaka T, Hara A. Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget 2016; 7(10): 11018-32.
[9]
Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev 2011; 7(2): 292-306.
[10]
Ji J, Wang XW. Clinical implications of cancer stem cell biology in hepatocellular carcinoma. Semin Oncol 2012; 39(4): 461-72.
[11]
Moitra K, Lou H, Dean M. Multidrug efflux pumps and cancer stem cells: insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther 2011; 89(4): 491-502.
[12]
Albermann N, Schmitz-Winnenthal FH. Z'Graggen K, et al. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol 2005; 70(6): 949-58.
[13]
Wang J, Gan C, Sparidans RW, et al. P-glycoprotein [MDR1/ABCB1] and Breast Cancer Resistance Protein [BCRP/ABCG2] affect brain accumulation and intestinal disposition of encorafenib in mice. Pharmacol Res 2018; 129: 414-23.
[14]
Peng XX, Tiwari AK, Wu HC, Chen ZS. Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells. Chin J Cancer 2012; 31(2): 110-8.
[15]
Tang L, Bergevoet SM, Gilissen C, et al. Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells. BMC Pharmacol 2010; 10: 12.
[16]
Begicevic RR, Falasca M. ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance. Int J Mol Sci 2017; 18(11)
[17]
Barcellos-Hoff MH, Lyden D, Wang TC. The evolution of the cancer niche during multistage carcinogenesis. Nat Rev Cancer 2013; 13(7): 511-8.
[18]
Cabarcas SM, Mathews LA, Farrar WL. The cancer stem cell niche--there goes the neighborhood? Int J Cancer 2011; 129(10): 2315-27.
[20]
Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2(1): 38-47.
[21]
Kaushik S, Singh R, Cuervo AM. Autophagic pathways and metabolic stress. Diabetes Obes Metab 2010; 12(Suppl. 2): 4-14.
[22]
Ojha R, Bhattacharyya S, Singh SK. Autophagy in cancer stem cells: A potential link between chemoresistance, recurrence, and metastasis Biores Open Access 2015; 4(1): 97-108
[23]
Oskarsson T, Batlle E, Massague J. Metastatic stem cells: Sources, niches, and vital pathways. Cell Stem Cell 2014; 14(3): 306-21.
[24]
Roato I, Ferracini R. Cancer stem cells, bone and tumor microenvironment: Key players in bone metastases. Cancers (Basel) 2018; 10(2) Pii: E56.
[25]
Ruijtenberg S, van den Heuvel S. Coordinating cell proliferation and differentiation: Antagonism between cell cycle regulators and cell type-specific gene expression. Cell Cycle 2016; 15(2): 196-212.
[26]
Mitra A, Mishra L, Li S. EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget 2015; 6(13): 10697-711.
[27]
Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9(4): 265-73.
[28]
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119(6): 1420-8.
[29]
Jayachandran A, Dhungel B, Steel JC. Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma. J Hematol Oncol 2016; 9(1): 74.
[30]
Shetzer Y, Solomon H, Koifman G, Molchadsky A, Horesh S, Rotter V. The paradigm of mutant p53-expressing cancer stem cells and drug resistance. Carcinogenesis 2014; 35(6): 1196-208.
[31]
Flores I, Blasco MAA. p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres. PLoS One 2009; 4(3)e4934
[32]
Sarig R, Rivlin N, Brosh R, et al. Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells. J Exp Med 2010; 207(10): 2127-40.
[33]
Zhou Z, Flesken-Nikitin A, Nikitin AY. Prostate cancer associated with p53 and Rb deficiency arises from the stem/progenitor cell-enriched proximal region of prostatic ducts. Cancer Res 2007; 67(12): 5683-90.
[35]
Kaltschmidt B, Kaltschmidt C, Hofmann TG, Hehner SP, Droge W, Schmitz ML. The pro- or anti-apoptotic function of NF-kappaB is determined by the nature of the apoptotic stimulus. Eur J Biochem 2000; 267(12): 3828-35.
[36]
Huang CY, Ju DT, Chang CF, Muralidhar Reddy P, Velmurugan BK. A review on the effects of current chemotherapy drugs and natural agents in treating non-small cell lung cancer. Biomedicine 2017; 7(4): 23. [Taipei].
[37]
Safa AR. Resistance to Cell Death and Its Modulation in Cancer Stem Cells. Crit Rev Oncog 2016; 21(3-4): 203-19.
