Effects of Platycodin D on apoptosis, migration, invasion and cell cycle arrest of gallbladder cancer cells

Zhang,Xiaoyu; Zhai,Tianyu; Hei,Zhenyu; Zhou,Di; Jin,Longyang; Han,Chao; Wang,Jiandong

doi:10.3892/ol.2020.12174

Effects of Platycodin D on apoptosis, migration, invasion and cell cycle arrest of gallbladder cancer cells

Authors:
- Xiaoyu Zhang
- Tianyu Zhai
- Zhenyu Hei
- Di Zhou
- Longyang Jin
- Chao Han
- Jiandong Wang
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Affiliations: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China, Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510655, P.R. China, Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
Published online on: September 30, 2020 https://doi.org/10.3892/ol.2020.12174
Article Number: 311
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Platycodin D (PD) is a triterpenoid saponin that exists in the roots of Platycodonis. It exhibits evident growth inhibitory effects and potent cytotoxicity against multiple types of cancer. Gallbladder cancer (GBC) is the most common malignant disease of the biliary tract system. Patients with GBC usually have limited available treatment strategies and a poor prognosis. The present study investigated the antitumor effects of PD on human GBC cells in vitro and its underlying molecular mechanisms of action. The results indicated that PD, as assessed using MTT and colony forming assays, induced evident growth inhibition. Flow cytometry indicated that PD robustly induced apoptosis and blocked GBC cells at the G₂/M phase. Cell migration and invasion assays demonstrated that PD effectively inhibited the migratory and invasive abilities of GBC cell lines. Western blotting indicated that PD may initiate mitochondrial destruction in GBC cells through the JNK signaling pathway, thereby inducing apoptosis. The present results indicated that PD may exhibit antitumor effects by inducing apoptosis; inhibiting migration and invasion; and affecting the cell cycle in GBC cells. Therefore, PD has the potential to become a novel antitumor drug for GBC therapy.

