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Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Research Article

Pseudo-ginsenoside Rh2 Induces Protective Autophagy in Hepatocellular Carcinoma HepG2 Cells

Author(s): Fuyuan Zhang, Huali Xu, Rui Xia, Ping Yu, Yuangeng Li, Xiaofeng Yu and Dayun Sui*

Volume 16, Issue 4, 2021

Published on: 06 June, 2021

Page: [521 - 532] Pages: 12

DOI: 10.2174/1574892816666210607100239

Price: $65

Abstract

Background: Pseudo-ginsenoside-Rh2 (pseudo-G-Rh2), a novel derivative of ginsenoside Rh2, is reported to exert a pro-apoptotic effect on various malignancies. However, whether this anti-cancer action of pseudo-G-Rh2 involves autophagy remains to be determined and explored.

Objective: The objective of this study was to investigate the pseudo-G-Rh2-induced apoptosis and autophagy and the underlying mechanism.

Methods: In the present study, the MTT assay was used for evaluating cell viability, and the lactate dehydrogenase (LDH) assay was performed to assess cell toxicity. Autophagy evaluation was performed using monodansylcadaverine (MDC) staining and transmission electron microscopy (TEM). The levels of autophagy-associated and apoptosis-associated proteins were determined using Western blotting. The Annexin V-FITC/propidium iodide (PI) assay was used to assess apoptosis.

Results: The Annexin V-FITC/PI assay revealed that the percentage of apoptotic cells in HepG2 cells at concentrations 0, 20, 40, and 60 μM was 3.75%±1.37%, 5.70%±1.04%, 12.30%±2.10%, and 34.26%±4.73%, respectively. Pseudo-G-Rh2 was observed to significantly increase the expressions of BAX, cleaved-caspase-3, and cleaved-caspase-9, while it decreased the Bcl-2 expression. MDC and TEM analysis revealed that pseudo-G-Rh2 at concentrations 20, 40, and 60 μM significantly facilitated the accumulation of autophagosomes and autolysosomes within the HepG2 cells. Moreover, pseudo-G-Rh2 significantly increased the expressions of LC3 II/LC3 I and Beclin-1 and decreased the expression of p62. The Annexin V-FITC/PI assay also revealed that in comparison to the pseudo-G-Rh2 group, the concurrent treatment with pseudo-G-Rh2 and an autophagy inhibitor (CQ or 3-MA) significantly induced distinct apoptosis. In addition, pseudo-G-Rh2 activated AMPK and inhibited the PI3K/Akt/mTOR pathway in a concentration-dependent manner. Pseudo- G-Rh2 is similar to the current patents, which enhanced its anti-cancer activity by combining with autophagy inhibitors.

Conclusion: Pseudo-G-Rh2 could induce protective autophagy in HepG2 cells, at least in part, via AMPK and the PI3K/Akt/mTOR pathway.

Keywords: AMPK, apoptosis, autophagy, HepG2 cells, mTOR, pseudo-ginsenoside Rh2.

