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The relationship between autophagy and multidrug resistance in cancer stem cells






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Abstract

Cancer stem cells (CSCs) are considered the origin of tumors and cancer. Recently, CSCs have been described as the cause of multidrug resistance (MDR) in almost all cancers. The MDR phenotype of CSCs manifests as the upregulation of ATP-binding cassette subfamily G, isoform 2 protein (ABCG2) in the cell membranes of CSCs. However, recent studies have demonstrated a relationship between MDR and the autophagy process of CSCs. Based on publications indexed in PubMed, Google Scholar, and Scopus, this review summarizes the relationship between autophagy and MDR in CSCs and the approaches to targeting autophagy to reduce MDR in CSCs. Autophagy can be considered a new target to overcome MDR in cancer treatment.

Keywords: autophagy multidrug resistance cancer stem cells cancer

Introduction

In recent years, cancer stem cells (CSCs) have been identified as the main cause of tumor initiation, growth, metastasis, and recurrence 1 , 2 , 3 , 4 , 5 . Therapies aimed at targeting and eliminating CSCs have been developed 6 , 7 , 8 , 9 , 10 , 11 ; however, the effect of these therapies remains controversial 12 . To address these inconsistencies, certain research fields have been promoted to elucidate the characteristics and capabilities of CSCs 13 , 14 .

One of the research directions of interest is the resistance of CSCs to therapeutic agents, especially their resistance to chemotherapy 15 , 16 . Multidrug resistance (MDR) of CSCs involves the autophagy process, which responds to stress conditions and maintains cell survival. Research has demonstrated that autophagy plays a pivotal role in the chemoresistance of various cancer cell lines 17 , 18 , 19 , 20 , 21 , 22 , 23 .

However, observations of the correlation between autophagy and MDR in CSCs are limited. Therefore, this review aims to provide reliable evidence for elucidating the close relationship between autophagy and MDR in CSCs and suggests a promising therapy to combine chemotherapy with autophagy regulation.

Cancer stem cells

History of CSCs

The history of CSCs began in the first half of the 19 th century and has undergone many stages of development over nearly two centuries to the present day 24 . In the 19 th century, Johannes Muller described cancer as an abnormal proliferation of “embryonic cells” that were residual and unused during development 25 . This idea was consolidated in the theory of cancer origin from “embryonal cell rests” that was pioneered by his pupils, Rudolf Virchow and Julius Cohnheim 26 . Based on this theory, a model of tumor initiation from a small group of undifferentiated cells gradually emerged.

However, it was not until the middle of the 20 th century that evidence of stem cells in cancer began to receive attention from scientists. In the 1950s, Leroy Stevens and Clarence C. Little demonstrated that both teratomas and teratocarcinomas were generated from highly undifferentiated cells, which were subsequently called “pluripotent embryonic stem cells” 25 , 27 . In 1961, Southam and Brunschwig demonstrated that only a minority population of cancer cells derived from patients had tumorigenic capacity when autotransplanted to different sites 6 , 28 . In 1963, Bruce et al. emphasized the pivotal role of a small group of lymphoma cells in tumor initiation 29 . In 1964, Kleinsmith and Pierce further demonstrated that embryonal carcinoma (EC) cells isolated from cancer tissue had diverse differentiation potentials 27 . In 1971, Pierce published evidence that differentiated cancer cells could not form tumors when injected into experimental mice 30 . The results indicated that tumor initiation and development were facilitated by a small group of undifferentiated cancer cells that were highly proliferative and had multidifferentiation potential. This was the foundational basis of the concept of CSCs.

In the 1990s, studies on human acute myeloid leukemia (AML) cells by Lapidot (1994) and Bonnet and Dick (1997) indicated that only a subpopulation of cells expressing specific surface markers CD34 + /CD38 - acted as the initiating cells in tumors 30 , 14 . Through this evidence, CSCs were officially identified and isolated from the cancer cell population. Subsequent studies showed that tumor-initiating cells, also known as CSCs, are characterized by distinct markers for different cancer tissues 14 . To date, numerous CSCs have been isolated and enriched due to their specific cell markers. An increasing number of studies have targeted CSCs to improve the effect of cancer therapies.

Characteristics of CSCs

Based on the results of existing studies, previous reports have proposed the characteristics of CSCs that contribute to their role in tumor initiation, survival, and development. These include (1) tumorigenesis capability, (2) self-renewal and differentiation into multiple cell lines, (3) expression of specific markers for isolation, (4) maintenance of a “stemness property” after more transplanted generations, and (5) resistance to conventional therapies 31 , 32 , 33 .

The tumor-forming ability of CSCs involves their cell origin. CSCs originate from normal stem cells or progenitor cells acquiring “stem cell attributes” 34 , 35 , 36 , 37 . By stimulating the microenvironment, these cells undergo uncontrolled proliferation and transform into CSCs 38 , 39 . Therefore, CSCs are inherited, self-renewing, multilineage-differentiated stem cells that are capable of driving tumor development. Similar to normal stem cells, the self-renewal capability of CSCs is regulated by specific signaling pathways, such as the Wnt/β-catenin, Notch, and Hedgehog pathways 40 , 41 , 42 , 43 . In addition, the other pathways of tumor suppressor genes, represented by phosphatase and tensin homolog on chromosome 10 (PTEN) and tumor protein p53 (TP53), contribute to both self-renewal and tumor initiation in CSCs 44 . Furthermore, the self-renewal and multidifferentiation potential of CSCs results in a hierarchy population of cancer cells that explains the existence of heterogeneous tumors 45 , 46 . The self-renewal characteristic of CSCs is the main basis for maintenance of their tumorigenesis potential during serial transplantations in subsequent mouse generations. Currently, the transplantation assay is used to identify the hallmarks of CSCs 47 , 48 , 49 , 50 , 51 .

Another characteristic of CSCs is the expression of specific markers ( i.e., cell membrane receptor proteins) on the cell surface. The difference in cell surface markers between CSCs and other tumor cells suggests a method for isolating CSCs from the cancer cell population 52 , 53 , 54 , 55 . CSCs that are isolated from different tissues express groups of distinctive molecular markers 31 , 33 , such as CD44 + /CD24 + /ESA + in pancreatic CSCs 56 , 57 , ESA + /CD44 + /CD24 - /Lin - in breast CSCs 58 , and CD133 + /α2β1 and integrin/CD44 + markers in prostate CSCs 59 . Due to the specificity of these markers in CSCs, they have been proposed as potential targets for cancer therapies 60 .

Although targeting CSCs seems promising to improve tumor treatment efficiency, it encounters an inherent problem that involves the resistance of CSCs to a majority of commonly used treatments. In general, the anti-therapy mechanisms of CSCs are divided into two types of resistance: acquired and intrinsic 61 . Acquired resistance is based on the response of the CSCs to therapeutic agents. Radiotherapy not only stimulates the DNA damage checkpoint and activates the DNA-repair systems of CSCs 62 , but it also activates the defense mechanism against reactive oxygen species (ROS) 63 . In contrast, chemotherapy is both influenced by acquired resistance, like radiotherapy, and affected by the intrinsic resistance of CSCs through processes such as quiescence (or dormancy), self-renewal, transformation between cell phenotypes (or plasticity), and the expression of drug transporters and detoxification proteins. In addition, the antitherapeutic activity of CSCs is supported by interaction between the tumor microenvironment and CSCs to generate resistance through signaling pathways 64 . Understanding of the mechanisms of CSC resistance paves the way for novel cancer treatment strategies that focus on inhibiting these mechanisms and reversing the sensitivity of CSCs to therapeutic agents 65 .

