Differential effects of ginkgol C17:1 on cisplatin‑induced cytotoxicity: Protecting human normal L02 hepatocytes versus sensitizing human hepatoma HepG2 cells

Li,Yueying; Zhang,Xinchi; Yang,Xiaoming; Liu,Jun; Li,Linjie; Ma,Wenbin; Chen,Min

doi:10.3892/ol.2019.9974

Differential effects of ginkgol C17:1 on cisplatin‑induced cytotoxicity: Protecting human normal L02 hepatocytes versus sensitizing human hepatoma HepG2 cells

Authors:
- Yueying Li
- Xinchi Zhang
- Xiaoming Yang
- Jun Liu
- Linjie Li
- Wenbin Ma
- Min Chen
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Affiliations: Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China, Department of Food Science and Engineering, School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China, Department of Biology, Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
Published online on: January 25, 2019 https://doi.org/10.3892/ol.2019.9974
Pages: 3181-3190
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Liver cancer is a major healthcare problem and one of the leading causes of cancer‑associated mortality in the world. To date, chemotherapy remains a common method for treating cancer and cisplatin is one of the most widely used chemotherapeutics. However, owing to drug resistance and side effects, it is imperative to identify a novel approach to improve the anticancer effect of cisplatin. Auxiliary chemotherapy drugs with minor toxicity to normal cells may represent a novel strategy for cancer therapy. Previous studies have indicated that ginkgol C17:1 exhibits anticancer effects in liver cancer cells in vitro and in vivo. The antitumor activity of ginkgol C17:1 has been reported in combination with cisplatin in human liver cancer cells. Owing to the route of systemic administration, liver cancer cells and normal hepatocytes were exposed to chemotherapeutics and auxiliary chemotherapy drugs. However, the effects of ginkgol C17:1 in normal hepatocytes remain unclear. In the present study, the biological effects of ginkgol C17:1 alone and as co‑treatment with cisplatin were compared in human hepatoma cells and normal hepatocytes. Consistently, the results confirmed that in human hepatoma HepG2 cells, ginkgol C17:1 or cisplatin alone induced autophagy and apoptosis. The co‑treatment increased cisplatin‑induced apoptosis and inhibited cisplatin‑induced autophagy. In comparison, the treatments in human normal L02 hepatocytes indicated that ginkgol C17:1 alone induced autophagy, whereas cisplatin alone induced apoptosis. The co‑treatment inhibited cisplatin‑induced apoptosis, but enhanced autophagy in L02 cells. Further investigation revealed that the AMP‑activated protein kinase/serine/threonine protein kinase ULK1 and phosphoinositide 3‑kinase/protein kinase B/mammalian target of rapamycin signaling pathways were involved in the underlying regulatory mechanisms. Taken together, the results of the present study provide the first evidence that ginkgol C17:1 protects normal hepatocytes against cisplatin‑induced cytotoxicity while potentiating the anticancer effect of cisplatin chemotherapy. The differential effects on normal and cancer cells suggest that ginkgol C17:1 is a promising candidate for auxiliary chemotherapy.