[1]
[2]
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379(9822): 1245-55.
[http://dx.doi.org/10.1016/S0140-6736(11)61347-0] [PMID: 22353262]
[3]
Spirina LV, Avgustinovich AV, Afanas’ev SG, et al. Molecular mechanism of resistance to chemotherapy in gastric cancers, the role of autophagy. Curr Drug Targets 2020; 21(7): 713-21.
[http://dx.doi.org/10.2174/1389450120666191127113854] [PMID: 31775598]
[4]
Selvakumar JN, Chandrasekaran SD, Doss GPC, Kumar TD. Inhibition of the ATPase domain of human topoisomerase IIa on HepG2 cells by 1, 2-benzenedicarboxylic Acid, Mono (2-ethylhexyl) ester: Molecular docking and dynamics simulations. Curr Cancer Drug Targets 2019; 19(6): 495-503.
[http://dx.doi.org/10.2174/1568009619666181127122230] [PMID: 30479215]
[5]
Barman J, Kumar R, Saha G, Tiwari K, Dubey VK. Apoptosis: Mediator molecules, interplay with other cell death processes and therapeutic potentials. Curr Pharm Biotechnol 2018; 19(8): 644-63.
[http://dx.doi.org/10.2174/1389201019666180821093239] [PMID: 30129409]
[6]
Matsuzawa-Ishimoto Y, Hwang S, Cadwell K. Autophagy and Inflammation. Annu Rev Immunol 2018; 36: 73-101.
[http://dx.doi.org/10.1146/annurev-immunol-042617-053253] [PMID: 29144836]
[7]
Baehrecke EH. Autophagy: dual roles in life and death? Nat Rev Mol Cell Biol 2005; 6(6): 505-10.
[http://dx.doi.org/10.1038/nrm1666] [PMID: 15928714]
[8]
Vlada CA, Kim JS, Behrns KE. Autophagy: self-preservation through cannibalism of proteins and organelles. Surgery 2015; 157(1): 1-5.
[http://dx.doi.org/10.1016/j.surg.2014.07.014] [PMID: 25482459]
[9]
Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest 2005; 115(10): 2679-88.
[http://dx.doi.org/10.1172/JCI26390] [PMID: 16200202]
[10]
Doherty J, Baehrecke EH. Life, death and autophagy. Nat Cell Biol 2018; 20(10): 1110-7.
[http://dx.doi.org/10.1038/s41556-018-0201-5] [PMID: 30224761]
[11]
Li YJ, Lei YH, Yao N, et al. Autophagy and multidrug resistance in cancer. Chin J Cancer 2017; 36(1): 52.
[http://dx.doi.org/10.1186/s40880-017-0219-2] [PMID: 28646911]
[12]
Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132(1): 27-42.
[http://dx.doi.org/10.1016/j.cell.2007.12.018] [PMID: 18191218]
[13]
Russo M, Russo GL. Autophagy inducers in cancer. Biochem Pharmacol 2018; 153: 51-61.
[http://dx.doi.org/10.1016/j.bcp.2018.02.007] [PMID: 29438677]
[14]
Li LJ, Wang YL, Yuan LQ, et al. Autophagy inhibition in childhood nephroblastoma and the therapeutic significance. Curr Cancer Drug Targets 2018; 18(3): 295-303.
[http://dx.doi.org/10.2174/1568009617666170330105433] [PMID: 28359249]
[15]
Bento CF, Renna M, Ghislat G, et al. Mammalian autophagy: How does it work? Annu Rev Biochem 2016; 85: 685-713.
[http://dx.doi.org/10.1146/annurev-biochem-060815-014556] [PMID: 26865532]
[16]
Wong JH, Sze SCW, Ng TB, et al. Apoptosis and anti-cancer drug discovery: The power of medicinal fungi and plants. Curr Med Chem 2018; 25(40): 5613-30.
[http://dx.doi.org/10.2174/0929867324666170720165005] [PMID: 28730971]
[17]
Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 2018; 19(2): 121-35.
[http://dx.doi.org/10.1038/nrm.2017.95] [PMID: 28974774]
[18]
Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 2015; 125(1): 25-32.
[http://dx.doi.org/10.1172/JCI73939] [PMID: 25654547]
[19]
Kim GN, Jang HD. Protective mechanism of quercetin and rutin using glutathione metabolism on HO-induced oxidative stress in HepG2 cells. Ann N Y Acad Sci 2009; 1171: 530-7.
[http://dx.doi.org/10.1111/j.1749-6632.2009.04690.x] [PMID: 19723100]
