Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Ginsenoside Rh2 Improves the Cisplatin Anti-tumor Effect in Lung Adenocarcinoma A549 Cells via Superoxide and PD-L1

Author(s): Yingying Chen, Yuqiang Zhang, Wei Song, Ying Zhang, Xiu Dong and Mingqi Tan*

Volume 20, Issue 4, 2020

Page: [495 - 503] Pages: 9

DOI: 10.2174/1871520619666191209091230

Price: $65

Abstract

Background: Ginsenoside Rh2 (Rh2) is a major biological component of ginseng that exerts antitumor activities in multiple cancers including Non-Small Cell Lung Cancers (NSCLCs). Rh2 also enhances the anti-tumor effects of various chemotherapy drugs including cisplatin at relatively low concentrations. Here, the mechanistic role of Rh2 in chemotherapy-treated NSCLCs will be investigated.

Methods: In this study, FACS, western blot and siRNA addition were used to analyze the role of Rh2 in cisplatin- treated lung adenocarcinoma A549 and H1299 cells.

Results: Subsequent observations indicated that Rh2 enhanced cisplatin-induced NSCLCs A549 and H1299 cells apoptosis. Cisplatin-induced productive autophagy was repressed by Rh2 in A549 cells. Rh2 also enhanced cisplatin cytotoxicity by elevating superoxide dismutase activity and repressing cisplatin-induced superoxide generation. Conversely, Rh2 was found to repress cisplatin-induced phosphorylation of epidermal growth factor receptor, phosphoinositide 3-kinase, protein kinase B, and autophagy. Cisplatin-induced Programmed Death- Ligand 1 (PD-L1) expression was repressed by Rh2 via the superoxide.

Conclusion: These findings suggest that Rh2 enhanced the function of cisplatin by repressing superoxide generation, PD-L1 expression, and autophagy in lung adenocarcinoma cells.

Keywords: Cisplatin, ginsenoside Rh2, lung adenocarcinoma, PD-L1, superoxide, anti-tumor.