Multidrug resistance of CSCs

Antichemotherapeutic activity of CSCs

One of the most popular cancer therapies is chemotherapy. Numerous drugs that are efficient in inducing cell death have been used to treat a variety of cancers 66 , 67 . MDR is defined as the “simultaneous resistance of cancer cells toward a broad spectrum of structurally unrelated cytotoxic drugs that have different modes of action” 68 . There are two types of chemoresistance in tumors: primary (or de novo ) resistance and acquired resistance, which can be observed in ovarian cancer 69 , glioblastoma 68 , 70 , 71 , pancreatic cancer 72 , breast cancer 73 , neuroblastoma, and hepatoblastoma 66 . Primary resistance (also called intrinsic resistance) confers drug resistance via factors that are intrinsic to cancer cells in tumors, usually due to CSC aptitude, before the administration of chemotherapies. Acquired resistance (or extrinsic resistance) is the acquired ability formed by the responsiveness of cancer cells to chemotherapy via genetic and epigenetic modifications for detoxification 68 , 69 , 74 .

Mechanisms of MDR in CSCs

Recent insights into CSCs have indicated their essential roles in MDR. Investigation of MDR mechanisms in CSCs provides an opportunity to overcome them 75 , 76 , 77 . MDR of CSCs is based on many cellular activities, such as the DNA repair system, transporter efflux pump, detoxification enzymes (aldehyde dehydrogenase, DNA topoisomerase, protein kinase C, dihydrofolate reductase, glutathione and glutathione S-transferases [GST]), EMT, autophagy, oncogenes (EGFR, PI3K/AKT, ERK, and NF-ĐşB), microRNAs, tumor suppressor genes ( e.g ., p53), and B-cell lymphoma 2 (Bcl-2). In addition, microenvironmental conditions, such as hypoxia, pH, and paracrine signals, affect the drug-resistance capacity of CSCs 78 , 79 , 80 , 81 , 82 , 83 .

Protein activity plays a role in the form of efflux pumps that excrete a broad range of chemotherapeutic drugs ( e.g. , doxorubicin [DOX], cisplatin, 5-fluorouracil [5-FU], colchicine, methotrexate, etoposide) out of CSCs, thereby preventing their cytotoxicity and supporting the chemoresistance of CSCs 82 . A main protein family for this task is ATP-binding cassette (ABC) transporters. Their crucial function is to transport a variety of substances, such as peptides, inorganic anions, amino acids, polysaccharides, proteins, vitamins, and metal ions. In CSCs, they function as a system to efflux toxins. ABC transporters are divided into seven subfamilies with 49 members, named ABC-A to ABC-G. An ABC protein has four domains: two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs) 84 . The expression of ABC transporters is affected by the signaling pathway, and energy from the hydrolyzation of a pair of ATP molecules that bind to transporters can drive the active transport of drugs and/or other substances out of cells 85 .

DNA repair systems that help to detect and repair mismatches on DNA strands are another important MDR mechanism in CSCs 86 . In general, DNA damage induced by both intra- and extracellular factors ( e.g. , endogenous ROS, ultraviolet radiation, X- and gamma rays, plant toxins, mutagenic chemicals, and chemotherapeutic agents) 80 activates a response network. First, DNA errors are identified by sensor complexes, including Mre11-Rad50-Nbs1 (MRN), which recognize DNA double-strand breaks (DSBs), while the RPA-ATRIP complex recognizes single-strand breaks (SSBs). Then, the repair systems restore DNA damage via six mechanisms: (1) the direct reversal pathway (MGMT, ABH2, ABH3), (2) the mismatch repair (MMR) pathway, (3) the nucleotide excision repair (NER) pathway, (4) the base excision repair (BER) pathway, (5) the homologous recombination (HR) pathway, and (6) the nonhomologous end-joining (NHEJ) pathway 87 , 88 .

Despite the activation of DNA repair systems, drugs still cause extensive damage. To survive, CSCs may prevent apoptosis by promoting the action of the Bcl-2 protein family, such as Bcl2-associated-X-protein (Bax), Bcl-2 homologous antagonist killer (Bak), B-cell lymphoma-extra small (Bcl-X S ), and anti-apoptosis proteins, such as Bcl-2, B-cell lymphoma-extra-large (Bcl-X L ), and myeloid cell leukemia 1 (Mcl-1) 79 , 89 . Under normal circumstances, apoptosis is induced by proapoptotic proteins via stimulation of apoptogenic proteins, such as cytochrome c produced by mitochondria. However, proapoptotic proteins are associated with antiapoptotic proteins that reduce their activity and interfere with cellular apoptosis 90 . The Bcl-2 protein family entirely restricts a variety of drugs: dexamethasone, cytosine arabinoside (Ara-C), methotrexate, cyclophosphamide, adriamycin, daunomycin, S-fluoro-deoxy-uridine, 2-chlorodeoxyadenosine, fludarabine, paclitaxel (Taxol), etoposide (VP-16), camptothecin, nitrogen mustards, mitoxantrone, cisplatin, vincristine, and some retinoids. Although these drugs affect different pathways, antiapoptotic Bcl-2 and its family members impede the effectiveness of drugs by inhibiting signals inducing cell death. Therefore, even if toxic molecules can penetrate the cell and destroy the DNA structure, cancer cells still survive and are able to prevent the effects of the drugs, repair DNA damage, and proliferate 91 .

Another MDR mechanism of CSCs involves a group of enzymes that are essential components in metabolism pathways: drug metabolism enzymes (DMEs). There are two phases of DMEs distinguished by two basic but distinct reactions. Phase I enzymes or metabolism enzymes comprise cytochrome P450 enzymes (CYPs), oxidoreductases, and epoxide hydrolases that oxidize appropriate substrates, namely therapeutic drugs. This oxidation alters the substrates to form favorable molecular structures for activating enzymes in phase II. Subsequently, phase II enzymes or transferase enzymes, such as GSTs, UDP glucuronosyltransferases (UGTs), sulfotransferases, and arylamine N-acetyltransferases (NATs), conjugate definite complexes to targeted substrates to create nontoxic compounds 88 , 92 , 93 , 94 . For example, UGTs have been demonstrated to transfer the glucuronic acid component of UDP-glucuronic acid to anthracycline (daunorubicin), which correlates with a reduction in daunorubicin cytotoxicity 95 . Finally, these compounds are pumped out of cells via ABC transporters 88 .

The conditions of the microenvironment, such as hypoxia or low pH, also contribute to hindering drug efficacy. Under hypoxic conditions, the low oxygen concentration reduces the cytotoxicity of chemotherapeutic drugs due to their oxidation requirement to transform into cytotoxic structures 88 . In addition, the hypoxia-inducible factors (HIFs) produced in response to hypoxia induce the expression of ABC transporters 78 . Furthermore, hypoxic conditions facilitate intracellular accumulation of lactic acid via the glycolysis pathway. Therefore, cancer cells induce proton pumps to efflux H + ions into the extracellular space and promote acidification of the microenvironment. The high concentration of extracellular H + ions causes “ion trapping,” ionizing weak bases to become positively-charged complexes. Because of the ion trapping phenomenon, the cell permeability of weakly basic chemotherapeutic agents ( e.g ., DOX, mitoxantrone, vincristine, anthracyclines, anthraquinones, vinca alkaloids) is decreased, and the effects of the drugs are impaired 96 , 97 . Other components of the tumor microenvironment, including the extracellular matrix (ECM), matrix rigidity, hypervascularization, and paracrine factors, mediate chemoresistance by controlling drug availability, stimulating EMT, and promoting oncogenic signaling pathways.

