The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy
Abstract
:1. Introduction
2. The Basic Mechanism of Autophagy
2.1. Macroautophagy
2.2. Mitophagy
2.3. Chaperone-Mediated Autophagy
3. The Bipolar Role of Autophagy in Cancer
3.1. The Mechanism of Autophagy in Tumorigenesis
3.2. The Relationship between Autophagy and Metastasis
3.3. The Roles of Autophagy in Chemoresistance
3.4. Autophagy in Cancer Stem Cells
4. Targeting Autophagy as an Anticancer Therapy
4.1. The Effect of Autophagy Inhibitors in Anticancer Therapy
4.2. The Effect of Autophagy Inducers in Anticancer Therapy
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Compound | Combination Treatment | Cancer Type | Experimental Model | Function | Reference |
---|---|---|---|---|---|
ATG5 siRNA Beclin-1 siRNA | Cisplatin | Lung cancer (A549) | In vitro | Inhibition of autophagy Restore the sensitivity of cisplatin Enhancement of cisplatin-mediated apoptosis Upregulation of caspase activity Reduction of cell viability | [155] |
3-MA | Colorectal cancer (HCT116) | In vitro | Promotion of hypoxia-mediated apoptosis | [9] | |
Enzalutamide | Chloroquine 3-MA Bafilomycin A1 | Bladder cancer (J82, T24, and UMUC3) | In vitro /In vivo | Restores the sensitivity against ENZ Reduction of autophagy and tumor growth Induction of apoptosis | [156] |
Atorvastatin | 3-MA Bafilomycin A1 | Cervical cancer (SiHa and Caski) | In vitro /In vivo | Enhancement of ATO-mediated apoptosis Reduction of autophagy | [157] |
Reactivation of p53 and induction of tumor cell apoptosis (RITA) | 3-MA | Head and neck cancer (AMC-HN2-10) | In vitro /In vivo | Promotion of therapeutic effects of cisplatin resistance or RITA-resistant cancer Inhibition of autophagy Induction of apoptosis | [158] |
Bafilomycin A1 | Pediatric B-cell acute lymphoblastic leukemia (RS4;11, NB4, HL-60, K562 and BV173) | In vitro /In vivo | Therapeutic effect at low concentrations Inhibition of autophagy Targeting mitochondria Induction of apoptosis | [160] | |
Cisplatin | Bafilomycin A1 chloroquine | Bladder cancer (5637 and T25) | In vitro | Enhancement of the therapeutic effect to cisplatin Inhibition of autophagy | [161] |
Bafilomycin A1 | 5-FU | Gastric cancer (SGC-7901) | In vitro | Inhibition of cell viability, colony formation, invasion, and migration Enhancement of apoptosis Suppression of autophagy | [162] |
Chloroquine and hydroxychloroquine | Bladder cancer (RT4, 5637, T24, PC3, and MCF-7) | In vitro | Inhibition of autophagy Induction of apoptosis | [163] | |
Recombinant Bacillus caldovelox arginase mutant | Chloroquine | Cervical cancer (Hela, ME-180, C-33A and SiHa) | In vitro | Reduction of tumor growth Increased apoptosis and cell cycle arrest Reduction of autophagy | [164] |
SBI-0206965 | mTOR inhibitors | Prostate cancer Lung cancer glioblastoma (HEK-293T, U87MG, PC3 and A549) | In vitro | Inhibition of autophagy Reduction of cell survival Promotion of cell death | [169] |
SAR405 | Everolimus | Renal cancer | In vitro | Inhibition of autophagy Suppression of catalytic activity of PI3KC3 Reduction of cell proliferation | [170] |
SB02024 | Sunitinib Erlotinib | Breast cancer (HOS and MDA-MB-231) | In vitro /In vivo | Inhibition of autophagy Improvement of sensitivity to Sunitinib and Erlotinib | [171] |
Doxorubicin | BNIP3L | Colorectal cancer (HCT8) | In vitro | Inhibition of mitophagy Restoration of the sensitivity of doxorubicin | [173] |
Tanshinone IIA | 3-MA | Colorectal cancer (SW837 and SW480) | In vitro | Reduction of mitophagy Promotion of mitochondrial apoptosis Decrease of AMPK and Parkin | [174] |
Mitochondrial division inhibitor 1 | Silibinin | Breast cancer (MCF7 and MDA-MB-231) | In vitro | Inhibition of DRP1 and Dynamin I Decrease of mitophagy Enhancement of silibinin-induced apoptosis | [175] |
Compound | Combination Treatment | Cancer Type | Experimental Model | Function | Reference |
---|---|---|---|---|---|
Quercetin | ABT-737 ABT-263 | Leukemic cell lines B-cells (HG3) | In vitro | Inhibition of the PI3K/AKT pathway Induction of autophagy Restoration of the sensitivity to ABT-737 | [178] |
ABT-737 ABT-263 ABT-199 | Glioblastoma cells | In vitro | Induction of autophagic cell death Interruption of the interaction with Beclin-1 and Bcl2 | [179] | |
Metformin | 3-MA Chloroquine | Endometrial cancer cells (Ishikawa cells) | In vitro | Inhibition of cell viability and proliferation Increased cell cycle arrest and apoptosis Enhancement of autophagy | [180] |
TRAIL-resistant lung cancer (A549, Calu-3 and HCC-15) | In vitro | Promotion of autophagic flux Accumulation of LC3-II Reduction of p62 | [181] | ||
Salinomycin | Melanoma cells (M7, M8, M21, M29, SK-MEL-1, SK-MEL-12 and A375) | In vitro /In vivo | Induction of cell death Accumulation of abnormal mitochondria Increased ER stress | [182] | |