« Previous Next »
Graphical Abstract

[1]
Cao, M.; Chen, W. Epidemiology of lung cancer in China. Thorac. Cancer, 2019, 10(1), 3-7.
[http://dx.doi.org/10.1111/1759-7714.12916] [PMID: 30485694]
[2]
Burstein, H.J.; Schwartz, R.S. Molecular origins of cancer. N. Engl. J. Med., 2008, 358(5), 527.
[http://dx.doi.org/10.1056/NEJMe0800065] [PMID: 18234758]
[3]
Pignon, J.P.; Tribodet, H.; Scagliotti, G.V.; Douillard, J.Y.; Shepherd, F.A.; Stephens, R.J.; Dunant, A.; Torri, V.; Rosell, R.; Seymour, L.; Spiro, S.G.; Rolland, E.; Fossati, R.; Aubert, D.; Ding, K.; Waller, D.; Le Chevalier, T. LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J. Clin. Oncol., 2008, 26(21), 3552-3559.
[http://dx.doi.org/10.1200/JCO.2007.13.9030] [PMID: 18506026]
[4]
Michaelis, M.; Rothweiler, F.; Barth, S.; Cinatl, J.; van Rikxoort, M.; Löschmann, N.; Voges, Y.; Breitling, R.; von Deimling, A.; Rödel, F.; Weber, K.; Fehse, B.; Mack, E.; Stiewe, T.; Doerr, H.W.; Speidel, D.; Cinatl, J., Jr Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis., 2011, 2 243
[http://dx.doi.org/10.1038/cddis.2011.129] [PMID: 22170099]
[5]
Sarin, N.; Engel, F.; Kalayda, G.V.; Mannewitz, M.; Cinatl, J., Jr; Rothweiler, F.; Michaelis, M.; Saafan, H.; Ritter, C.A.; Jaehde, U.; Frötschl, R. Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest. PLoS One, 2017, 12(7) e0181081
[http://dx.doi.org/10.1371/journal.pone.0181081] [PMID: 28746345]
[6]
Rybak, L.P.; Mukherjea, D.; Jajoo, S.; Ramkumar, V. Cisplatin ototoxicity and protection: clinical and experimental studies. Tohoku J. Exp. Med., 2009, 219(3), 177-186.
[http://dx.doi.org/10.1620/tjem.219.177] [PMID: 19851045]
[7]
Majumdar, P.; Bathula, C.; Basu, S.M.; Das, S.K.; Agarwal, R.; Hati, S.; Singh, A.; Sen, S.; Das, B.B. Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity. Eur. J. Med. Chem., 2015, 102, 540-551.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.032] [PMID: 26312433]
[8]
Hati, S.; Tripathy, S.; Dutta, P.K.; Agarwal, R.; Srinivasan, R.; Singh, A.; Singh, S.; Sen, S. Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification. Sci. Rep., 2016, 6, 32213.
[http://dx.doi.org/10.1038/srep32213] [PMID: 27573798]
[9]
Liu, T.; Zhao, L.; Zhang, Y.; Chen, W.; Liu, D.; Hou, H.; Ding, L.; Li, X. Ginsenoside 20(S)-Rg3 targets HIF-1α to block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells. PLoS One, 2014, 9(9) e103887
[http://dx.doi.org/10.1371/journal.pone.0103887] [PMID: 25197976]
[10]
Kiefer, D.; Pantuso, T. Panax ginseng. Am. Fam. Physician, 2003, 68(8), 1539-1542.
[PMID: 14596440]
[11]
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), 1670-1674.
[PMID: 22007558]
[12]
Oh, M.; Choi, Y.H.; Choi, S.; Chung, H.; Kim, K.; Kim, S.I.; Kim, D.K.; Kim, N.D. Anti-proliferating effects of ginsenoside Rh2 on MCF-7 human breast cancer cells. Int. J. Oncol., 1999, 14(5), 869-875.
[http://dx.doi.org/10.3892/ijo.14.5.869] [PMID: 10200336]
[13]
Jia, W.W.; Bu, X.; Philips, D.; Yan, H.; Liu, G.; Chen, X.; Bush, J.A.; Li, G. Rh2, a compound extracted from ginseng, hypersensitizes multidrug-resistant tumor cells to chemotherapy. Can. J. Physiol. Pharmacol., 2004, 82(7), 431-437.
[http://dx.doi.org/10.1139/y04-049] [PMID: 15389289]
[14]
Glick, D.; Barth, S.; Macleod, K.F. Autophagy: cellular and molecular mechanisms. J. Pathol., 2010, 221(1), 3-12.
[http://dx.doi.org/10.1002/path.2697] [PMID: 20225336]
[15]
Dikic, I.; Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol., 2018, 19(6), 349-364.
[http://dx.doi.org/10.1038/s41580-018-0003-4] [PMID: 29618831]
[16]
Lin, J.F.; Lin, Y.C.; Tsai, T.F.; Chen, H.E.; Chou, K.Y.; Hwang, T.I. Cisplatin induces protective autophagy through activation of BECN1 in human bladder cancer cells. Drug Des. Devel. Ther., 2017, 11, 1517-1533.
[http://dx.doi.org/10.2147/DDDT.S126464] [PMID: 28553083]
[17]