Autophagy of CSCs

Discovery and definition

Autophagy is a combination of two words that originate from Greek: “auto” means self, while “phagy” means eating, so autophagy means “self-eating” 98 . This process was discovered many years ago. In 1859, this term was first introduced under the name “autophagie” in a magazine published by the French Academy of Science and was used by physiologist M. Anselmier 99 . In 1963, Christian de Duve was the first to use the term autophagy in accordance with its current functional definition: a process by which cellular materials are taken to and decomposed in lysosomes (in animals) or vacuoles (in plants, yeasts) 100 . To date, 42 autophagy-related genes (ATGs) responsible for autophagosome formation and autophagy regulation have been identified 101 . Microtubule-associated protein 1 light chain 3 (LC3), which is the main autophagy indicator in mammals, was identified by Kabeya et al . 102 . Beclin 1 was reported to play dual roles as an autophagy inducer when it binds to phosphatidylinositol 3-kinase 103 and as a tumor suppressor due to its mediation of E-cadherin localization 104 , 105 .

In summary, many previous reports have indicated that autophagy is an important cellular process through which different cytoplasmic components are broken down and recycled via lysosomal degradation 106 . This process is often activated in response to a shortage of nutrients, leading to regeneration of other organelles and substances to provide essential precursors for metabolic activity 107 .

In vitro and in vivo mechanisms

There are three main types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) 100 . Macroautophagy (hereafter termed “autophagy”) is the most studied form. Macroautophagy mainly involves the degradation of long-lived proteins via lysosomes 108 , especially faulty proteins in specific diseases, such as huntingtin (in Huntington’s disease 109 ), a-synuclein (in Parkinson’s disease 110 ), or fibrinogen g-chain (in hypofibrinogenemia 111 ). After receiving a stress signal, macroautophagy begins in the cytoplasm with the formation of a double-membrane-bound structure called an autophagosome 112 . Autophagosomes then fuse with lysosomes to form autolysosomes, where their cytoplasmic contents are degraded by hydrolases and sent back to the cytoplasm as recycling material for cellular metabolism 112 . In microautophagy, the membranes of lysosomes or vacuoles are randomly invaded and differentiate into autophagic tubes enclosing cytosolic components 113 , which are then degraded by hydrolases 100 .

The two phenomena mentioned above were described by Duve and Wattiaux in rats in 1966 113 . Fifteen years later, CMA was first described in human fibroblasts cultured in medium without serum containing growth factors 114 . The CMA process begins when degraded proteins are recognized by cytosolic chaperone complexes and brought to the surface of lysosomes. At the lysosomal membrane, after binding to specific molecules, the proteins are translocated into the lumens of lysosomes, where they are completely degraded 115 . CMA is known to be activated as part of the amino acid response during prolonged nutritional starvation 116 .

Recently discovered types of autophagy with roles in specific organelles are being studied to elucidate their mechanisms and functions. Typical examples include mitophagy (mediating mitochondria removal) 117 , ribophagy (degradation system for ribosomes) 118 , xenophagy 119 , and lipophagy (connection between autophagy and lipid metabolism) 120 .

Relationship between autophagy and MDR in CSCs

Autophagy contributes to MDR in CSCs

The contribution of autophagy to MDR development in CSC lines has been investigated for many years. An underlying mechanism of autophagy-stimulated MDR in CSCs has also been gradually elucidated. In 2013, Wu et al. evaluated the resistance of colon CSCs, which were isolated from the SW1222 and HCT116 cell lines via CD44 + /CD24 + markers, to paclitaxel. A cytotoxic result indicated that SW1222 stem cells were more resistant to paclitaxel than HCT116 stem cells. A further experiment on signaling pathways demonstrated that Cdx1 stimulated autophagy activation by increasing Bcl-2 and LC3-II levels in SW1222 stem cells. In addition, silencing Cdx1 expression with siRNAs or inhibiting autophagy with the lysosomal inhibitor bafilomycin A250 (BafA) caused SW1222 stem cells to become more sensitive to paclitaxel. However, HCT116 stem cells do not express Cdx1 but express p53, which induces apoptosis due to increased expression of the Bax protein. Reviving the expression of Cdx1 in HCT116 stem cells promotes autophagy, significantly restricting apoptosis in these cells 121 . In conclusion, Cdx1-induced autophagy based on the Cdx1-Bcl-2-LC3-II signaling pathway plays a pivotal role in the resistance of colon CSCs to paclitaxel.

Another study on colorectal cancer (CRC) was published by Yang et al. in 2015. The role of autophagy in chemoresistance was investigated in both CRC cells and CSCs. In the CRC cell lines SW620 and SW480, autophagy is induced by oxaliplatin; otherwise, the hypoxia/starving (H/S) environment enhances autophagy activation in CRC cells. The results indicated that autophagy reduced cell death by inhibiting oxaliplatin-induced apoptosis in CRC cells cultured in an H/S environment. In addition, treatment with oxaliplatin was demonstrated to enrich CD44 + CRC cells, especially when they were cultured in an H/S environment. In further investigations, the enriched CD44 + CRC cells were sorted to obtain CSCs based on CD44, which is a characteristic surface marker for colon cancer CSCs. CSCs (CD44 + cells) and CD44 - cells were exposed to oxaliplatin. The data indicated that autophagy enhanced by the H/S environment improved the survival proportion of CD44 + cells, which was higher than that of CD44 - cells. In contrast, the presence of 3-methyladenine (3-MA) prevented autophagy activation so that the survival of both cell groups was not significantly different 122 . Therefore, autophagy stimulated by stress conditions functions to inhibit the oxaliplatin effect and promotes the survival of colorectal CSCs.

In another study, Yue You et al. demonstrated that autophagy regulated by BCRA1 enhanced the drug resistance of ovarian CSCs to cisplatin. BCRA1 is a tumor suppressor gene that contributes to multiple cell processes in cancerous tissues, especially drug resistance. The results revealed that SKOV3 cells, an ovarian cancer cell line, inhibited increased expression of both autophagy proteins and BCRA1. SKOV3 cells were isolated from epithelial ovarian cancer stem cells (EOCSCs) via CD133. Comparison of EOCSCs and parental cells revealed that EOCSCs had higher activation of autophagy and BCRA1 than SKOV3 cells, which had a greater effect on stemness and drug resistance. Furthermore, transfection of the BCRA1 plasmid into EOCSCs resulted in overexpression of BCRA1 and upregulation of Beclinâ€1, ATG5, Pâ€gp, and ABCG2. The increase in the LC3-II/I ratio confirmed the regulation of autophagy by BCRA1. Furthermore, knocking down BCRA1 and inhibiting autophagy sensitized EOCSCs to cisplatin due to increased apoptosis and interference with the cell cycle. In addition, treatment with torkinib stimulated autophagy and attenuated cell cycle arrest in EOCSCs with BRCA1 knockdown 123 . The results indicate crosstalk between BCRA1 and autophagy that allows BCRA1 to increase cisplatin resistance in EOCSCs through autophagy.

