20(S)-Ginsenoside Rg3 is a novel inhibitor of autophagy and sensitizes hepatocellular carcinoma to doxorubicin

Oncotarget

Volumn 5, Issue 12, 2014, Pages 4438-4451

  Kim, Dong Gun ^a   Jung, Kyung Hee ^b   Lee, Da Gyum ^a   Yoon, Jung Ho ^a   Choi, Kyeong Sook ^a   Kwon, Sung Won ^c   Shen, Han Ming ^d   Morgan, Michael J ^e   Hong, Soon Sun ^b   Kim, You Sun ^a  

^a Ajou University School of Medicine   (South Korea)

^b Inha University School of Medicine   (South Korea)

^c Seoul National University   (South Korea)

^d NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^e UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

Author keywords

Autophagy; Cell death; Doxorubicin; HCC

Indexed keywords

AUTOPHAGY PROTEIN 5; BAFILOMYCIN A1; CASPASE 3; CHLOROQUINE; CYCLOHEXIMIDE; DEATH RECEPTOR 5; DOXORUBICIN; GINSENOSIDE RG 3; GROWTH ARREST AND DNA DAMAGE INDUCIBLE PROTEIN 153; LC3 II PROTEIN; MEMBRANE PROTEIN; PROTEIN P62; UNCLASSIFIED DRUG; ANTINEOPLASTIC ANTIBIOTIC; GINSENOSIDE;

ADJUVANT THERAPY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; AUTOPHAGOSOME; AUTOPHAGY; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CELL DEATH; CHEMOSENSITIZATION; CONTROLLED STUDY; DOSE TIME EFFECT RELATION; DRUG EFFECT; DRUG EFFICACY; DRUG INHIBITION; DRUG MECHANISM; DRUG POTENTIATION; DRUG RESPONSE; DRUG TOLERABILITY; ENANTIOMER; ENZYME ACTIVATION; GENE EXPRESSION; GINSENG; IN VITRO STUDY; IN VIVO STUDY; LIVER CELL CARCINOMA; MALE; MOUSE; NONHUMAN; PROTEIN CLEAVAGE; PROTEIN STABILITY; TUMOR VOLUME; TUMOR XENOGRAFT; UPREGULATION; CARCINOMA, HEPATOCELLULAR; FEMALE; HUMAN; LIVER NEOPLASMS;

ANTIBIOTICS, ANTINEOPLASTIC; AUTOPHAGY; CARCINOMA, HEPATOCELLULAR; DOXORUBICIN; FEMALE; GINSENOSIDES; HUMANS; LIVER NEOPLASMS; MALE;

EID: 84905113362     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.2034     Document Type: Article

References (67)

1. Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science. 2004; 306(5698):990-995.
2. Mizushima N, Klionsky DJ. Protein Turnover Via Autophagy: Implications for Metabolism. Annu Rev Nutr. 2007; 27:19-40.
3. Rubinsztein D, Gestwicki J, Murphy L, Klionsky D. Potential therapeutic applications of autophagy. Nat Rev Drug Discov. 2007; 6(4):304-312.
4. Mizushima N, Levine B, Cuervo A, Klionsky D. Autophagy fights disease through cellular self-digestion. Nature. 2008; 451(7182):1069-1075.
5. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period. Nature. 2004; 432(7020):1032-1036.
6. Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A. 2005; 102(23):8204-8209.
7. 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. Proc Natl Acad Sci U S A. 2003; 100(25):15077-15082.
8. Shen HM, Codogno P. Autophagic cell death: Loch Ness monster or endangered species? Autophagy. 2011; 7(5):457-465.
9. Kroemer G, Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol. 2008; 9(12):1004-1010.
10. Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest. 2005; 115(10):2679-2688.
11. Scarlatti F, Granata R, Meijer A, Codogno P. Does autophagy have a license to kill mammalian cells? Cell Death Differ. 2008; 16(1):12-20.
12. Takimoto CH, Awada A. Safety and anti-tumor activity of sorafenib (Nexavar®) in combination with other anti-cancer agents: a review of clinical trials. Cancer Chemother Pharmacol. 2008; 61(4):535-548.
13. Cabibbo G, Latteri F, Antonucci M, Craxì A. Multimodal approaches to the treatment of hepatocellular carcinoma. Nat Clin Pract Gastroenterol Hepatol. 2009; 6(3):159-169.
14. Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW, Wang XY, Dai Z, Peng YF, Gu CY, Qiu SJ, Fan J. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy. 2011; 7(10):1159-1172.
15. Ding ZB, Hui B, Shi YH, Zhou J, Peng YF, Gu CY, Yang H, Shi GM, Ke AW, Wang XY, Song K, Dai Z, Shen YH, et al. Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation. Clin Cancer Res. 2011; 17(19):6229-6238.
16. Jia L, Zhao Y, Liang XJ. Current evaluation of the millennium phytomedicine-ginseng (II): Collected chemical entities, modern pharmacology, and clinical applications emanated from traditional Chinese medicine. Curr Med Chem. 2009; 16(22):2924-2942.
17. Wei XJ, Su F, Su XY, Hu TJ, Hu SH. Stereospecific antioxidant effects of ginsenoside Rg3 on oxidative stress induced by cyclophosphamide in mice. Fitoterapia. 2012; 83(4):636-642.
18. Wei XJ, Chen J, Su F, Su XY, Hu TJ, Hu SH. Stereospecificity of ginsenoside Rg3 in promotion of the immune response to ovalbumin in mice. Int Immunol. 2012; 24(7):465-471.
19. Park MW, Ha J, Chung SH. 20(S)-ginsenoside Rg3 enhances glucose-stimulated insulin secretion and activates AMPK. Biol Pharm Bull. 2008; 31(4):748-751.
20. Liu JP, Lu D, Nicholson RC, Li PY, Wang F. Toxicity of a novel anti-tumor agent 20(S)-ginsenoside Rg3: A 26-week intramuscular repeated administration study in Beagle dogs. Food Chem Toxicol. 2011; 49(8):1718-1727.
21. Liu JP, Lu D, Nicholson RC, Zhao WJ, Li PY, Wang F. Toxicity of a novel anti-tumor agent 20(S)-ginsenoside Rg3: A 26-week intramuscular repeated administration study in rats. Food Chem Toxicol. 2012; 50(10):3388-3396.
22. Lee JY, Jung KH, Morgan MJ, Kang YR, Lee HS, Koo GB, Hong SS, Kwon SW, Kim YS. Sensitization of TRAIL-Induced Cell Death by 20(S)-Ginsenoside Rg(3) via CHOP-Mediated DR5 Upregulation in Human Hepatocellular Carcinoma Cells. Mol Cancer Ther. 2013; 12(3):274-285.
23. Liu TG, Huang Y, Cui DD, Huang XB, Mao SH, Ji LL, Song HB, Yi C. Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice. Bmc Cancer. 2009; 9.
24. Zhang QY, Kang XM, Zhao WH. Antiangiogenic effect of low-dose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma. Biochem Bioph Res Co. 2006; 342(3):824-828.
