Deoxypodophyllotoxin induces cell cycle arrest and apoptosis in human cholangiocarcinoma cells

Xiao,Meifang; Fan,Xuegong; Fu,Yongming; Zhou,Yujuan; Liu,Shaohui; Peng,Shifang

doi:10.3892/ol.2018.8978

Deoxypodophyllotoxin induces cell cycle arrest and apoptosis in human cholangiocarcinoma cells

Authors:
- Meifang Xiao
- Xuegong Fan
- Yongming Fu
- Yujuan Zhou
- Shaohui Liu
- Shifang Peng
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Affiliations: Department of Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Radiotherapy, Hunan Cancer Hospital, Changsha, Hunan 410013, P.R. China
Published online on: June 18, 2018 https://doi.org/10.3892/ol.2018.8978
Pages: 3177-3182

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Abstract

Deoxypodophyllotoxin (DPT), a naturally occurring flavolignan, has a broad range of biological effects, including anti‑inflammatory, anti‑viral and anticancer properties. The present study investigated the anti‑proliferative effect of DPT on human cholangiocarcinoma QBC939 and RBE cell lines and its underlying mechanisms of inducing cytotoxicity. MTT assays demonstrated that DPT inhibited the viability of the QBC939 and RBE cells in a dose and time‑dependent manner. In addition, DPT treatment resulted in G2/M phase cell cycle arrest associated with the downregulation of Cyclin B and cyclin dependent kinase 1 and caused an increase in apoptosis that was confirmed by characteristic morphological changes. Apoptosis was accompanied by increasing B‑cell lymphoma-2 (Bcl‑2)/Bcl‑2 associated X protein ratios and activated expression of caspase‑3, ‑8 and ‑9. These findings suggested that DPT may be a novel anticancer agent against human cholangiocarcinoma.