A recent report by Li et al. suggested a relationship between autophagy and chemoresistance in gastric CSCs. Stem cells were isolated from the gastric cancer cell lines MGC-803 and MKN-45 using CD54 and CD44 markers. The LC3-II proportion was enhanced in CD44 + /CD54 + gastric cells to induce increased activity of autophagy in these cells compared with the original cancer cells. Treatment of gastric CSCs with a combination of chloroquine (CQ) and 5-FU revealed that autophagy inhibition increased the chemosensitivity of gastric CSCs. Furthermore, suppressing the Notch signaling pathway enhanced cell death in chemotherapy-treated gastric CSCs. This result indicated an association of the Notch signaling pathway with autophagy-mediated chemoresistance in gastric CSCs 124 . This evidence indicates the effect of autophagy on chemoresistance in gastric CSCs based on the Notch signaling pathway.

The described studies investigated the effective mechanisms of autophagy through signaling pathways to regulate MDR in CSCs from different tissues. These results consolidate an essential contribution of autophagy to chemoresistance in CSCs.

Autophagy facilitates reversal of MDR in CSCs

Autophagy has been declared a “double-edged sword” 125 , 126 . In brief, this process not only plays a pro-survival role to protecting cancer cells from therapeutic drugs, but it also kills resistant cells by stimulating programmed cell death and facilitating MDR reversal 23 . Although the mechanism of autophagy-mediated cell death in cancer cells, especially CSCs, is unclear, some evidence indicates that autophagy can induce cell death of MDR cells 127 , 128 , 129 or promote apoptotic signaling pathways 23 .

Some studies on rottlerin, a plant-derived chemopreventive agent isolated from Mallotus philippensis 130 , 131 , reported that autophagy induced by rottlerin is followed by induction of apoptosis 132 . CSCs treated with rottlerin exhibited enhanced conversion of LC3-I to LC3-II, which is a hallmark of autophagy 131 . In addition, rottlerin increased the expression of Atg7 and Beclin-1 in pancreatic CSCs 132 , Atg12 in breast CSCs 130 , and other genes in prostate CSCs 131 , which accumulated during autophagy processing. In contrast, silencing of the Atg7 and Beclin-1 genes led to the inhibition of rottlerin-induced autophagy 132 . Furthermore, rottlerin-treated CSCs suppressed the phosphorylation of the PI3K/AKT/MTOR signaling pathway, which is associated with the maintenance of CSCs 133 , decreased expression of anti-apoptosis proteins, such as Bcl-2, Bcl-XL, XIAP, and cIAP-1, induction of Bax, activation of caspase-3 and -9, and concomitant degradation of poly (ADP-ribose) polymerase (PARP). These results confirmed the correlation between rottlerin treatment and apoptosis induction. Moreover, there are also data indicating that the inhibition of autophagy by 3-MA and bafilomycin may arrest apoptosis 130 . In summary, rottlerin-induced autophagy mediates apoptosis in CSCs from different tumors via inhibition of the PI3K/AKT/mTOR signaling pathway.

Another report in MDR human A549 lung cancer cells by Kaewpiboon et al. demonstrated that feroniellin A (FERO) reduces the expression of NF-ÎşB, which correlates with MDR reversal and leads to sensitization to apoptosis via downregulation of P-gp. In addition, FERO enhances the conversion of LC3-I to LC3-II and induces autophagy, and the activation of autophagy by rapamycin increases FERO-induced apoptosis. This evidence suggests that FERO-induced autophagy functions as a mediating factor in reversing MDR and facilitating apoptosis in MDR human A549 lung cancer cells 134 . Furthermore, Xu et al. reported that cryptotanshinone (CTS), an active quinoid diterpene isolated from Salvia miltiorrhiza Bunge, induces autophagic cell death in MRD colon cancer cells based on activation of the ROS-p38/MAPK/NF-kB signaling pathway 135 .

These studies provide evidence that autophagy induced by the identified substances can stimulate programmed cell death and MDR reversal in both CSCs and MDR cancer cell lines in some cases.

Autophagy is a potential target to overcome the MDR of CSCs

According to the previously mentioned studies, autophagy and MDR in CSCs have an intimate relationship. Therefore, autophagy has become a potential target to overcome the MDR of CSCs in the last decade. A report by Pagotto et al. indicated that inhibiting autophagy using CQ or CRISPR/Cas9 ATG5 knockout reduced both chemoresistance in vitro and tumorigenicity in vivo in human ovarian CSCs 136 . Another study demonstrated that autophagy suppression by CQ in CSCs promoted chemosensitivity to cisplatin in non-small cell lung carcinoma 137 . A report on colon CSCs showed that microRNAs could be utilized to disrupt autophagy to promote apoptosis, overcome MDR, and decrease the tumorigenicity of CSCs 138 . Furthermore, Liao et al. demonstrated that autophagy blockade by Ai Du Qing formula, a traditional Chinese medicine, attenuated the GRP78/β-Catenin/ABCG2 signaling pathway and stimulated the chemosensitivity of breast CSCs 139 . In the same case, Sun et al. demonstrated that the combination of inhibiting autophagy and chemotherapy by nanoparticles loaded with CQ, DOX, and docetaxel (DTXL) increased the effect of the drug on breast CSCs 140 . Bousquet et al. investigated whether inhibition of the autophagic pathway of breast CSCs reverses the chemoresistance of these cells in pretreatment biopsies of triple negative breast cancer patients 141 . Other studies have provided additional evidence that autophagy inhibition leads to sensitization of cancer cells to drugs, apoptosis induction, and decreased resistance in MDR cancer cells ( Table 1 ).

Table 1 Overcoming chemo-resistance of CSCs and multi-drug resistant cells by targeting to autophagy

Conclusion

Evidence from scientific reports reveals an intimate correlation between MDR and autophagy in CSCs. The elucidation of this relationship will pave the way to understanding the anti-therapeutic mechanism of tumors, thereby contributing to resolving challenges in current cancer treatment.

Acknowledgments

This research is funded by Vietnam National University HoChiMinh City (VNU-HCM) under grant number C2020-18-27 and University of Science, VNU-HCM under grant number T2021-62.

Authors’ contributions

Nhan Ngo-Tran The and Khan Dinh Bui have equal role in composing the content. Phuc Van Pham suggests ideas for the manuscript, checks form of presentation and edits script.

Conflicts of interest

There are no conflicts of interest among authors.

Patient consent

Not applicable

Ethics approval

Not applicable

List of abbereviations

ABC transporter: ATP-binding cassette transporter, ALDH: aldehyde dehydrogenase, AMPK: AMP-activated protein kinase, ATG: autophagy-related gene, CD: cluster of differentiation, CMA: chaperone-mediation autophagy, CSCs: Cancer stem cells, EMT: epithelial-to-mesenchymal transition, LC3: light chain 3, MDR: Multidrug resistance, mTOR: mechanistic target of rapamycin