[20]
Yang Y, Huang J, Li J, Yang H, Yin Y. The effects of butyric acid on the differentiation, proliferation, apoptosis, and autophagy of IPEC-J2 cells. Curr Mol Med 2020; 20(4): 307-17.
[http://dx.doi.org/10.2174/1566524019666191024110443] [PMID: 31749427]
[21]
Schröder M, Yusein-Myashkova S, Petrova M, et al. The effect of a ferrocene containing camphor sulfonamide DK-164 on breast cancer cell lines. Anticancer Agents Med Chem 2019; 19(15): 1874-86.
[http://dx.doi.org/10.2174/1871520619666190724094334] [PMID: 31339077]
[22]
White E, Mehnert JM, Chan CS. Autophagy, metabolism, and cancer. Clin Cancer Res 2015; 21(22): 5037-46.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0490] [PMID: 26567363]
[23]
Fan P, Wang N, Wang L, Xie X-Q . Autophagy and apoptosis specific knowledgebases-guided systems pharmacology drug research. Curr Cancer Drug Targets 2019; 19(9): 716-28.
[http://dx.doi.org/10.2174/1568009619666190206122149] [PMID: 30727895]
[24]
Li B, Wu GL, Dai W, et al. Aescin-induced reactive oxygen species play a pro-survival role in human cancer cells via ATM/AMPK/ULK1-mediated autophagy. Acta Pharmacol Sin 2018; 39(12): 1874-84.
[http://dx.doi.org/10.1038/s41401-018-0047-1] [PMID: 29921885]
[25]
Feng H, Cheng X, Kuang J, et al. Apatinib-induced protective autophagy and apoptosis through the AKT-mTOR pathway in anaplastic thyroid cancer. Cell Death Dis 2018; 9(10): 1030.
[http://dx.doi.org/10.1038/s41419-018-1054-3] [PMID: 30301881]
[26]
Devary Y. Methods of sensitizing cancer cells to anti-cancer treatment. WO2018211514, 2018.
[27]
Xia M, Zhao X, Jiang X, Jiang X. Inhibitor, pharmaceutical composition and use thereof. WO2019141254, 2019.
[28]
Huang L, Zhang J, Shen L. Nano co-delivery of quercetin and alantolactone promotes antitumor response through synergistic immunogenic cell death for microsatellite-stable colorectal cancer. WO2020219628, 2020.
[29]
Flynn DL, Ahn YM, Caldwell T, Vogeti L. Preparation of (heteroarylamino)pyrimidine compounds as autophagy inhibitors for treatment of cancer. US20200354346, 2020.
[30]
Flynn DL, Ahn YM, Caldwell T, Vogeti L. Preparation of (phenylamino)pyrimidine compounds as autophagy inhibitors for treating cancers. US20200354352, 2020.
[31]
Amaravadi RK, Winkler J. Preparation of asymmetric bisaminoquinolines and bisaminoquinolines with varied linkers as autophagy inhibitors for cancer and other therapy. WO2016022956, 2016.
[32]
Kalid O, Gotliv I, Levy-Apter E, Finkelshtein Beker D, Jagtap P. Preparation of piperidine derivatives for inhibiting protein degradation and methods of use thereof in the treatment of cancer. WO2019171379, 2019.
[33]
Lee H, Lee S, Jeong D, Kim SJ. Ginsenoside Rh2 epigenetically regulates cell-mediated immune pathway to inhibit proliferation of MCF-7 breast cancer cells. J Ginseng Res 2018; 42(4): 455-62.
[http://dx.doi.org/10.1016/j.jgr.2017.05.003] [PMID: 30337805]
[34]
Tang YC, Zhang Y, Zhou J, et al. Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo. Int J Oncol 2018; 52(1): 127-38.
[PMID: 29115601]
[35]
Qian Y, Huang R, Li S, et al. Ginsenoside Rh2 reverses cyclophosphamide-induced immune deficiency by regulating fatty acid metabolism. J Leukoc Biol 2019; 106(5): 1089-100.
[http://dx.doi.org/10.1002/JLB.2A0419-117R] [PMID: 31211478]
[36]
Zhang C, Yu H, Hou J. [Effects of 20 (S) -ginsenoside Rh2 and 20 (R) -ginsenoside Rh2 on proliferation and apoptosis of human lung adenocarcinoma A549 cells]. Zhongguo Zhongyao Zazhi 2011; 36(12): 1670-4.