Esomeprazole | Paclitaxel | Non-small cell lung cancer (A549) | In vitro | Restoration of the sensitivity to paclitaxel Inhibition of V-ATPase and cell proliferation Enhancement of autophagy | [183] |
AZD3463 | Rapamycin | Breast cancer (MCF7) | In vitro | AZD3463: ALK/IGF1R inhibitor Promotion of apoptosis and autophagy Reduction of cell proliferation | [184] |
Isoliquiritigenin | Hepatocellular carcinoma (MHCC97-H, LO2 and SMMC7721) | In vitro /In vivo | Inhibition of cell growth Enhancement of apoptosis and autophagy Modulation of the PI3K/AKT/mTOR pathway | [185] | |
RAD-001 | Paclitaxel | Endometrial cancer cells (Ishikawa and HEC-1A) | In vitro | Induction of sensitivity to paclitaxel Promotion of apoptosis and autophagy Downregulation of AKT/mTOR Accumulation of LC3 | [188] |
Rapamycin | Pancreatic carcinoma (PC-2) | In vitro | Activation of Beclin-1 Induction of autophagic vacuoles Inhibition of proliferation and induction of apoptosis | [189] | |
Everolimus | Hydroxychloroquine | Lymphangioleiomyomatosis | Phase I /Complete | Investigation of the effect on the regulation of autophagy in lymphangioleiomyomatosis | NCT01687179 |
Rapamune | Hydroxychloroquine | Advanced cancer | Phase I /Active | Investigation of the effect on the regulation of autophagy in advanced cancer | NCT01266057 |
NCT Number | Title | Status | Cancer Type | Drugs | Phase |
---|---|---|---|---|---|
NCT03037437 | Sorafenib Induced Autophagy Using Hydroxychloroquine in Hepatocellular Cancer | Recruiting | Hepatocellular cancer | Sorafenib Hydroxychloroquine | Phase II |
NCT01649947 | Modulation of Autophagy in Patients With Advanced/Recurrent Non-small Cell Lung Cancer | Complete | Non-small cell lung cancer | Paclitaxel Carboplatin Hydroxychloroquine Bevacizumab | Phase II |
NCT04214418 | Study of Combination Therapy With the MEK Inhibitor, Cobimetinib, Immune Checkpoint Blockade, Atezolizumab, and the AUTOphagy Inhibitor, Hydroxychloroquine in KRAS-mutated Advanced Malignancies | Recruiting | Gastrointestinal cancer | Cobimetinib Hydroxychloroquine Atezolizumab | Phase I/II |
NCT04333914 | Prospective Study in Patients With Advanced or Metastatic Cancer and SARS-CoV-2 Infection | Recruiting | Advanced or Metastatic Hematological or Solid Tumor | Autophagy inhibitor (GNS651) Avdoralimab Monalizumab | Phase II |
NCT01206530 | FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer | Complete | Rectal and colon cancer | Hydroxychloroquine Oxaliplatin Leucovorin | Phase I/II |
NCT03774472 | Hydroxychloroquine, Palbociclib, and Letrozole Before Surgery in Treating Participants With Estrogen Receptor Positive, HER2 Negative Breast Cancer | Recruiting | Breast cancer | Hydroxychloroquine Letrozole Palbociclib | Phase I/II |
NCT02316340 | Vorinostat Plus Hydroxychloroquine Versus Regorafenib in Colorectal Cancer | Complete | Colorectal cancer | Voriostat Hydroxychloroquine Regorafenib | Phase II |
NCT04132505 | Binimetinib and Hydroxychloroquine in Treating Patients With KRAS Mutant Metastatic Pancreatic Cancer | Recruiting | Pancreatic cancer | Binimetinib Hydroxychloroquine | Phase I |
NCT04524702 | Paricalcitol and Hydroxychloroquine in Combination With Gemcitabine and Nab-Paclitaxel for the Treatment of Advanced or Metastatic Pancreatic Cancer | Recruiting | Pancreatic cancer | Cemcitabine Hydroxychloroquine Nab-paclitaxel Paricaitol | Phase II |
NCT03377179 | A Study of ABC294640 (Yeliva ®) Alone and in Combination With Hydroxychloroquine Sulfate in Treatment of Patients With Advanced Cholangiocarcinoma | Recruiting | Cholangiocarcinoma | ABC294640 Hydroxychloroquine | Phase II |
NCT04163107 | Combined Carfilzomib and Hydroxychloroquine in Patients With Relapsed/Refractory Multiple Myeloma | Recruiting | Multiple Myeloma | Hydroxychloroquine Carfizomib Dexamethasone | Phase I |
NCT03598595 | Gemcitabine, Docetaxel, and Hydroxychloroquine in Treating Participants With Recurrent or Refractory Osteosarcoma | Recruiting | Osteosarcoma | Docetaxel Gemcitabine Hydroxychloroquine | Phase I/II |
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Yun, C.W.; Jeon, J.; Go, G.; Lee, J.H.; Lee, S.H. The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy. Int. J. Mol. Sci. 2021, 22, 179. https://doi.org/10.3390/ijms22010179
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. International Journal of Molecular Sciences. 2021; 22(1):179. https://doi.org/10.3390/ijms22010179
Chicago/Turabian StyleYun, Chul Won, Juhee Jeon, Gyeongyun Go, Jun Hee Lee, and Sang Hun Lee. 2021. "The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy" International Journal of Molecular Sciences 22, no. 1: 179. https://doi.org/10.3390/ijms22010179
APA StyleYun, C. W., Jeon, J., Go, G., Lee, J. H., & Lee, S. H. (2021). The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy. International Journal of Molecular Sciences, 22(1), 179. https://doi.org/10.3390/ijms22010179