Chen, J.; Zhang, L.; Zhou, H.; Wang, W.; Luo, Y.; Yang, H.; Yi, H. Inhibition of autophagy promotes cisplatin-induced apoptotic cell death through Atg5 and Beclin 1 in A549 human lung cancer cells. Mol. Med. Rep., 2018, 17(5), 6859-6865.
[http://dx.doi.org/10.3892/mmr.2018.8686] [PMID: 29512762]
[18]
Yang, Z.; Zhao, T.; Liu, H.; Zhang, L. Ginsenoside Rh2 inhibits hepatocellular carcinoma through β-catenin and autophagy. Sci. Rep., 2016, 6, 19383.
[http://dx.doi.org/10.1038/srep19383] [PMID: 26783250]
[19]
Tran, L.; Allen, C.T.; Xiao, R.; Moore, E.; Davis, R.; Park, S.J.; Spielbauer, K.; Van Waes, C.; Schmitt, N.C.; Van, Waes, C.; Schmitt, N.C. Cisplatin alters antitumor immunity and synergizes with PD-1/PD-L1 inhibition in head and neck squamous cell carcinoma. Cancer Immunol. Res., 2017, 5(12), 1141-1151.
[http://dx.doi.org/10.1158/2326-6066.CIR-17-0235] [PMID: 29097421]
[20]
Lin, E.; Yang, C.; Lin, C.; Huang, B.; Lai, W.; Tseng, Y.; Tseng, Y.; Yang, P. Priming PD-L1 expression by chemotherapeutic agents in non-small cell lung cancers. J. Clin. Oncol., 2017, 35, e20087-e20087.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.e20087]
[21]
Li, Y.; Li, F.; Jiang, F.; Lv, X.; Zhang, R.; Lu, A.; Zhang, G. A mini-review for cancer immunotherapy: Molecular understanding of PD-1/PD-L1 pathway and translational blockade of immune checkpoints. Int. J. Mol. Sci., 2016, 17(7) E1151
[http://dx.doi.org/10.3390/ijms17071151] [PMID: 27438833]
[22]
Riaz, N.; Havel, J.J.; Makarov, V.; Desrichard, A.; Urba, W.J.; Sims, J.S.; Hodi, F.S.; Martín-Algarra, S.; Mandal, R.; Sharfman, W.H.; Bhatia, S.; Hwu, W.J.; Gajewski, T.F.; Slingluff, C.L., Jr; Chowell, D.; Kendall, S.M.; Chang, H.; Shah, R.; Kuo, F.; Morris, L.G.T.; Sidhom, J.W.; Schneck, J.P.; Horak, C.E.; Weinhold, N.; Chan, T.A. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell, 2017, 171(4), 934-949.
[http://dx.doi.org/10.1016/j.cell.2017.09.028] [PMID: 29033130]
[23]
Wangpaichitr, M.; Kandemir, H.; Li, Y.Y.; Wu, C.; Nguyen, D.; Feun, L.G.; Kuo, M.T.; Savaraj, N. Relationship of metabolic alterations and PD-L1 expression in cisplatin resistant lung cancer. Cell Dev. Biol., 2017, 6(2), 183.
[PMID: 28819582]
[24]
Munafó, D.B.; Colombo, M.I. A novel assay to study autophagy: regulation of autophagosome vacuole size by amino acid deprivation. J. Cell Sci., 2001, 114(Pt 20), 3619-3629.
[PMID: 11707514]
[25]
Kalai Selvi, S.; Vinoth, A.; Varadharajan, T.; Weng, C.F.; Vijaya Padma, V. KalaiSelvi. Neferine augments therapeutic efficacy of cisplatin through ROS- mediated non-canonical autophagy in human lung adenocarcinoma (A549 cells). Food Chem. Toxicol., 2017, 103, 28-40.
[http://dx.doi.org/10.1016/j.fct.2017.02.020] [PMID: 28223119]
[26]
Marullo, R.; Werner, E.; Degtyareva, N.; Moore, B.; Altavilla, G.; Ramalingam, S.S.; Doetsch, P.W. Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One, 2013, 8(11) e81162
[http://dx.doi.org/10.1371/journal.pone.0081162] [PMID: 24260552]
[27]
Lin, Q.; Wang, Y.; Chen, D.; Sheng, X.; Liu, J.; Xiong, H. Cisplatin regulates cell autophagy in endometrial cancer cells via the PI3K/AKT/mTOR signalling pathway. Oncol. Lett., 2017, 13(5), 3567-3571.
[http://dx.doi.org/10.3892/ol.2017.5894] [PMID: 28521459]
[28]
Chen, L.M.; Song, T.J.; Xiao, J.H.; Huang, Z.H.; Li, Y.; Lin, T.Y. Tripchlorolide induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR pathway and improves cisplatin sensitivity in A549/DDP cells. Oncotarget, 2017, 8(38), 63911-63922.
[http://dx.doi.org/10.18632/oncotarget.19201] [PMID: 28969040]
[29]
Kikuchi, Y.; Sasa, H.; Kita, T.; Hirata, J.; Tode, T.; Nagata, I. Inhibition of human ovarian cancer cell proliferation in vitro by ginsenoside Rh2 and adjuvant effects to cisplatin in vivo. Anticancer Drugs, 1991, 2(1), 63-67.
[http://dx.doi.org/10.1097/00001813-199102000-00009] [PMID: 1958854]