[PMID: 22007558]
[37]
Zhang J, Li W, Yuan Q, et al. Transcriptome analyses of the anti-proliferative effects of 20(s)-ginsenoside Rh2 on HEPG2 cells. Front Pharmacol 2019; 10: 1331.
[http://dx.doi.org/10.3389/fphar.2019.01331] [PMID: 31780945]
[38]
Qian G, Wang Z, Zhao J, et al. Synthesis and anti-cancer cell activity of pseudo-ginsenoside Rh2. Steroids 2014; 92: 1-6.
[http://dx.doi.org/10.1016/j.steroids.2014.08.021] [PMID: 25218677]
[39]
Wang Y, Xu H, Lu Z, et al. Pseudo-Ginsenoside Rh2 induces A549 cells apoptosis via the Ras/Raf/ERK/p53 pathway. Exp Ther Med 2018; 15(6): 4916-24.
[http://dx.doi.org/10.3892/etm.2018.6067] [PMID: 29805515]
[40]
Qu X, Qu S, Yu X, et al. pseudo-G-Rh2 induces mitochondrial-mediated apoptosis in SGC-7901 human gastric cancer cells. Oncol Rep 2011; 26(6): 1441-6.
[PMID: 21887470]
[41]
Xu HL, Yu XF, Qu SC, et al. Anti-proliferative effect of Juglone from Juglans mandshurica Maxim on human leukemia cell HL-60 by inducing apoptosis through the mitochondria-dependent pathway. Eur J Pharmacol 2010; 645(1-3): 14-22.
[http://dx.doi.org/10.1016/j.ejphar.2010.06.072] [PMID: 20655907]
[42]
Fotakis G, Timbrell JA. In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol Lett 2006; 160(2): 171-7.
[http://dx.doi.org/10.1016/j.toxlet.2005.07.001] [PMID: 16111842]
[43]
Munafó DB, Colombo MI. A novel assay to study autophagy: regulation of autophagosome vacuole size by amino acid deprivation. J Cell Sci 2001; 114(Pt 20): 3619-29.
[http://dx.doi.org/10.1242/jcs.114.20.3619] [PMID: 11707514]
[44]
Wang YF, Li T, Tang ZH, et al. Baicalein triggers autophagy and inhibits the protein kinase B/Mammalian target of rapamycin pathway in hepatocellular carcinoma HepG2 cells. Phytother Res 2015; 29(5): 674-9.
[http://dx.doi.org/10.1002/ptr.5298] [PMID: 25641124]
[45]
Limpert AS, Lambert LJ, Bakas NA, et al. Autophagy in cancer: Regulation by small molecules. Trends Pharmacol Sci 2018; 39(12): 1021-32.
[http://dx.doi.org/10.1016/j.tips.2018.10.004] [PMID: 30454769]
[46]
Kimura T, Takabatake Y, Takahashi A, Isaka Y. Chloroquine in cancer therapy: a double-edged sword of autophagy. Cancer Res 2013; 73(1): 3-7.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-2464] [PMID: 23288916]
[47]
Hou H, Zhang Y, Huang Y, et al. Inhibitors of phosphatidylinositol 3′-kinases promote mitotic cell death in HeLa cells. PLoS One 2012; 7(4)e35665
[http://dx.doi.org/10.1371/journal.pone.0035665] [PMID: 22545128]
[48]
Greten TF, Manns MP, Korangy F. Immunotherapy of HCC. Rev Recent Clin Trials 2008; 3(1): 31-9.
[http://dx.doi.org/10.2174/157488708783330549] [PMID: 18474013]
[49]
Li L, Qi J, Li H. Natural products modulating autophagy pathway against the pathogenesis of diabetes mellitus. Curr Drug Targets 2019; 20(1): 96-110.
[http://dx.doi.org/10.2174/1389450119666180726115805] [PMID: 30047328]
[50]
Mete M, Ünsal UU, Aydemir I, Sönmez PK, Tuglu MI. Punicic acid inhibits glioblastoma migration and proliferation via the PI3K/AKT1/mTOR signaling pathway. Anticancer Agents Med Chem 2019; 19(9): 1120-31.
[http://dx.doi.org/10.2174/1871520619666190405112507] [PMID: 30950355]
[51]
Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta 2010; 1806(2): 220-9.
[PMID: 20637264]
[52]
Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 2004; 36(12): 2503-18.
[http://dx.doi.org/10.1016/j.biocel.2004.05.009] [PMID: 15325588]
[53]
Moscat J, Diaz-Meco MT. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 2009; 137(6): 1001-4.