[38]
Wang YH, Scadden DT. Harnessing the apoptotic programs in cancer stem-like cells. EMBO Rep 2015; 16(9): 1084-98.
[39]
Nemoto T, Kitagawa M, Hasegawa M, et al. Expression of IAP family proteins in esophageal cancer. Exp Mol Pathol 2004; 76(3): 253-9.
[40]
Dhar S, Kolishetti N, Lippard SJ, Farokhzad OC. Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo. Proc Natl Acad Sci USA 2011; 108(5): 1850-5.
[41]
Wang QE. DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies. World J Biol Chem 2015; 6(3): 57-64.
[42]
Cheng L, Wu Q, Huang Z, et al. L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. EMBO J 2011; 30(5): 800-13.
[43]
Desai A, Webb B, Gerson SL. CD133+ cells contribute to radioresistance via altered regulation of DNA repair genes in human lung cancer cells. Radiother Oncol 2014; 110(3): 538-45.
[44]
Leslie EM, Haimeur A, Waalkes MP. Arsenic transport by the human multidrug resistance protein 1 [MRP1/ABCC1]. Evidence that a tri-glutathione conjugate is required. J Biol Chem 2004; 279(31): 32700-8.
[45]
Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 2009; 458(7239): 780-3.
[46]
Shi X, Zhang Y, Zheng J, Pan J. Reactive oxygen species in cancer stem cells. Antioxid Redox Signal 2012; 16(11): 1215-28.
[47]
Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat Rev Drug Discov 2009; 8(7): 579-91.
[48]
Ozols RF, Cunnion RE, Klecker RW Jr, et al. Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients. J Clin Oncol 1987; 5(4): 641-7.
[49]
Shiraga K, Sakaguchi K, Senoh T, et al. Modulation of doxorubicin sensitivity by cyclosporine A in hepatocellular carcinoma cells and their doxorubicin-resistant sublines. J Gastroenterol Hepatol 2001; 16(4): 460-6.
[50]
Safa AR. Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil. Proc Natl Acad Sci USA 1988; 85(19): 7187-91.
[51]
Bark H, Choi CH. PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB. Cancer Chemother Pharmacol 2010; 65(6): 1131-6.
[52]
Bates SF, Chen C, Robey R, Kang M, Figg WD, Fojo T. Reversal of multidrug resistance: lessons from clinical oncologyNovartis Found Symp 2002; 243: 83-96; discussion 102, 80-5
[53]
Biscardi M, Teodori E, Caporale R, et al. Multidrug reverting activity toward leukemia cells in a group of new verapamil analogues with low cardiovascular activity. Leuk Res 2006; 30(1): 1-8.
[54]
Lee SY, Rhee YH, Jeong SJ, et al. Hydrocinchonine, cinchonine, and quinidine potentiate paclitaxel-induced cytotoxicity and apoptosis via multidrug resistance reversal in MES-SA/DX5 uterine sarcoma cells. Environ Toxicol 2011; 26(4): 424-31.
[55]
Pires MM, Emmert D, Hrycyna CA, Chmielewski J. Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly linked quinine homodimers. Mol Pharmacol 2009; 75(1): 92-100.
[56]
Palmeira A, Rodrigues F, Sousa E, Pinto M, Vasconcelos MH, Fernandes MX. New uses for old drugs: Pharmacophore-based screening for the discovery of P-glycoprotein inhibitors. Chem Biol Drug Des 2011; 78(1): 57-72.
[57]
Kelly RJ, Draper D, Chen CC, et al. A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar [XR9576] in patients with lung, ovarian, and cervical cancer. Clin Cancer Res 2011; 17(3): 569-80.
[58]
Kuppens IE, Witteveen EO, Jewell RC, et al. A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar [GF120918] and oral topotecan in cancer patients. Clin Cancer Res 2007; 13(11): 3276-85.
[59]
Sandler A, Gordon M, De Alwis DP, et al. A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride [LY335979], administered intravenously in combination with doxorubicin in patients with advanced malignancy. Clin Cancer Res 2004; 10(10): 3265-72.
[60]
Oldham RK, Reid WK, Preisler HD, Barnett D. A phase I and pharmacokinetic study of CBT-1 as a multidrug resistance modulator in the treatment of patients with advanced cancer. Cancer Biother Radiopharm 1998; 13(2): 71-80.