25. Keum YS, Han SS, Chun KS, Park KK, Park JH, Lee SK, Surh YJ. Inhibitory effects of the ginsenoside Rg3 on phorbol ester-induced cyclooxygenase-2 expression, NF-kappaB activation and tumor promotion. Mutat Res. 2003; 523-524:75-85.
26. Chen QJ, Zhang MZ, Wang LX. Gensenoside Rg3 Inhibits Hypoxia-induced VEGF Expression in Human Cancer Cells. Cell Physiol Biochem. 2010; 26(6):849-858.
27. Kim JW, Jung SY, Kwon YH, Lee JH, Lee YM, Lee BY, Kwon SM. Ginsenoside Rg3 attenuates tumor angiogenesis via inhibiting bioactivities of endothelial progenitor cells. Cancer Biol Ther. 2012; 13(7):504-515.
28. Xu TM, Xin Y, Cui MH, Jiang X, Gu LP. Inhibitory effect of ginsenoside Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian cancer. Chinese Med J-Peking. 2007; 120(7):584-588.
29. Chen Z, Lu T, Yue X, Wei N, Jiang Y, Chen M, Ni G, Liu X, Xu G. Neuroprotective effect of ginsenoside Rb1 on glutamate-induced neurotoxicity: With emphasis on autophagy. Neurosci Lett. 2010; 482(3):264-268.
30. Ko H, Kim Y, Park J, Park J, Yang H. Autophagy Inhibition Enhances Apoptosis Induced by Ginsenoside Rk1 in Hepatocellular Carcinoma Cells. Biosci Biotechnol Biochem. 2009; 73(10):2183-2189.
31. Hosokawa N, Hara Y, Mizushima N. Generation of cell lines with tetracycline-regulated autophagy and a role for autophagy in controlling cell size. FEBS Lett. 2006; 580(11):2623-2629.
32. Wu Y, Tan H, Huang Q, Kim Y, Pan N, Ong W, Liu Z, Ong C, Shen H. Autophagy plays a protective role during zVAD-induced necrotic cell death. Autophagy. 2008; 4(4):457-466.
33. Mizushima N. Methods for monitoring autophagy. Int J Biochem Cell Biol. 2004; 36(12):2491-2502.
34. Mizushima N, Yoshimori T. How to interpret LC3 immunoblotting. Autophagy. 2007; 3(6):542-545.
35. Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, Baba M, Baehrecke EH, Bahr BA, Ballabio A. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 2008; 4(2):151-175.
36. Pankiv S, Clausen T, Lamark T, Brech A, Bruun J, Outzen H, Overvatn A, Bjorkoy G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007; 282(33):24131-24145.
37. Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Øvervatn A, Stenmark H, Johansen T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. The Journal of Cell Biology. 2005; 171(4):603-614.
38. Kimura S, Noda T, Yoshimori T. Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy. 2007; 3(5):452-460.
39. Katayama H, Yamamoto A, Mizushima N, Yoshimori T, Miyawaki A. GFP-like proteins stably accumulate in lysosomes. Cell struct Funct. 2007; 33(1):1-12.
40. Li J, Hou N, Faried A, Tsutsumi S, Kuwano H. Inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model. Eur J Cancer. 2010; 46(10):1900-1909.
41. Lambert LA, Qiao N, Hunt KK, Lambert DH, Mills GB, Meijer L, Keyomarsi K. Autophagy: a novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model. Cancer Res. 2008; 68(19):7966-7974.
42. Lee T, Lau T, Ng I. Doxorubicin-induced apoptosis and chemosensitivity in hepatoma cell lines. Cancer Chemother Pharmacol. 2002; 49(1):78-86.
43. Kim Y, Ma AG, Kitta K, Fitch SN, Ikeda T, Ihara Y, Simon AR, Evans T, Suzuki YJ. Anthracycline-induced suppression of GATA-4 transcription factor: implication in the regulation of cardiac myocyte apoptosis. Mol Pharmacol. 2003; 63(2):368-377.
44. Aries A, Paradis P, Lefebvre C, Schwartz RJ, Nemer M. Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity. Proc Natl Acad Sci U S A. 2004; 101(18):6975-6980.
45. Li L, Takemura G, Li Y, Miyata S, Esaki M, Okada H, Kanamori H, Khai NC, Maruyama R, Ogino A. Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Circulation. 2006; 113(4):535-543.
46. Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, Eppenberger HM, Suter TM, Liao R, Sawyer DB. Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem. 2004; 279(9):8290-8299.