References

  1. Sell S, Leffert HL. Liver cancer stem cells. J Clin Oncol. 2008;26(17):2800-5. . ;:. PubMed Google Scholar
  2. Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. J Clin Invest. 2013;123(5):1911-8. . ;:. PubMed Google Scholar
  3. Ricci-Vitiani L, Fabrizi E, Palio E, De Maria R. Colon cancer stem cells. J Mol Med (Berl). 2009;87(11):1097-104. . ;:. PubMed Google Scholar
  4. Takaishi S, Okumura T, Wang TC. Gastric cancer stem cells. J Clin Oncol. 2008;26(17):2876-82. . ;:. PubMed Google Scholar
  5. Bai X, Ni J, Beretov J, Graham P, Li Y. Cancer stem cell in breast cancer therapeutic resistance. Cancer Treat Rev. 2018;69:152-63. . ;:. PubMed Google Scholar
  6. Crea F, Mathews LA, Farrar WL, Hurt EM. Targeting Prostate Cancer Stem Cells. Anti-Cancer Agents in Medicinal Chemistry. 2009;9:1105-13. . ;:. PubMed Google Scholar
  7. Dingli D, Michor F. Successful therapy must eradicate cancer stem cells. Stem Cells. 2006;24(12):2603-10. . ;:. PubMed Google Scholar
  8. Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5(1):8. . ;:. PubMed Google Scholar
  9. Sin WC, Lim CL. Breast cancer stem cells-from origins to targeted therapy. Stem Cell Investig. 2017;4:96. . ;:. PubMed Google Scholar
  10. Lou H, Dean M. Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene. 2007;26(9):1357-60. . ;:. PubMed Google Scholar
  11. Todaro M, Francipane MG, Medema JP, Stassi G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology. 2010;138(6):2151-62. . ;:. PubMed Google Scholar
  12. Wang T, Shigdar S, Gantier MP, Hou Y, Wang L, Li Y, et al. Cancer stem cell targeted therapy: progress amid controversies. Oncotarget. 2015;6(42):44191-206. . ;:. PubMed Google Scholar
  13. Deshmukh A, Deshpande K, Arfuso F, Newsholme P, Dharmarajan A. Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer. 2016;15(1):69. . ;:. PubMed Google Scholar
  14. Yu Z, Pestell TG, Lisanti MP, Pestell RG. Cancer stem cells. Int J Biochem Cell Biol. 2012;44(12):2144-51. . ;:. PubMed Google Scholar
  15. Najafi M, Mortezaee K, Majidpoor J. Cancer stem cell (CSC) resistance drivers. Life Sci. 2019;234:116781. . ;:. PubMed Google Scholar
  16. Olivares-Urbano MA, Grinan-Lison C, Marchal JA, Nunez MI. CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer. Cells. 2020;9(7). . ;:. PubMed Google Scholar
  17. Xu JL, Yuan L, Tang YC, Xu ZY, Xu HD, Cheng XD, et al. The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe? Front Cell Dev Biol. 2020;8:621428. . ;:. PubMed Google Scholar
  18. Rothe K, Porter V, Jiang X. Current Outlook on Autophagy in Human Leukemia: Foe in Cancer Stem Cells and Drug Resistance, Friend in New Therapeutic Interventions. Int J Mol Sci. 2019;20(3). . ;:. PubMed Google Scholar
  19. Usman RM, Razzaq F, Akbar A, Farooqui AA, Iftikhar A, Latif A, et al. Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance. Asia Pac J Clin Oncol. 2021;17(3):193-208. . ;:. PubMed Google Scholar
  20. Khan I, Baig MH, Mahfooz S, Rahim M, Karacam B, Elbasan EB, et al. Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma. Int J Mol Sci. 2021;22(3). . ;:. PubMed Google Scholar
  21. Kumar P, Zhang DM, Degenhardt K, Chen ZS. Autophagy and transporter-based multi-drug resistance. Cells. 2012;1(3):558-75. . ;:. PubMed Google Scholar
  22. Kwan BLY, Wai VWK. Autophagy in Multidrug-Resistant Cancers. 2016. . ;:. Google Scholar
  23. Li YJ, Lei YH, Yao N, Wang CR, Hu N, Ye WC, et al. Autophagy and multidrug resistance in cancer. Chin J Cancer. 2017;36(1):52. . ;:. PubMed Google Scholar
  24. Rajasekhar VK, Vemuri MC. History of Cancer Stem Cells. Regulatory Networks in Stem Cells. Stem Cell Biology and Regenerative Medicine2009. p. 495-503. . ;:. Google Scholar
  25. Capp JP. Cancer Stem Cells: From Historical Roots to a New Perspective. J Oncol. 2019;2019:5189232. . ;:. PubMed Google Scholar
  26. Houghton J, Morozov A, Smirnova I, Wang TC. Stem cells and cancer. Semin Cancer Biol. 2007;17(3):191-203. . ;:. PubMed Google Scholar
  27. Vaz AP, Ponnusamy MP, Batra SK. Cancer stem cells and therapeutic targets: an emerging field for cancer treatment. Drug Deliv Transl Res. 2013;3(2):113-20. . ;:. PubMed Google Scholar
  28. Hurt EM, Farrar WL. CHARACTERIZATION OF CANCER STEM CELLS. In: Farrar WL, editor. Cancer Stem Cells. the United States of America by Cambridge University Press, New York: Cambridge University Press; 2009. p. 2. . ;:. Google Scholar
  29. Gammaitoni L, Leuci V, Mesiano G, Giraudo L, Todorovic M, Carnevale-Schianca F, et al. Immunotherapy of cancer stem cells in solid tumors: initial findings and future prospective. Expert Opin Biol Ther. 2014;14(9). . ;:. PubMed Google Scholar
  30. Roesch A. Melanoma stem cells. J Dtsch Dermatol Ges. 2015;13(2):118-24. . ;:. PubMed Google Scholar
  31. Yadav AK, Desai NS. Cancer Stem Cells: Acquisition, Characteristics, Therapeutic Implications, Targeting Strategies and Future Prospects. Stem Cell Rev Rep. 2019;15(3):331-55. . ;:. PubMed Google Scholar
  32. Chen L-S, Wang A-X, Dong B, Pu K-F, Yuan L-H, Zhu Y-M. A new prospect in cancer therapy: targeting cancer stem cells to eradicate cancer. Chin J Cancer. 2012;31(12):564-72. . ;:. PubMed Google Scholar
  33. Deonarain MP, Kousparou CA, Epenetos AA. Antibodies targeting cancer stem cells: a new paradigm in immunotherapy? MAbs. 2009;1(1):12-25. . ;:. PubMed Google Scholar
  34. Velasco-Velazquez MA, Homsi N, De La Fuente M, Pestell RG. Breast cancer stem cells. Int J Biochem Cell Biol. 2012;44(4):573-7. . ;:. PubMed Google Scholar
  35. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-7. . ;:. PubMed Google Scholar
  36. Collins AT, Maitland NJ. Prostate cancer stem cells. Eur J Cancer. 2006;42(9):1213-8. . ;:. PubMed Google Scholar
  37. Dang HT, Budhu A, Wang XW. The origin of cancer stem cells. J Hepatol. 2014;60(6):1304-5. . ;:. PubMed Google Scholar
  38. Walcher L, Kistenmacher AK, Suo H, Kitte R, Dluczek S, Strauss A, et al. Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Front Immunol. 2020;11:1280. . ;:. PubMed Google Scholar
  39. Ayob AZ, Ramasamy TS. Cancer stem cells as key drivers of tumour progression. J Biomed Sci. 2018;25(1):20. . ;:. PubMed Google Scholar
  40. Holland JD, Klaus A, Garratt AN, Birchmeier W. Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol. 2013;25(2):254-64. . ;:. PubMed Google Scholar
  41. Xiao W, Gao Z, Duan Y, Yuan W, Ke Y. Notch signaling plays a crucial role in cancer stem-like cells maintaining stemness and mediating chemotaxis in renal cell carcinoma. J Exp Clin Cancer Res. 2017;36(1):41. . ;:. PubMed Google Scholar
  42. Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12(5):468-76. . ;:. PubMed Google Scholar
  43. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458(7239):776-9. . ;:. PubMed Google Scholar
  44. Korkaya H, Wicha MS. Selective Targeting of Cancer Stem Cells. Biodrugs. 2007;21(5):299-310. . ;:. PubMed Google Scholar
  45. Vermeulen L, Todaro M, de Sousa Mello F, Sprick MR, Kemper K, Perez Alea M, et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci U S A. 2008;105(36):13427-32. . ;:. PubMed Google Scholar
  46. Bajaj J, Diaz E, Reya T. Stem cells in cancer initiation and progression. J Cell Biol. 2020;219(1). . ;:. PubMed Google Scholar
  47. Han L, Shi S, Gong T, Zhang Z, Sun X. Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharmaceutica Sinica B. 2013;3(2):65-75. . ;:. Google Scholar
  48. Chao MP, Weissman IL, Park CY. Cancer Stem Cells: On the Verge of Clinical Translation. Laboratory Medicine. 2008;39(11):679-86. . ;:. Google Scholar
  49. Rycaj K, Tang DG. Cell-of-Origin of Cancer versus Cancer Stem Cells: Assays and Interpretations. Cancer Res. 2015;75(19):4003-11. . ;:. PubMed Google Scholar
  50. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104(3):973-8. . ;:. PubMed Google Scholar
  51. Aiken C, Werbowetski-Ogilvie T. Animal Models of Cancer Stem Cells: What are They Really Telling Us? Current Pathobiology Reports. 2013;1(2):91-9. . ;:. Google Scholar
  52. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65(23):10946-51. . ;:. PubMed Google Scholar
  53. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104(24):10158-63. . ;:. PubMed Google Scholar