[30]
Xu, F.Y.; Shang, W.Q.; Yu, J.J.; Sun, Q.; Li, M.Q.; Sun, J.S. The antitumor activity study of ginsenosides and metabolites in lung cancer cell. Am. J. Transl. Res., 2016, 8(4), 1708-1718.
[PMID: 27186294]
[31]
Ge, G.; Yan, Y.; Cai, H. Ginsenoside Rh2 inhibited proliferation by inducing ROS mediated ER stress dependent apoptosis in lung cancer cells. Biol. Pharm. Bull., 2017, 40(12), 2117-2124.
[http://dx.doi.org/10.1248/bpb.b17-00463] [PMID: 28966297]
[32]
Cao, S.S.; Kaufman, R.J. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid. Redox Signal., 2014, 21(3), 396-413.
[http://dx.doi.org/10.1089/ars.2014.5851] [PMID: 24702237]
[33]
Lu, C.; Wang, Y.; Lv, J.; Jiang, N.; Fan, B.; Qu, L.; Li, Y.; Chen, S.; Wang, F.; Liu, X. Ginsenoside Rh2 reverses sleep deprivation-induced cognitive deficit in mice. Behav. Brain Res., 2018, 349, 109-115.
[http://dx.doi.org/10.1016/j.bbr.2018.03.005] [PMID: 29544964]
[34]
Chen, H.H.; Kuo, M.T. Role of glutathione in the regulation of Cisplatin resistance in cancer chemotherapy. Met. Based Drugs, 2010, 2010 430939
[http://dx.doi.org/10.1155/2010/430939] [PMID: 20885916]
[35]
Bartosz, G. Reactive oxygen species: destroyers or messengers? Biochem. Pharmacol., 2009, 77(8), 1303-1315.
[http://dx.doi.org/10.1016/j.bcp.2008.11.009] [PMID: 19071092]
[36]
Clément, M.V.; Pervaiz, S. Intracellular superoxide and hydrogen peroxide concentrations: a critical balance that determines survival or death. Redox Rep., 2001, 6(4), 211-214.
[http://dx.doi.org/10.1179/135100001101536346] [PMID: 11642710]
[37]
Chen, Y.; Azad, M.B.; Gibson, S.B. Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ., 2009, 16(7), 1040-1052.
[http://dx.doi.org/10.1038/cdd.2009.49] [PMID: 19407826]
[38]
Afanas’ev, I. Reactive oxygen species signaling in cancer: comparison with aging. Aging Dis., 2011, 2(3), 219-230.
[PMID: 22396874]
[39]
Sheth, S.; Mukherjea, D.; Rybak, L.P.; Ramkumar, V. Mechanisms of cisplatin- induced ototoxicity and otoprotection. Front. Cell. Neurosci., 2017, 11, 338.
[http://dx.doi.org/10.3389/fncel.2017.00338] [PMID: 29163050]
[40]
Hazlitt, R.A.; Teitz, T.; Bonga, J.D.; Fang, J.; Diao, S.; Iconaru, L.; Yang, L.; Goktug, A.N.; Currier, D.G.; Chen, T.; Rankovic, Z.; Min, J.; Zuo, J. Development of second-generation CDK2 inhibitors for the prevention of cisplatin-induced hearing loss. J. Med. Chem., 2018, 61(17), 7700-7709.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00669] [PMID: 30091915]
[41]
Wu, Y.J.; Muldoon, L.L.; Neuwelt, E.A. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J. Pharmacol. Exp. Ther., 2005, 312(2), 424-431.
[http://dx.doi.org/10.1124/jpet.104.075119] [PMID: 15496615]
[42]
Lastwika, K.J.; Wilson, W., III; Li, Q.K.; Norris, J.; Xu, H.; Ghazarian, S.R.; Kitagawa, H.; Kawabata, S.; Taube, J.M.; Yao, S.; Liu, L.N.; Gills, J.J.; Dennis, P.A. A8. Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res., 2016, 76(2), 227-238.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-3362] [PMID: 26637667]
[43]
Jiang, Z.; Yang, Y.; Yang, Y.; Zhang, Y.; Yue, Z.; Pan, Z.; Ren, X. Ginsenoside Rg3 attenuates cisplatin resistance in lung cancer by downregulating PD-L1 and resuming immune. Biomed. Pharmacother., 2017, 96, 378-383.
[http://dx.doi.org/10.1016/j.biopha.2017.09.129] [PMID: 29031195]
[44]
Kang, S.; Min, H. Ginseng, the ‘Immunity Boost’: The effects of Panax ginseng on immune system. J. Ginseng Res., 2012, 36(4), 354-368.
[http://dx.doi.org/10.5142/jgr.2012.36.4.354] [PMID: 23717137]
[45]
Jung, C.H.; Ro, S.H.; Cao, J.; Otto, N.M.; Kim, D.H. mTOR regulation of autophagy. FEBS Lett., 2010, 584(7), 1287-1295.
[http://dx.doi.org/10.1016/j.febslet.2010.01.017] [PMID: 20083114]

Rights & Permissions Print Cite
Article Metrics
67
2
© 2024 Bentham Science Publishers | Privacy Policy