[http://dx.doi.org/10.1016/j.cell.2009.05.023] [PMID: 19524504]
[54]
Lamark T, Svenning S, Johansen T. Regulation of selective autophagy: the p62/SQSTM1 paradigm. Essays Biochem 2017; 61(6): 609-24.
[http://dx.doi.org/10.1042/EBC20170035] [PMID: 29233872]
[55]
Zheng C, Liu T, Liu H, Wang J. Role of BCL-2 family proteins in apoptosis and its regulation by nutrients. Curr Protein Pept Sci 2020; 21(8): 799-806.
[http://dx.doi.org/10.2174/1389203721666191227122252] [PMID: 31880257]
[56]
Vázquez CL, Colombo MI. Assays to assess autophagy induction and fusion of autophagic vacuoles with a degradative compartment, using monodansylcadaverine (MDC) and DQ-BSA. Methods Enzymol 2009; 452: 85-95.
[http://dx.doi.org/10.1016/S0076-6879(08)03606-9] [PMID: 19200877]
[57]
Yuan L, Wei S, Wang J, Liu X. Isoorientin induces apoptosis and autophagy simultaneously by reactive oxygen species (ROS)-related p53, PI3K/Akt, JNK, and p38 signaling pathways in HepG2 cancer cells. J Agric Food Chem 2014; 62(23): 5390-400.
[http://dx.doi.org/10.1021/jf500903g] [PMID: 24841907]
[58]
Alipourfard I, Bakhtiyari S, Gheysarzadeh A, et al. The key role of Akt protein kinase in metabolic-inflammatory pathways cross-talk: TNF-α down-regulation and improving of insulin resistance in HepG2 cell line. Curr Mol Med 2020; •••
[http://dx.doi.org/10.2174/1566524020666200427102209] [PMID: 32338219]
[59]
Li L, Liu WL, Su L, Lu ZC, He XS. The role of autophagy in cancer radiotherapy. Curr Mol Pharmacol 2020; 13(1): 31-40.
[http://dx.doi.org/10.2174/1874467212666190809154518] [PMID: 31400274]
[60]
Ho WM, Akyol O, Reis H, et al. Autophagy after Subarachnoid Hemorrhage: Can Cell Death be Good? Curr Neuropharmacol 2018; 16(9): 1314-9.
[http://dx.doi.org/10.2174/1570159X15666171123200646] [PMID: 29173174]
[61]
Li Y, Ren L, Song G, et al. Silibinin ameliorates fructose-induced lipid accumulation and activates autophagy in HepG2 cells. Endocr Metab Immune Disord Drug Targets 2019; 19(5): 632-42.
[http://dx.doi.org/10.2174/1871530319666190207163325] [PMID: 30734689]
[62]
Tanida I, Ueno T, Kominami E. Autophagosome and Phagosome. Totowa, NJ: Humana Press 2008.
[63]
Morsi RZ, Hage-Sleiman R, Kobeissy H, Dbaibo G. Noxa: Role in cancer pathogenesis and treatment. Curr Cancer Drug Targets 2018; 18(10): 914-28.
[http://dx.doi.org/10.2174/1568009618666180308105048] [PMID: 29521234]
[64]
Zhou J, Li Z, Li J, Gao B, Song W. Chemotherapy resistance molecular mechanism in small cell lung cancer. Curr Mol Med 2019; 19(3): 157-63.
[http://dx.doi.org/10.2174/1566524019666190226104909] [PMID: 30813876]
[65]
Ola MS, Al-Dosari D, Alhomida AS. Role of oxidative stress in diabetic retinopathy and the beneficial effects of flavonoids. Curr Pharm Des 2018; 24(19): 2180-7.
[http://dx.doi.org/10.2174/1381612824666180515151043] [PMID: 29766782]
[66]
Mauthe M, Orhon I, Rocchi C, et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 2018; 14(8): 1435-55.
[http://dx.doi.org/10.1080/15548627.2018.1474314] [PMID: 29940786]
[67]
Chen J, Zhu Y, Zhang W, et al. Delphinidin induced protective autophagy via mTOR pathway suppression and AMPK pathway activation in HER-2 positive breast cancer cells. BMC Cancer 2018; 18(1): 342.
[http://dx.doi.org/10.1186/s12885-018-4231-y] [PMID: 29587684]
[68]
Seglen PO, Gordon PB. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA 1982; 79(6): 1889-92.
[http://dx.doi.org/10.1073/pnas.79.6.1889] [PMID: 6952238]
[69]