  54. Du L, Wang H, He L, Zhang J, Ni B, Wang X, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 2008;14(21):6751-60. . ;:. PubMed Google Scholar
  55. Tirino V, Desiderio V, d'Aquino R, De Francesco F, Pirozzi G, Graziano A, et al. Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS One. 2008;3(10):e3469. . ;:. PubMed Google Scholar
  56. Lee CJ, Dosch J, Simeone DM. Pancreatic cancer stem cells. J Clin Oncol. 2008;26(17):2806-12. . ;:. PubMed Google Scholar
  57. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030-7. . ;:. PubMed Google Scholar
  58. Liu S, Wicha MS. Targeting breast cancer stem cells. J Clin Oncol. 2010;28(25):4006-12. . ;:. PubMed Google Scholar
  59. Maitland NJ, Collins AT. Prostate cancer stem cells: a new target for therapy. J Clin Oncol. 2008;26(17):2862-70. . ;:. PubMed Google Scholar
  60. Haraguchi N, Ishii H, Mimori K, Tanaka F, Ohkuma M, Kim HM, et al. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 2010;120(9):3326-39. . ;:. PubMed Google Scholar
  61. Prieto-Vila M, Takahashi RU, Usuba W, Kohama I, Ochiya T. Drug Resistance Driven by Cancer Stem Cells and Their Niche. Int J Mol Sci. 2017;18(12). . ;:. PubMed Google Scholar
  62. Rich JN. Cancer stem cells in radiation resistance. Cancer Res. 2007;67(19):8980-4. . ;:. PubMed Google Scholar
  63. OGAWA K, YOSHIOKA Y, ISOHASHI F, SEO Y, YOSHIDA K, YAMAZAKI H. Radiotherapy Targeting Cancer Stem Cells: Current Views and Future Perspectives. ANTICANCER RESEARCH. 2013;33:747-54. . ;:. Google Scholar
  64. Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, et al. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int. 2018;2018:5416923. . ;:. PubMed Google Scholar
  65. Alison MR, Lin WR, Lim SM, Nicholson LJ. Cancer stem cells: in the line of fire. Cancer Treat Rev. 2012;38(6):589-98. . ;:. PubMed Google Scholar
  66. Alisi A, Cho WC, Locatelli F, Fruci D. Multidrug resistance and cancer stem cells in neuroblastoma and hepatoblastoma. Int J Mol Sci. 2013;14(12):24706-25. . ;:. PubMed Google Scholar
  67. Kozovska Z, Gabrisova V, Kucerova L. Colon cancer: cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother. 2014;68(8):911-6. . ;:. PubMed Google Scholar
  68. Lu C, Shervington A. Chemoresistance in gliomas. Mol Cell Biochem. 2008;312(1-2):71-80. . ;:. PubMed Google Scholar
  69. Kuppa SS, Murph MM. Platinum Agents, Taxanes and PARP Inhibitors: The Ovarian Cancer Drug Formulary and Molecular Mechanisms of Chemoresistance Emergence. Ovarian Cancer: SM Journal; 2016. . ;:. Google Scholar
  70. Beier D, Schulz JB, Beier CP. Chemoresistance of glioblastoma cancer stem cells - much more complex than expected. Molecular Cancer. 2011;10(128). . ;:. PubMed Google Scholar
  71. Sorensen MD, Fosmark S, Hellwege S, Beier D, Kristensen BW, Beier CP. Chemoresistance and chemotherapy targeting stem-like cells in malignant glioma. Adv Exp Med Biol. 2015;853:111-38. . ;:. PubMed Google Scholar
  72. Wei J, Wu A, Kong L-Y, Wang Y, Fuller G, Fokt I, et al. Hypoxia potentiates glioma-mediated immunosuppression. PloS one. 2011;6(1):e16195. . ;:. PubMed Google Scholar
  73. Chen W, Qin Y, Liu S. Cytokines, breast cancer stem cells (BCSCs) and chemoresistance. Clin Transl Med. 2018;7(1):27. . ;:. PubMed Google Scholar
  74. Buhagiar A, Ayers D. Chemoresistance, cancer stem cells, and miRNA influences: the case for neuroblastoma. Anal Cell Pathol (Amst). 2015;2015:150634. . ;:. PubMed Google Scholar
  75. Kim JK, Jeon HY, Kim H. The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res. 2015;38(3):389-401. . ;:. PubMed Google Scholar
  76. Nunes T, Hamdan D, Leboeuf C, El Bouchtaoui M, Gapihan G, Nguyen TT, et al. Targeting Cancer Stem Cells to Overcome Chemoresistance. Int J Mol Sci. 2018;19(12). . ;:. PubMed Google Scholar
  77. Maugeri-Sacca M, Vigneri P, De Maria R. Cancer stem cells and chemosensitivity. Clin Cancer Res. 2011;17(15):4942-7. . ;:. PubMed Google Scholar
  78. Ji X, Lu Y, Tian H, Meng X, Wei M, Cho WC. Chemoresistance mechanisms of breast cancer and their countermeasures. Biomed Pharmacother. 2019;114:108800. . ;:. PubMed Google Scholar
  79. Li S, Sun W, Wang H, Zuo D, Hua Y, Cai Z. Research progress on the multidrug resistance mechanisms of osteosarcoma chemotherapy and reversal. Tumour Biol. 2015;36(3):1329-38. . ;:. PubMed Google Scholar
  80. Zheng H-C. The molecular mechanisms of chemoresistance in cancers. Oncotarget. 2017;8(35):59950-64. . ;:. PubMed Google Scholar
  81. David W Chan MXL, Ys Ngan H. Mechanisms of Chemoresistance in Human Ovarian Cancer at a Glance. Gynecology & Obstetrics. 2012;02(03). . ;:. Google Scholar
  82. Thomas ML, Coyle KM, Sultan M, Vaghar-Kashani A, Marcato P. Chemoresistance in Cancer Stem Cells and Strategies to Overcome Resistance. Chemotherapy: Open Access. 2014;03(01). . ;:. Google Scholar
  83. Thomas ML, Coyle KM, Sultan M, Marcato P. Cancer Stem Cells and Chemoresistance: Strategies to Overcome Therapeutic Resistance. 2015:477-518. . ;:. Google Scholar
  84. Begicevic RR, Falasca M. ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance. Int J Mol Sci. 2017;18(11). . ;:. PubMed Google Scholar
  85. Dean M. ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia. 2009;14(1):3-9. . ;:. PubMed Google Scholar
  86. He H, Ni J, Huang JUN. Molecular mechanisms of chemoresistance in osteosarcoma (Review). Oncology Letters. 2014;7(5):1352-62. . ;:. PubMed Google Scholar
  87. Ferreira JA, Peixoto A, Neves M, Gaiteiro C, Reis CA, Assaraf YG, et al. Mechanisms of cisplatin resistance and targeting of cancer stem cells: Adding glycosylation to the equation. Drug Resist Updat. 2016;24:34-54. . ;:. PubMed Google Scholar
  88. Gillet JP, Gottesman MM. Mechanisms of multidrug resistance in cancer. Methods Mol Biol. 2010;596:47-76. . ;:. PubMed Google Scholar
  89. Sun S, Lee D, Leung GKK. Chemoresistance in Glioma. 2013:243-70. . ;:. Google Scholar
  90. Abdullah LN, Chow EK-H. Mechanisms of chemoresistance in cancer stem cells. Clinical and Translational Medicine. 2013;2(1). . ;:. PubMed Google Scholar
  91. Reed JC. BCL-2 AND CHEMORESISTANCE IN CANCER. In: Kellen JA, editor. Alternative Mechanisms of Multidrug Resistance in Cancer. 1. Birkhäuser Boston: Birkhäuser Boston; 1995. p. 191-214. . ;:. Google Scholar
  92. Verma H, Singh Bahia M, Choudhary S, Kumar Singh P, Silakari O. Drug metabolizing enzymes-associated chemo resistance and strategies to overcome it. Drug Metab Rev. 2019;51(2):196-223. . ;:. PubMed Google Scholar
  93. Pathania S, Bhatia R, Baldi A, Singh R, Rawal RK. Drug metabolizing enzymes and their inhibitors' role in cancer resistance. Biomed Pharmacother. 2018;105:53-65. . ;:. PubMed Google Scholar
  94. Bellamy WT. THE ROLE OF GLUTATHIONE S-TRANSFERASES IN DRUG RESISTANCE. In: Kellen JA, editor. Alternative Mechanisms of Multidrug Resistance in Cancer. Birkhauser Boston: Birkhauser Boston; 1995. p. 31-65. . ;:. Google Scholar
  95. Allain EP, Rouleau M, Levesque E, Guillemette C. Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression. Br J Cancer. 2020;122(9):1277-87. . ;:. PubMed Google Scholar
  96. Milito AD, Fais S. Tumor acidity, chemoresistance and proton pump inhibitors. Future Oncol. 2005;1(6):779-86. . ;:. PubMed Google Scholar
  97. Wojtkowiak JW, Verduzco D, Schramm KJ, Gillies RJ. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol Pharm. 2011;8(6):2032-8. . ;:. PubMed Google Scholar
  98. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221(1):3-12. . ;:. PubMed Google Scholar
  99. Ktistakis NT. In praise of M. Anselmier who first used the term "autophagie" in 1859. Taylor & Francis; 2017. . ;:. PubMed Google Scholar
  100. Mizushima N. A brief history of autophagy from cell biology to physiology and disease. Nature cell biology. 2018;20(5):521-7. . ;:. PubMed Google Scholar
  101. Sheng R, Qin Z-H. History and Current Status of Autophagy Research. Adv Exp Med Biol. 2019;1206:3-37. . ;:. PubMed Google Scholar
  102. Majeski AE, Dice JF. Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol. 2004;36(12):2435-44. . ;:. PubMed Google Scholar
  103. Kihara A, Noda T, Ishihara N, Ohsumi Y. Two Distinct Vps34 Phosphatidylinositol 3-Kinase complexes function in autophagy and carboxypeptidase Y Sorting inSaccharomyces cerevisiae. Journal of Cell Biology. 2001;152(3):519-30. . ;:. PubMed Google Scholar