47. Olson RD, Gambliel HA, Vestal RE, Shadle SE, Charlier HA, Cusack BJ. Doxorubicin cardiac dysfunction: effects on calcium regulatory proteins, sarcoplasmic reticulum, and triiodothyronine. Cardiovasc Toxicol. 2005; 5(3):269-283.
48. Oliveira PJ, Wallace KB. Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats--relevance for mitochondrial dysfunction. Toxicology. 2006; 220(2-3):160-168.
49. Kumarapeli ARK, Horak KM, Glasford JW, Li J, Chen Q, Liu J, Zheng H, Wang X. A novel transgenic mouse model reveals deregulation of the ubiquitin-proteasome system in the heart by doxorubicin. FASEB J. 2005; 19(14):2051-2053.
50. Semenov D, Lushnikova E, Nepomnyashchikh L. Anthracycline-induced cardiomyopathy is manifested in decreased protein synthesis, impaired intracellular regeneration, and non-necrotic death of cardiomyocytes. Bull Exp Biol Med. 2001; 131(5):505-510.
51. Kobayashi S, Volden P, Timm D, Mao K, Xu X, Liang Q. Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death. J Biol Chem. 2010; 285(1):793-804.
52. Yuan HD, Quan HY, Zhang Y, Kim SH, Chung SH. 20(S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway. Mol Med Rep. 2010; 3(5): 825-831
53. Vandenabeele P, Declercq W, Berghe TV. Necrotic cell death and 'necrostatins': now we can control cellular explosion. Trends Biochem Sci. 2008; 33(8):352-355.
54. Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat chem biol. 2008; 4(5):313-321.
55. B'Chir W, Chaveroux C, Carraro V, Averous J, Maurin AC, Jousse C, Muranishi Y, Parry L, Fafournoux P, Bruhat A. Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation. Cell Signal 2014; 26(7): 1385-1391.
56. Yu ZG, Wang AM, Adachi H, Katsuno M, Sobue G, Yue ZY, Robins DM, Lieberman AP (2011) Macroautophagy Is Regulated by the UPR-Mediator CHOP and Accentuates the Phenotype of SBMA Mice. Plos Genet 7(10): e1002321.
57. Apel A, Zentgraf H, Buchler MW, Herr I. Autophagy-A double-edged sword in oncology. Int J Cancer. 2009; 125(5):991-995.
58. Chen N, Debnath J. Autophagy and tumorigenesis. FEBS Lett. 2010; 584(7):1427-1435.
59. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008; 132(1):27-42.
60. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007; 7(12):961-967.
61. Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B. Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy. 2010; 6(3):322-329.
62. Lee SY, Kim GT, ROH SH, Song JS, Kim HJ, Hong SS, Kwon SW, Park JH. Proteomic Analysis of the Anti-Cancer Effect of 20S-Ginsenoside Rg 3 in Human Colon Cancer Cell Lines. Bioscience, biotechnology, and biochemistry. 2009; 73(4):811-816.
63. Rosenfeld MR, Grossman SA, Brem S, Mikkelsen T, Wang D, Piao S, Davis LE, ODwyer PJ, Amaravadi RK. (2010). Pharmacokinetic analysis and pharmacodynamic evidence of autophagy inhibition in patients with newly diagnosed glioblastoma treated on a phase I trial of hydroxychloroquine in combination with adjuvant temozolomide and radiation (ABTC 0603). J Clin Oncol 28:15s, 2010 (suppl; abstr 3086)
64. Pellegrini P, Strambi A, Zipoli C, Hagg-Olofsson M, Buoncervello M, Linder S, De Milito A. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: Implications for cancer therapies. Autophagy. 2014; 10(4).
65. Pan Y, Gao Y, Chen L, Gao G, Dong H, Yang Y, Dong B, Chen X. Targeting autophagy augments in vitro and in vivo antimyeloma activity of DNA-damaging chemotherapy. Clin Cancer Res. 2011; 17(10):3248-3258.
66. Manov I, Pollak Y, Broneshter R, Iancu TC. Inhibition of Doxorubicin-induced autophagy in hepatocellular carcinoma Hep3B cells by Sorafenib: the role of extracellular signal-regulated kinase counteraction. FEBS Journal. 2011; 278(18):3494-3507.
67. Li Z, Xu XL, Bai L, Chen WS, Lin Y. Epidermal Growth Factor Receptor-mediated Tissue Transglutaminase Overexpression Couples Acquired Tumor Necrosis Factor-related Apoptosis-inducing Ligand Resistance and Migration through c-FLIP and MMP-9 Proteins in Lung Cancer Cells. J Biol Chem. 2011; 286(24): 21164-21172.