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1	Pascual S, Herrera I and Irurzun J: New advances in hepatocellular carcinoma. World J Hepatol. 8:421–438. 2016. View Article : Google Scholar : PubMed/NCBI
2	Marquardt JU, Andersen JB and Thorgeirsson SS: Functional and genetic deconstruction of the cellular origin in liver cancer. Nat Rev Cancer. 15:653–667. 2015. View Article : Google Scholar : PubMed/NCBI
3	Sun BS, Dong QZ, Ye QH, Sun HJ, Jia HL, Zhu XQ, Liu DY, Chen J, Xue Q, Zhou HJ, et al: Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology. 48:1834–1842. 2008. View Article : Google Scholar : PubMed/NCBI
4	Yang Y, Lu Y, Wang C, Bai W, Qu J, Chen Y, Chang X, An L, Zhou L, Zeng Z, et al: Cryotherapy is associated with improved clinical outcomes of Sorafenib therapy for advanced hepatocellular carcinoma. Cell Biochem Biophys. 63:159–169. 2012. View Article : Google Scholar : PubMed/NCBI
5	Boulikas T and Vougiouka M: Cisplatin and platinum drugs at the molecular level (Review). Oncol Rep. 10:1663–1682. 2003.PubMed/NCBI
6	Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 7:573–584. 2007. View Article : Google Scholar : PubMed/NCBI
7	Markman M: Toxicities of the platinum antineoplastic agents. Expert Opin Drug Saf. 2:597–607. 2003. View Article : Google Scholar : PubMed/NCBI
8	Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, Wang BY, Teng YE, Tong ZS, Pan YY, et al: Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): A randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 16:436–446. 2015. View Article : Google Scholar : PubMed/NCBI
9	Mizushima N and Komatsu M: Autophagy: Renovation of cells and tissues. Cell. 147:728–741. 2011. View Article : Google Scholar : PubMed/NCBI
10	Lu SZ and Harrison-Findik DD: Autophagy and cancer. World J Biol Chem. 4:64–70. 2013. View Article : Google Scholar : PubMed/NCBI
11	White E: The role for autophagy in cancer. J Clin Invest. 125:42–46. 2015. View Article : Google Scholar : PubMed/NCBI
12	Amaravadi R, Kimmelman AC and White E: Recent insights into the function of autophagy in cancer. Genes Dev. 30:1913–1930. 2016. View Article : Google Scholar : PubMed/NCBI
13	Chen J, Wang Q, Yin FQ, Zhang W, Yan LH and L Li: MTRR silencing inhibits growth and cisplatin resistance of ovarian carcinoma via inducing apoptosis and reducing autophagy. Am J Transl Res. 7:1510–1527. 2015.PubMed/NCBI
14	Nikoletopoulou V, Markaki M, Palikaras K and Tavernarakis N: Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta 1833. 3448–3359. 2013.
15	Li F, Zeng J, Gao Y, Guan Z, Ma Z, Shi Q, Du C, Jia J, Xu S, Wang X, et al: G9a inhibition induces autophagic cell death via AMPK/mTOR pathway in bladder transitional cell carcinoma. PLoS One. 10:e01383902015. View Article : Google Scholar : PubMed/NCBI
16	Vanhaesebroeck B, Stephens L and Hawkins P: PI3K signaling: The path to discovery and understanding. Nat Rev Mol Cell Biol. 13:195–203. 2012. View Article : Google Scholar : PubMed/NCBI
17	Xu K, Liu P and Wie W: mTOR signaling in tumorigenesis. Biochim Biophys Acta 1846. 638–654. 2014.
18	Cheong H, Lindsten T, Wu J, Lu C and Thompson CB: Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc Natl Acad Sci USA. 108:11121–11126. 2011. View Article : Google Scholar : PubMed/NCBI
19	Nash KM and Shah ZA: Current perspectives on the beneficial role of ginkgo biloba in neurological and cerebrovascular disorders. Integr Med Insights. 10:1–9. 2015. View Article : Google Scholar : PubMed/NCBI
20	Ni XW and Wu MC: Study on antitumor activities of ginkgolic acids from Ginkgo sarcotestas. J Huazhong Agricul Univ. 4:49–51. 2006.
21	Wang YF, Yang XM, Li YY, Li J, Huang BZ, Guo CY, Yi N and Xing CH: Inhibitory effect of ginkgols on SMMC-7721 liver cancer cells in vitro and liver cancer H22-bearing mice in vivo. J Jiangsu Univ. 23:2332013.
22	Chen Q, Yang GW and An LG: Apoptosis of hepatoma cells SMMC-7721 induced by Ginkgo biloba seed polysaccharide. World J Gastroenterol. 8:832–836. 2002. View Article : Google Scholar : PubMed/NCBI