Su Z, Yang Z, Xu Y, Chen Y, Yu Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer 2015; 14: 48.
[http://dx.doi.org/10.1186/s12943-015-0321-5] [PMID: 25743109]
[70]
Badar UI, Khan MS, Husain FM, et al. mTor targeting by different flavonoids for cancer prevention. Curr Med Chem, 2020. Online ahead of print
[PMID: 33167824]
[71]
Visnjic D, Dembitz V, Lalic H. The role of AMPK/mTOR modulators in the therapy of acute myeloid leukemia. Curr Med Chem 2019; 26(12): 2208-29.
[http://dx.doi.org/10.2174/0929867325666180117105522] [PMID: 29345570]
[72]
Nellaiappan K, Yerra VG, Kumar A. Role of AMPK in diabetic cardiovascular complications: An overview. Cardiovasc Hematol Disord Drug Targets 2019; 19(1): 5-13.
[http://dx.doi.org/10.2174/1871529X18666180508104929] [PMID: 29737267]
[73]
Cho KS, Lee JH, Cho J, Cha GH, Song GJ. Autophagy modulators and neuroinflammation. Curr Med Chem 2020; 27(6): 955-82.
[http://dx.doi.org/10.2174/0929867325666181031144605] [PMID: 30381067]
[74]
Allouch S, Munusamy S. AMP-activated protein kinase as a drug target in chronic kidney disease. Curr Drug Targets 2018; 19(6): 709-20.
[http://dx.doi.org/10.2174/1389450118666170601130947] [PMID: 28571536]
[75]
Belousov DM, Mikhaylenko EV, Somasundaram SG, Kirkland CE, Aliev G. The dawn of mitophagy: What do we know by now? Curr Neuropharmacol 2021; 19(2): 170-92.
[http://dx.doi.org/10.2174/1570159X18666200522202319] [PMID: 32442087]
[76]
Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6(4): 463-77.
[http://dx.doi.org/10.1016/S1534-5807(04)00099-1] [PMID: 15068787]
[77]
Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27(41): 5497-510.
[http://dx.doi.org/10.1038/onc.2008.245] [PMID: 18794884]
[78]
Zhu S, Chen X, Chen Y, et al. role of micrornas in hepatic stellate cells and hepatic fibrosis: An update. Curr Pharm Des 2021; 27(27): 3000-11.
[http://dx.doi.org/10.2174/1381612826666201023143542] [PMID: 33100194]
[79]
Zhao X, Liu J, Cheng G, et al. Application of Platycodon grandiflorum polysaccharide in antagonizing fumonisin B1 induced apoptosis through autophagy. CN111358805, 2020.
[80]
Nomura DK, Zoncu R, Ward C, Fung SK, Varma CK, Fontaine B. Methods and compounds for targeted autophagy. WO2019183600, 2019.
[81]
Lee M-S, Lim H, Jeon YE, Ahn JH, Pagire HS. Autophagy improving material and use thereof. WO2018012769, 2018.
[82]
Depamphilis ML, Sharma G, Marugan JJ, Ferrer M, Roy A. Autophagy modulators for use in treating cancer. US20200369649, 2020.
[83]
Katsuta I, Taniguchi T, Suzuki K, Inoue A. Autophagy-inducing pharmaceutical composition comprising andrographolid. JP2020121959, 2020.
[84]
Yang D, Zhang J, Zhang S. Cancer treatment using compounds that selectively target polyploid cancer cells for disruption. US20200140364, 2020.
[85]
Tan N, Chen L, Song L, Yang J, Wang Z. Cell autophagy inhibitor and preparation method therefor and application thereof. WO2019071875, 2019.
[86]
Rangnekar VM. Chloroquine induction of prostate apoptosis response-4 (Par-4) and treatment of cancer. WO2016196614, 2016.
[87]
Zaupa C, Hortelano J, Silvestre N, Spindler A. Combination product with autophagy modulator. WO2016131945, 2016.
[88]
Young RN, Bosc D. Compounds and methods for treatment of cancer by inhibiting ATG4B and blocking autophagy. WO2017027984, 2017.
[89]
Tiwari AK, Chandrabose K, Amawi H, Erhardt PW, Trivedi P. Materials and methods useful to induce cancer cell death via methuosis or autophagy or a combination thereof. WO2019067511, 2019.

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