  104. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402(6762):672-6. . ;:. PubMed Google Scholar
  105. Wijshake T, Zou Z, Chen B, Zhong L, Xiao G, Xie Y, et al. Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin. Proceedings of the National Academy of Sciences. 2021;118(5). . ;:. PubMed Google Scholar
  106. Jiang M, Liu K, Luo J, Dong Z. Autophagy is a renoprotective mechanism during in vitro hypoxia and in vivo ischemia-reperfusion injury. The American journal of pathology. 2010;176(3):1181-92. . ;:. PubMed Google Scholar
  107. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proceedings of the National Academy of Sciences. 2003;100(25):15077-82. . ;:. PubMed Google Scholar
  108. Ding W-X, Yin X-M. Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy. 2008;4(2):141-50. . ;:. PubMed Google Scholar
  109. Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. Journal of Biological Chemistry. 2006;281(20):14474-85. . ;:. PubMed Google Scholar
  110. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. α-Synuclein is degraded by both autophagy and the proteasome. Journal of Biological Chemistry. 2003;278(27):25009-13. . ;:. PubMed Google Scholar
  111. Kruse KB, Dear A, Kaltenbrun ER, Crum BE, George PM, Brennan SO, et al. Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. The American journal of pathology. 2006;168(4):1299-308. . ;:. PubMed Google Scholar
  112. Eskelinen E-L. New insights into the mechanisms of macroautophagy in mammalian cells. International review of cell and molecular biology. 2008;266:207-47. . ;:. PubMed Google Scholar
  113. Li W-w, Li J, Bao J-k. Microautophagy: lesser-known self-eating. Cellular and molecular life sciences. 2012;69(7):1125-36. . ;:. PubMed Google Scholar
  114. Majeski AE, Dice JF. Mechanisms of chaperone-mediated autophagy. The international journal of biochemistry & cell biology. 2004;36(12):2435-44. . ;:. PubMed Google Scholar
  115. Cuervo AM, Wong E. Chaperone-mediated autophagy: roles in disease and aging. Cell research. 2014;24(1):92-104. . ;:. PubMed Google Scholar
  116. Cuervo AM, Knecht E, Terlecky SR, Dice JF. Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation. American Journal of Physiology-Cell Physiology. 1995;269(5):C1200-C8. . ;:. PubMed Google Scholar
  117. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nature reviews Molecular cell biology. 2011;12(1):9-14. . ;:. PubMed Google Scholar
  118. Bąkowska-Żywicka K, Tyczewska A. Ribophagy-the novel degradation system of the ribosome. biotechnologia. 2009;1(84):99-103. . ;:. Google Scholar
  119. Bauckman KA, Owusu-Boaitey N, Mysorekar IU. Selective autophagy: xenophagy. Methods. 2015;75:120-7. . ;:. PubMed Google Scholar
  120. Singh R, Cuervo AM. Lipophagy: connecting autophagy and lipid metabolism. International journal of cell biology. 2012;2012. . ;:. PubMed Google Scholar
  121. Wu S, Wang X, Chen J, Chen Y. Autophagy of cancer stem cells is involved with chemoresistance of colon cancer cells. Biochem Biophys Res Commun. 2013;434(4):898-903. . ;:. PubMed Google Scholar
  122. Yang HZ, Ma Y, Zhou Y, Xu LM, Chen XJ, Ding WB, et al. Autophagy contributes to the enrichment and survival of colorectal cancer stem cells under oxaliplatin treatment. Cancer Lett. 2015;361(1):128-36. . ;:. PubMed Google Scholar
  123. You Y, Bi FF, Jiang Y, Xu YT, An YY, Li D, et al. BRCA1 affects the resistance and stemness of SKOV3-derived ovarian cancer stem cells by regulating autophagy. Cancer Med. 2019;8(2):656-68. . ;:. PubMed Google Scholar
  124. LI L-Q, PAN D, ZHANG S-W, XIE D-Y-, ZHENG X-L, CHEN H. Autophagy regulates chemoresistance of gastric cancer stem cells via the Notch signaling pathway. European Review for Medical and Pharmacological Sciences. 2018;22:3402-7. . ;:. Google Scholar
  125. White E, DiPaola RS. The double-edged sword of autophagy modulation in cancer. Clin Cancer Res. 2009;15(17):5308-16. . ;:. PubMed Google Scholar
  126. Yun CW, Jeon J, Go G, Lee JH, Lee SH. The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy. Int J Mol Sci. 2020;22(1). . ;:. PubMed Google Scholar
  127. Denton D, Nicolson S, Kumar S. Cell death by autophagy: facts and apparent artefacts. Cell Death Differ. 2012;19(1):87-95. . ;:. PubMed Google Scholar
  128. Liu Y, Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 2015;22(3):367-76. . ;:. PubMed Google Scholar
  129. Jung S, Jeong H, Yu SW. Autophagy as a decisive process for cell death. Exp Mol Med. 2020;52(6):921-30. . ;:. PubMed Google Scholar
  130. Kumar D, Shankar S, Srivastava RK. Rottlerin-induced autophagy leads to the apoptosis in breast cancer stem cells: molecular mechanisms. Molecular Cancer. 2013;12(171). . ;:. PubMed Google Scholar
  131. Kumar D, Shankar S, Srivastava RK. Rottlerin induces autophagy and apoptosis in prostate cancer stem cells via PI3K/Akt/mTOR signaling pathway. Cancer Lett. 2014;343(2):179-89. . ;:. PubMed Google Scholar
  132. Singh BN, Kumar D, Shankar S, Srivastava RK. Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochem Pharmacol. 2012;84(9):1154-63. . ;:. PubMed Google Scholar
  133. Xia P, Xu X-Y. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res. 2015;5(5):1602-9. . ;:. Google Scholar
  134. Kaewpiboon C, Surapinit S, Malilas W, Moon J, Phuwapraisirisan P, Tip-Pyang S, et al. Feroniellin A-induced autophagy causes apoptosis in multidrug-resistant human A549 lung cancer cells. Int J Oncol. 2014;44(4):1233-42. . ;:. PubMed Google Scholar
  135. Xu Z, Jiang H, Zhu Y, Wang H, Jiang J, Chen L, et al. Cryptotanshinone induces ROS-dependent autophagy in multidrug-resistant colon cancer cells. Chem Biol Interact. 2017;273:48-55. . ;:. PubMed Google Scholar
  136. Pagotto A, Pilotto G, Mazzoldi EL, Nicoletto MO, Frezzini S, Pasto A, et al. Autophagy inhibition reduces chemoresistance and tumorigenic potential of human ovarian cancer stem cells. Cell Death Dis. 2017;8(7):e2943. . ;:. PubMed Google Scholar
  137. Hao C, Liu G, Tian G. Autophagy inhibition of cancer stem cells promotes the efficacy of cisplatin against non-small cell lung carcinoma. Ther Adv Respir Dis. 2019;13:1753466619866097. . ;:. PubMed Google Scholar
  138. Fesler A, Guo S, Liu H, Wu N, Ju J. Overcoming chemoresistance in cancer stem cells with the help of microRNAs in colorectal cancer. Epigenomics. 2017;11(6):793-6. . ;:. PubMed Google Scholar
  139. Liao M, Wang C, Yang B, Huang D, Zheng Y, Wang S, et al. Autophagy Blockade by Ai Du Qing Formula Promotes Chemosensitivity of Breast Cancer Stem Cells Via GRP78/beta-Catenin/ABCG2 Axis. Front Pharmacol. 2021;12:659297. . ;:. PubMed Google Scholar
  140. Sun R, Shen S, Zhang YJ, Xu CF, Cao ZT, Wen LP, et al. Nanoparticle-facilitated autophagy inhibition promotes the efficacy of chemotherapeutics against breast cancer stem cells. Biomaterials. 2016;103:44-55. . ;:. PubMed Google Scholar
  141. Bousquet G, Bouchtaoui ME, Sophie T, Leboeuf C, Bazelaire Cd, Ratajczak P, et al. Targeting autophagic cancer stem-cells to reverse chemoresistance in human triple negative breast cancer. Oncotarget. 2017;8(21):35205-21. . ;:. PubMed Google Scholar
  142. Du X, Liu B, Luan X, Cui Q, Li L. miR-30 decreases multidrug resistance in human gastric cancer cells by modulating cell autophagy. Exp Ther Med. 2018;15(1):599-605. . ;:. Google Scholar
  143. Bhardwaj M, Cho HJ, Paul S, Jakhar R, Khan I, Lee S-J, et al. Vitexin induces apoptosis by suppressing autophagy in multidrug resistant colorectal cancer cells. Oncotarget. 2018;9(3):3278-91. . ;:. PubMed Google Scholar
  144. Ahn JH, Lee M. Suppression of autophagy sensitizes multidrug resistant cells towards Src tyrosine kinase specific inhibitor PP2. Cancer Lett. 2011;310(2):188-97. . ;:. PubMed Google Scholar
  145. Xiao-ai L, Bei W, Xiao-hong X, Lei P, Bin W, Xiao-xue D, et al. Curcumin re-sensitizes multidrug resistant (MDR) breast cancer to cisplatin through inducing autophagy by decreasing CCAT1 expression. RSC Advances. 2017;7(53):33572-9. . ;:. Google Scholar
  146. Chen S, Wu J, Jiao K, Wu Q, Ma J, Chen D, et al. MicroRNA-495-3p inhibits multidrug resistance by modulating autophagy through GRP78/mTOR axis in gastric cancer. Cell Death Dis. 2018;9(11):1070. . ;:. PubMed Google Scholar