23	Yang XM, Wang YF, Li YY and Ma HL: Thermal stability of ginkgolic acids from Ginkgo biloba and the effects of ginkgol C17:1 on the apoptosis and migration of SMMMC7721 cells. Fitoterapia. 98:66–76. 2014. View Article : Google Scholar : PubMed/NCBI
24	Liu J, Li Y, Yang X, Dong Y, Wu J and Chen M: Effects of ginkgol C17:1 on cisplatin-induced autophagy and apoptosis in HepG2 cells. Oncol Lett. 15:1021–1029. 2018.PubMed/NCBI
25	Yang XM, Zhang XL, Chen YC and Liu F: LC method for determination of ginkgolic acids in mice plasma and its application to pharmacokinetic study. Chromatographia. 69:593–596. 2009. View Article : Google Scholar
26	Fang YY, Yang XM, Li YY and Feng CL: Spectroscopic studies on the interaction of bovine serum albumin with Ginkgol C15:1 from Ginkgo biloba L. J Luminesceence. 162:203–211. 2015. View Article : Google Scholar
27	Li Y, Liu J, Yang X, Dong Y, Liu Y and Chen M: Ginkgol C17:1 inhibits tumor growth by blunting the EGF- PI3K/Akt signaling pathway. J Biomed Res. 31:232–239. 2017.PubMed/NCBI
28	Ni HM, Bockus A, Wozniak AL, Jones K, Weinman S, Yin XM and Ding WX: Dissecting the dynamic turnover of GFP-LC3 in the autolysosome. Autophagy. 7:188–204. 2011. View Article : Google Scholar : PubMed/NCBI
29	Hu D, Wu J, Xu L, Zhang R and Chen L: A method for the establishment of a cell line with stable expression of the GFP-LC3 reporter protein. Mol Med Rep. 6:783–786. 2012. View Article : Google Scholar : PubMed/NCBI
30	Ndagi U, Mhlongo N and Soliman ME: Metal complexes in cancer therapy-an update from drug design perspective. Drug Des Devel Ther. 11:599–616. 2017. View Article : Google Scholar : PubMed/NCBI
31	Ziko L, Riad S, Amer M, Zdero R, Bougherara H and Amleh A: Mechanical stress promotes cisplatin-induced hepatocellular carcinoma cell death. Biomed Res Int 2015. 4305692015.
32	Cavallo F, Feldman DR and Barchi M: Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors. Int J Dev Biol. 57:273–280. 2013. View Article : Google Scholar : PubMed/NCBI
33	Zhang HQ, He B, Fang N, Lu S, Liao YQ and Wan YY: Autophagy inhibition sensitizes cisplatin cytotoxicity in human gastric cancer cell line SGC7901. Asian Pac J Cancer Prev. 14:4685–4688. 2013. View Article : Google Scholar : PubMed/NCBI
34	Li Y, Liu J, Liu Y, Yang X, Huang B and Chen M: Inhibitory effect of Ginkgol C17:1 on the biological behavior of tumor cells. Oncol Lett. 13:1873–1879. 2017. View Article : Google Scholar : PubMed/NCBI
35	Wang J and Wu GS: Role of autophagy in cisplatin resistance in ovarian cancer cells. J Biol Chem. 289:17163–17173. 2014. View Article : Google Scholar : PubMed/NCBI
36	Yu L, Gu C, Zhong D, Shi L, Kong Y, Zhou Z and Liu S: Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance. Cancer Lett. 355:34–45. 2014. View Article : Google Scholar : PubMed/NCBI
37	Xu Y, Yu H, Qin H, Kang J, Yu C, Zhong J, Su J, Li H and Sun L: Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells. Cancer Lett. 314:232–243. 2012. View Article : Google Scholar : PubMed/NCBI
38	Yan MM, Ni JD, Song D, Ding M and Huang J: Interplay between unfolded protein response and autophagy promotes tumor drug resistance. Oncol Lett. 10:1959–1969. 2015. View Article : Google Scholar : PubMed/NCBI
39	Zhao J, Nie Y, Wang H and Lin Y: MiR-181a suppresses autophagy and sensitizes gastric cancer cells to cisplatin. Gene. 576:828–833. 2016. View Article : Google Scholar : PubMed/NCBI
40	Kondo Y, Kanzawa T, Sawaya R and Kondo S: The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 5:726–734. 2005. View Article : Google Scholar : PubMed/NCBI
41	Xie BS, Zhao HC, Yao SK, Zhou DX, Jin B, Lv DC, Wu CL, Ma DL, Gao C, Shu XM and Ai ZL: Autophagy inhibition enhances etoposide-induced cell death in human hepatoma G2 cells. Int J Mol Med. 27:599–606. 2011.PubMed/NCBI
42	Shi SQ and Cao H: Shikonin promotes autophagy in BXPC-3 human pancreatic cancer cells through the PI3K/Akt signaling pathway. Oncol Lett. 8:1087–1089. 2014. View Article : Google Scholar : PubMed/NCBI
43	Sharma N, Nanta R, Sharma J, Gunewardena S, Singh KP, Shankar S and Srivastava RK: PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth. Oncotarget. 6:32039–32060. 2015. View Article : Google Scholar : PubMed/NCBI