[61]
Kong DH, Kim MR, Jang JH, Na HJ, Lee S. A Review of Anti-Angiogenic Targets for Monoclonal Antibody Cancer Therapy. Int J Mol Sci 2017; 18(8)
[62]
Scholz A, Harter PN, Cremer S, et al. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol Med 2016; 8(1): 39-57.
[63]
Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: Bevacizumab [Avastin] as treatment of recurrent glioblastoma multiforme. Oncologist 2009; 14(11): 1131-8.
[64]
Planchard D. Bevacizumab in non-small-cell lung cancer: A review. Expert Rev Anticancer Ther 2011; 11(8): 1163-79.
[65]
Rinne ML, Lee EQ, Nayak L, et al. Update on bevacizumab and other angiogenesis inhibitors for brain cancer. Expert Opin Emerg Drugs 2013; 18(2): 137-53.
[66]
Shih T, Lindley C. Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 2006; 28(11): 1779-802.
[68]
Vincent L, Kermani P, Young LM, et al. Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J Clin Invest 2005; 115(11): 2992-3006.
[69]
Di C, Zhao Y. Multiple drug resistance due to resistance to stem cells and stem cell treatment progress in cancer. [Review]. Exp Ther Med 2015; 9(2): 289-93.
[70]
Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 2007; 99(19): 1441-54.
[71]
Foehrenbacher A, Secomb TW, Wilson WR, Hicks KO. Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling. Front Oncol 2013; 3: 314.
[72]
Hunter FW, Wouters BG, Wilson WR. Hypoxia-activated prodrugs: Paths forward in the era of personalised medicine. Br J Cancer 2016; 114(10): 1071-7.
[73]
Chawla SP, Cranmer LD, Van Tine BA, et al. Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. J Clin Oncol 2014; 32(29): 3299-306.
[74]
Brown JM, Giaccia AJ. The unique physiology of solid tumors: Opportunities [and problems] for cancer therapy. Cancer Res 1998; 58(7): 1408-16.
[75]
Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Hypoxia-inducible factor [HIF1A and HIF2A], angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002; 53(5): 1192-202.
[76]
Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 2005; 77(1): 18-24.
[77]
Evans JW, Chernikova SB, Kachnic LA, et al. Homologous recombination is the principal pathway for the repair of DNA damage induced by tirapazamine in mammalian cells. Cancer Res 2008; 68(1): 257-65.
[78]
Wigerup C, Pahlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 2016; 164: 152-69.
[79]
Mimeault M, Batra SK. New promising drug targets in cancer- and metastasis-initiating cells. Drug Discov Today 2010; 15(9-10): 354-64.
[80]
Carlisi D, Buttitta G, Di Fiore R, et al. Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis. Cell Death Dis 2016; 7e2194
[81]
Shibue T, Takeda K, Oda E, et al. Integral role of Noxa in p53-mediated apoptotic response. Genes Dev 2003; 17(18): 2233-8.
[82]
Hervouet E, Cheray M, Vallette FM, Cartron PF. DNA methylation and apoptosis resistance in cancer cells. Cells 2013; 2(3): 545-73.
[83]
Labi V, Grespi F, Baumgartner F, Villunger A. Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy? Cell Death Differ 2008; 15(6): 977-87.
[84]
Taylor Ripley R, Surman DR, Diggs LP, et al. Metabolomic and BH3 profiling of esophageal cancers: novel assessment methods for precision therapy. BMC Gastroenterol 2018; 18(1): 94.
[85]
Triscott J, Lee C, Hu K, et al. Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide. Oncotarget 2012; 3(10): 1112-23.
[86]
Mohammad IS, He W, Yin L. A Smart Paclitaxel-Disulfiram Nanococrystals for Efficient MDR Reversal and Enhanced Apoptosis. Pharm Res 2018; 35(4): 77.
[87]
Smith KM, Datti A, Fujitani M, et al. Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens. EMBO Mol Med 2010; 2(9): 371-84.
[88]
Alvero AB, Montagna MK, Chen R, et al. NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathway. Cancer 2009; 115(14): 3204-16.
[89]
Khanna A. DNA damage in cancer therapeutics: A boon or a curse? Cancer Res 2015; 75(11): 2133-8.
[90]
Wang Y, Xu H, Liu T, et al. Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells. JCI Insight 2018; 3(3)
[91]
Glorieux M, Dok R, Nuyts S. Novel DNA targeted therapies for head and neck cancers: Clinical potential and biomarkers. Oncotarget 2017; 8(46): 81662-78.