Author's Affiliation

  • Nhan Ngo-The Tran

    Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City, Viet Nam; Vietnam National University, Ho Chi Minh City, Viet Nam
    Google Scholar Pubmed

  • Khan Dinh Bui

    Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City, Viet Nam; Vietnam National University, Ho Chi Minh City, Viet Nam
    Google Scholar Pubmed

  • Phuc Van Pham

    Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City, Viet Nam; Vietnam National University, Ho Chi Minh City, Viet Nam; Stem Cell Institute, University of Science, Ho Chi Minh City, Viet Nam; Laboratory of Cancer Research, University of Science, Ho Chi Minh City, Viet Nam
    Email I'd for correspondance: phucpham@sci.edu.vn
    Google Scholar Pubmed https://orcid.org/0000-0001-7254-0717
Article Details

Issue: Vol 25 No 4 (2022)
Page No.: 2625-2636
Published: Jan 27, 2023
Section: Section: HEALTH SCIENCES
DOI: https://doi.org/10.32508/stdj.v25i4.4036

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Copyright: The Authors. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 How to Cite
Tran, N. N.-T., Bui, K. D., & Pham, P. (2023). The relationship between autophagy and multidrug resistance in cancer stem cells. Science and Technology Development Journal, 25(4), 2625-2636. https://doi.org/https://doi.org/10.32508/stdj.v25i4.4036


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