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1	Burger I, Hong K, Schulick R, Georgiades C, Thuluvath P, Choti M, Kamel I and Geschwind JF: Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: Initial experience in a single institution. J Vasc Interv Radiol. 16:353–361. 2005. View Article : Google Scholar : PubMed/NCBI
2	Gatto M, Bragazzi MC, Semeraro R, Napoli C, Gentile R, Torrice A, Gaudio E and Alvaro D: Cholangiocarcinoma: Update and future perspectives. Dig Liver Dis. 42:253–260. 2010. View Article : Google Scholar : PubMed/NCBI
3	Hammill CW and Wong LL: Intrahepatic cholangiocarcinoma: A malignancy of increasing importance. J Am Coll Surg. 207:594–603. 2008. View Article : Google Scholar : PubMed/NCBI
4	Yap TA and Workman P: Exploiting the cancer genome: Strategies for the discovery and clinical development of targeted molecular therapeutics. Annu Rev Pharmacol Toxicol. 52:549–573. 2012. View Article : Google Scholar : PubMed/NCBI
5	Ikeda R, Nagao T, Okabe H, Nakano Y, Matsunaga H, Katano M and Mori M: Antiproliferative constituents in umbelliferae plants. III. Constituents in the root and the ground part of Anthriscus sylvestris Hoffm. Chem Pharm Bull. 46:871–874. 1998. View Article : Google Scholar : PubMed/NCBI
6	Masuda T, Oyama Y, Yonemori S, Takeda Y, Yamazaki Y, Mizuguchi S, Nakata M, Tanaka T, Chikahisa L, Inabak Y and Okada Y: Flow cytometric estimation on cytotoxic activity of leaf extracts from seashore plants in subtropical Japan: Isolation, quantification and cytotoxic action of (−)-deoxypodophyllotoxin. Phytother Res. 16:353–358. 2002. View Article : Google Scholar : PubMed/NCBI
7	Muto N, Tomokuni T, Haramoto M, Tatemoto H, Nakanishi T, Inatomi Y, Murata H and Inada A: Isolation of apoptosis- and differentiation-inducing substances toward human promyelocytic leukemia HL-60 cells from leaves of Juniperus taxifolia. Biosci Biotechnol Biochem. 72:477–484. 2008. View Article : Google Scholar : PubMed/NCBI
8	Yong Y, Shin SY, Lee YH and Lim Y: Antitumor activity of deoxypodophyllotoxin isolated from Anthriscus sylvestris: Induction of G2/M cell cycle arrest and caspase-dependent apoptosis. Bioorg Med Chem Lett. 9:4367–4371. 2009. View Article : Google Scholar
9	Shin SY, Yong Y, Kim CG, Lee YH and Lim Y: Deoxypodophyllotoxin induces G2/M cell cycle arrest and apoptosis in HeLa cells. Cancer Lett. 287:231–239. 2010. View Article : Google Scholar : PubMed/NCBI
10	Wu M, Jiang Z, Duan H, Sun L, Zhang S, Chen M, Wang Y, Gao Q, Song Y, Zhu X and Zhang L: Deoxypodophyllotoxin triggers necroptosis in human non-small cell lung cancer NCI-H460 cells. Biomed Pharmacother. 67:701–706. 2013. View Article : Google Scholar : PubMed/NCBI
11	Wang YR, Xu Y, Jiang ZZ, Guerram M, Wang B, Zhu X and Zhang LY: Deoxypodophyllotoxin induces G2/M cell cycle arrest and apoptosis in SGC-7901 cells and inhibits tumor growth in vivo. Molecules. 20:1661–1675. 2015. View Article : Google Scholar : PubMed/NCBI
12	Benzina S, Harquail J, Jean S, Beauregard AP, Colguhoun CD, Carroll M, Bos A, Gray CA and Robichaud GA: Deoxypodophyllotoxin isolated from Juniperus communis induces apoptosis in breast cancer cells. Anticancer Agents Med Chem. 15:79–88. 2015. View Article : Google Scholar : PubMed/NCBI
13	Mounia G, Jiang ZZ, Sun LX, Zhu X and Zhang LX: Antineoplastic effects of deoxypodophyllotoxin, a potent cytotoxic agent of plant origin, on glioblastoma U-87 MG and SF126 cells. Pharmacol Rep. 67:245–252. 2015. View Article : Google Scholar : PubMed/NCBI
14	Lee SH, Son MJ, Ju HK, Lin CX, Moom TC, Choi HG, Son JK and Chang HW: Dual inhibition of cyclooxygenases-2 and 5-lipoxygenase by deoxypodophyllotoxin in mouse bone narrow-derivd mast cells. Biol Pharm Bill. 27:786–788. 2004. View Article : Google Scholar
15	Sudo K, Konno K, Shigeta S and Yokota T: Inhibitory effects of podophyllotoxin derivatives on herpes simplex virus replication. Antivir Chem Chemother. 9:263–267. 1998. View Article : Google Scholar : PubMed/NCBI
16	Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI
17	Niemann-Jönsson A, Ares MP, Yan ZQ, Bu DX, Fredrikson GN, Brånén L, Pörn-Ares I, Nilsson AH and Nilsson J: Increased rate of apoptosis in intimal arterial smooth muscle cells through endogenous activation of TNF receptors. Arterioscler Thromb Vasc Biol. 21:1909–1914. 2001. View Article : Google Scholar : PubMed/NCBI
18	Meier P, Finch A and Evan G: Apoptosis in development. Nature. 407:796–801. 2000. View Article : Google Scholar : PubMed/NCBI
19	Lizotte E, Tremblay A, Allen BG and Fiset C: Isolation and characterization of subcellular protein fractions from mouse heart. Anal Biochem. 345:47–54. 2015. View Article : Google Scholar
20	Cho JH, Lee JG, Yang YI, Kim JH, Ahn JH, Baek NI, Lee KT and Choi JH: Eupatilin, a dietary flavonoid, induces G2/M cell cycle arrest in human endometrial cancer cells. Food Chem Toxicol. 49:1737–1744. 2011. View Article : Google Scholar : PubMed/NCBI
21	Taylor WR and Stark GR: Regulation of the G2/M transition by p53. Oncogene. 20:1803–1815. 2001. View Article : Google Scholar : PubMed/NCBI
22	Smits VJ and Medema RH: Checking out the G(2)/M transition. Biochim Biophys Acta. 1519:1–12. 2001. View Article : Google Scholar : PubMed/NCBI
23	Yang R, Liu A, Ma X, Li L, Su D and Liu J: Sodium tanshinone IIA sulfonate protects cardiomyocytes against oxidative stress-mediated apoptosis through inhibiting JNK activation. J Cardiovasc Pharmacol. 51:396–401. 2008. View Article : Google Scholar : PubMed/NCBI
24	Hengartner MO: The biochemistry of apoptosis. Nature. 407:770–776. 2000. View Article : Google Scholar : PubMed/NCBI
25	Neto CC, Amoroso JW and Liberty AM: Anticancer activities of cranberry phytochemicals: An update. Mol Nutr Food Res. 52 Suppl 1:S18–S27. 2008.PubMed/NCBI
26	Wei H and John JK: Anticancer therapy targeting the apoptotic pathway. Oncology. 4:721–729. 2003.PubMed/NCBI
27	Delivani P and Martin SJ: Mitochondrial membrane remodeling apoptosis: An inside story. Cell Death Differ. 13:2007–2010. 2006. View Article : Google Scholar : PubMed/NCBI
28	Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT and Thompson CB: Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell. 91:627–637. 1997. View Article : Google Scholar : PubMed/NCBI
29	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
30	Green DR: Apoptotic pathways: Ten min to dead. Cell. 121:671–674. 2005. View Article : Google Scholar : PubMed/NCBI
31	Liu X, Yue P, Zhou Z, Khuri FR and Sun SY: Death receptor regulation and celecoxib-induced apoptosis in human lung cancer cells. J Natl Cancer Inst. 96:1769–1780. 2004. View Article : Google Scholar : PubMed/NCBI