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1	Kanthan R, Senger JL, Ahmed S and Kanthan SC: Gallbladder cancer in the 21st century. J Oncol. 2015:9674722015. View Article : Google Scholar : PubMed/NCBI
2	Are C, Ahmad H, Ravipati A, Croo D, Clarey D, Smith L, Price RR, Butte JM, Gupta S, Chaturvedi A and Chowdhury S: Global epidemiological trends and variations in the burden of gallbladder cancer. J Surg Oncol. 115:580–590. 2017. View Article : Google Scholar : PubMed/NCBI
3	Ma MZ, Li CX, Zhang Y, Weng MZ, Zhang MD, Qin YY, Gong W and Quan ZW: Long non-coding RNA HOTAIR, a c-myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. Mol Cancer. 13:1562014. View Article : Google Scholar : PubMed/NCBI
4	Weng M, Gong W, Ma M, Chu B, Qin Y, Zhang M, Lun X, McFadden G, Forsyth P, Yang Y and Quan Z: Targeting gallbladder cancer: Oncolytic virotherapy with myxoma virus is enhanced by rapamycin in vitro and further improved by hyaluronan in vivo. Mol Cancer. 13:822014. View Article : Google Scholar : PubMed/NCBI
5	Millimouno FM, Dong J, Yang L, Li J and Li X: Targeting apoptosis pathways in cancer and perspectives with natural compounds from mother nature. Cancer Prev Res (Phila). 7:1081–1107. 2014. View Article : Google Scholar : PubMed/NCBI
6	Cragg GM and Newman DJ: Plants as a source of anti-cancer agents. J Ethnopharmacol. 100:72–79. 2005. View Article : Google Scholar : PubMed/NCBI
7	Balunas MJ and Kinghorn AD: Drug discovery from medicinal plants. Life Sci. 78:431–441. 2005. View Article : Google Scholar : PubMed/NCBI
8	Chin YW, Balunas MJ, Chai HB and Kinghorn AD: Drug discovery from natural sources. AAPS J. 8:E239–E253. 2006. View Article : Google Scholar : PubMed/NCBI
9	Tada A, Kaneiwa Y, Shoji J and Shibata S: Studies on the saponins of the root of platycodon grandiflorum A. De candolle. I. Isolation and the structure of platycodin-D. Chem Pharm Bulletin (Tokyo). 23:2965–2972. 1975. View Article : Google Scholar
10	Zhou R, Lu Z, Liu K, Guo J, Liu J, Zhou Y, Yang J, Mi M and Xu H: Platycodin D induces tumor growth arrest by activating FOXO3a expression in prostate cancer in vitro and in vivo. Curr Cancer Drug Targets. 14:860–871. 2015. View Article : Google Scholar : PubMed/NCBI
11	Xu C, Sun G, Yuan G, Wang R and Sun X: Effects of platycodin D on proliferation, apoptosis and PI3K/akt signal pathway of human glioma U251 cells. Molecules. 19:21411–21423. 2014. View Article : Google Scholar : PubMed/NCBI
12	Kim MO, Moon DO, Choi YH, Lee JD, Kim ND and Kim GY: Platycodin D induces mitotic arrest in vitro, leading to endoreduplication, inhibition of proliferation and apoptosis in leukemia cells. Int J Cancer. 122:2674–2681. 2008. View Article : Google Scholar : PubMed/NCBI
13	Li T, Xu WS, Wu GS, Chen XP, Wang YT and Lu JJ: Platycodin D induces apoptosis, and inhibits adhesion, migration and invasion in hepG2 hepatocellular carcinoma cells. Asian Pac J Cancer Prev. 15:1745–1749. 2014. View Article : Google Scholar : PubMed/NCBI
14	Yu JS and Kim AK: Platycodin D induces apoptosis in MCF-7 human breast cancer cells. J Med Food. 13:298–305. 2010. View Article : Google Scholar : PubMed/NCBI
15	Chun J, Joo EJ, Kang M and Kim YS: Platycodin D induces anoikis and caspase-mediated apoptosis via p38 MAPK in AGS human gastric cancer cells. J Cell Biochem. 114:456–470. 2013. View Article : Google Scholar : PubMed/NCBI
16	Ahn KS, Noh EJ, Zhao HL, Jung SH, Kang SS and Kim YS: Inhibition of inducible nitric oxide synthase and cyclooxygenase II by platycodon grandiflorum saponins via suppression of nuclear factor-kappaB activation in RAW 264.7 cells. Life Sci. 76:2315–2328. 2005. View Article : Google Scholar : PubMed/NCBI
17	Chun J and Kim YS: Platycodin D inhibits migration, invasion, and growth of MDA-MB-231 human breast cancer cells via suppression of EGFR-mediated akt and MAPK pathways. Chem Biol Interact. 205:212–221. 2013. View Article : Google Scholar : PubMed/NCBI
18	Li T, Tang ZH, Xu WS, Wu GS, Wang YF, Chang LL, Zhu H, Chen XP, Wang YT, Chen Y and Lu JJ: Platycodin D triggers autophagy through activation of extracellular signal-regulated kinase in hepatocellular carcinoma HepG2 cells. Eur J Pharmacol. 749:81–88. 2015. View Article : Google Scholar : PubMed/NCBI
19	Cosulich SC, Savory PJ and Clarke PR: Bcl-2 regulates amplification of caspase activation by cytochrome c. Curr Biol. 9:147–150. 1999. View Article : Google Scholar : PubMed/NCBI
20	Nuñez G and Clarke MF: The Bcl-2 family of proteins: Regulators of cell death and survival. Trends Cell Biol. 4:399–403. 1994. View Article : Google Scholar : PubMed/NCBI
21	Li T, Chen X, Chen X, Ma DL, Leung CH and Lu JJ: Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells. Sci Rep. 6:379972016. View Article : Google Scholar : PubMed/NCBI
22	Li T, Xu XH, Tang ZH, Wang YF, Leung CH, Ma DL, Chen XP, Wang YT, Chen Y and Lu JJ: Platycodin D induces apoptosis and triggers ERK- and JNK-mediated autophagy in human hepatocellular carcinoma BEL-7402 cells. Acta Pharmacol Sin. 36:1503–1513. 2015. View Article : Google Scholar : PubMed/NCBI
23	Bauvois B: New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: Outside-in signaling and relationship to tumor progression. Biochim Biophys Acta. 1825:29–36. 2012.PubMed/NCBI
24	Cory S and Adams JM: The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002. View Article : Google Scholar : PubMed/NCBI
25	Thornberry NA and Lazebnik Y: Caspases: Enemies within. Science. 281:1312–1316. 1998. View Article : Google Scholar : PubMed/NCBI
26	Campbell KJ and Tait SW: Targeting BCL-2 regulated apoptosis in cancer. Open Biol. 8:1800022018. View Article : Google Scholar : PubMed/NCBI
27	Wang W, Guo Q, You Q, Zhang K, Yang Y, Yu J, Liu W, Zhao L, Gu H, Hu Y, et al: Involvement of bax/bcl-2 in wogonin-induced apoptosis of human hepatoma cell line SMMC-7721. Anticancer Drugs. 17:797–805. 2006. View Article : Google Scholar : PubMed/NCBI
28	Jin CY, Moon DO, Choi YH, Lee JD and Kim GY: Bcl-2 and caspase-3 are major regulators in agaricus blazei-induced human leukemic U937 cell apoptosis through dephoshorylation of akt. Biol Pharm Bull. 30:1432–1437. 2007. View Article : Google Scholar : PubMed/NCBI
29	Vaux DL, Cory S and Adams JM: Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 335:440–442. 1988. View Article : Google Scholar : PubMed/NCBI
30	Cheng N, Janumyan YM, Didion L, Van Hofwegen C, Yang E and Knudson CM: Bcl-2 inhibition of T-cell proliferation is related to prolonged T-cell survival. Oncogene. 23:3770–3780. 2004. View Article : Google Scholar : PubMed/NCBI
31	Pistritto G, Trisciuoglio D, Ceci C, Garufi A and D'Orazi G: Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 8:603–619. 2016. View Article : Google Scholar : PubMed/NCBI
32	Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI
33	Zaman S, Wang R and Gandhi V: Targeting the apoptosis pathway in hematologic malignancies. Leuk Lymphoma. 55:1980–1992. 2014. View Article : Google Scholar : PubMed/NCBI
34	Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 270:1326–1331. 1995. View Article : Google Scholar : PubMed/NCBI
35	Stark GR and Taylor WR: Control of the G2/M transition. Mol Biotechnol. 32:227–248. 2006. View Article : Google Scholar : PubMed/NCBI
36	Malumbres M: Cyclin-dependent kinases. Genome Biol. 15:1222014. View Article : Google Scholar : PubMed/NCBI