[92]
Dungl DA, Maginn EN, Stronach EA. Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy. Front Oncol 2015; 5: 240.
[93]
Munck JM, Batey MA, Zhao Y, et al. Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K. Mol Cancer Ther 2012; 11(8): 1789-98.
[94]
Sibanda BL, Chirgadze DY, Blundell TL. Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats. Nature 2010; 463(7277): 118-21.
[95]
Gavande NS, VanderVere-Carozza PS, Hinshaw HD, et al. DNA repair targeted therapy: The past or future of cancer treatment? Pharmacol Ther 2016; 160: 65-83.
[96]
Lu B, Chen XB, Ying MD, He QJ, Cao J, Yang B. The role of ferroptosis in cancer development and treatment response. Front Pharmacol 2017; 8: 992.
[97]
Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 2014; 3e02523
[98]
Xie Y, Hou W, Song X, et al. Ferroptosis: Process and function. Cell Death Differ 2016; 23(3): 369-79.
[99]
Yu H, Guo P, Xie X, Wang Y, Chen G. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med 2017; 21(4): 648-57.
[100]
Moreb JS, Maccow C, Schweder M, Hecomovich J. Expression of antisense RNA to aldehyde dehydrogenase class-1 sensitizes tumor cells to 4-hydroperoxycyclophosphamide in vitro. J Pharmacol Exp Ther 2000; 293(2): 390-6.
[101]
Yan Y, Li Z, Xu X, et al. All-trans retinoic acids induce differentiation and sensitize a radioresistant breast cancer cells to chemotherapy. BMC Complement Altern Med 2016; 16: 113.
[102]
Conticello C, Martinetti D, Adamo L, et al. Disulfiram, an old drug with new potential therapeutic uses for human hematological malignancies. Int J Cancer 2012; 131(9): 2197-203.
[103]
Duan L, Shen H, Zhao G, et al. Inhibitory effect of Disulfiram/copper complex on non-small cell lung cancer cells. Biochem Biophys Res Commun 2014; 446(4): 1010-6.
[104]
Liu P, Brown S, Goktug T, et al. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br J Cancer 2012; 107(9): 1488-97.
[105]
Bista R, Lee DW, Pepper OB, Azorsa DO, Arceci RJ, Aleem E. Disulfiram overcomes bortezomib and cytarabine resistance in Down-syndrome-associated acute myeloid leukemia cells. J Exp Clin Cancer Res 2017; 36(1): 22.
[106]
Zhao Y, Xiao Z, Chen W, Yang J, Li T, Fan B. Disulfiram sensitizes pituitary adenoma cells to temozolomide by regulating O6-methylguanine-DNA methyltransferase expression. Mol Med Rep 2015; 12(2): 2313-22.
[107]
Aulmann S, Waldburger N, Penzel R, Andrulis M, Schirmacher P, Sinn HP. Reduction of CD44[+]/CD24[-] breast cancer cells by conventional cytotoxic chemotherapy. Hum Pathol 2010; 41(4): 574-81.
[108]
Croker AK, Allan AL. Inhibition of aldehyde dehydrogenase [ALDH] activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44[+] human breast cancer cells. Breast Cancer Res Treat 2012; 133(1): 75-87.
[109]
Venton G, Perez-Alea M, Baier C, et al. Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors. Blood Cancer J 2016; 6(9)e469
Related Journals
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Bioactive Compounds
Current Diabetes Reviews
Current Enzyme Inhibition
Current Molecular Medicine
Current Medicinal Chemistry
Current Neurovascular Research
Current Topics in Medicinal Chemistry
Current Protein & Peptide Science
Current Signal Transduction Therapy
Related Books
Frontiers in Clinical Drug Research-Dementia
COVID-19: Causes, Transmission, Diagnosis, and Treatment
Skeletal Muscle Health in Metabolic Diseases
Common Lip Diseases: A Clinical Guide
Interventional Pain Surgery
Endoscopy and Fetoscopy Techniques for the Brain and Neuroaxis
Frontiers in Stem Cell and Regenerative Medicine Research
Textbook of Advanced Dermatology: Pearls for Academia and Skin Clinics (Part 2)
Women’s Health: A Comprehensive Guide to Common Health Issues in Women
Regenerative Medicine & Peripheral Nerve Endoscopy
Article Metrics
55
3