Bufalin exerts antitumor effects by inducing cell cycle arrest and triggering apoptosis in pancreatic cancer cells
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As one of the most aggressive human malignancies, pancreatic cancer is a leading cause of cancer-related deaths worldwide and only about 4 % of patients will live 5 years after diagnosis. Eighty to approximately eighty-five percent of patients are diagnosed with an unresectable or metastatic disease, which is correlated with poor prognosis and low survival rate. Therefore, it is tremendously significant to exploit novel chemicals to prevent and treat pancreatic cancer. Previous research and clinical studies have demonstrated that many natural products derived from traditional Chinese medicine (TCM) such as camptothecin derivatives and vinca alkaloids could be effective antitumor compounds, hinting that TCM is a promising source for developing new antitumor drugs. In this report, we investigated the effects of bufalin, a primary active ingredient of the traditional Chinese medicine Chan-Su, on pancreatic cancer cell lines PANC-1 and CFPAC-1 and studied the underlying molecular mechanism. We found that exposure to bufalin could suppress the proliferation of pancreatic cancer cells time and dose dependently. We used flow cytometry to study the effects of bufalin on apoptosis and cell cycle distribution in PANC-1 and CFPAC-1 cells. The results indicated that bufalin could significantly induce both apoptosis and G2/M cell cycle arrest in pancreatic cancer cells. With western blotting, we found that the expression level of an antiapoptotic protein heat shock protein 27 (Hsp27) and its partner molecule p-Akt was decreased upon the treatment with bufalin. Besides, bufalin activated pro-caspase-3 and pro-caspase-9 and modulated the expression level of Bcl-2 and Bax. These data suggested that bufalin may trigger apoptosis by targeting Hsp27, which could inhibit apoptosis by interfering with key apoptotic proteins. The influence on the level of cylinB1, CDK1, and p21 was also observed after bufalin treatment, and the relationship between Hsp27 and the cell cycle-related proteins mentioned above deserves much more research. In addition, our data showed that bufalin could enhance the growth inhibition effect of gemcitabine in above pancreatic cancer cells. Taken together, bufalin might be worthy of further study for its potential as a therapeutic agent for pancreatic cancer treatment.
KeywordsPancreatic cancer Bufalin Antitumor Cell cycle arrest Apoptosis Hsp27
This study was supported by the National Natural Science Foundation of China (81201934, 81100645), Specialized Research Fund for the Doctoral Program of Higher Education (20120131120061), China Postdoctoral Science Foundation (2013 M531612) and Independent Innovation Foundation of Shandong University (2012TS155).
Conflicts of interest
- 6.Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale. Cancer. 2002;94:902–10.PubMedCrossRefGoogle Scholar
- 7.Colucci G, Labianca R, Di Costanzo F, Gebbia V, Carteni G, Massidda B, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the gip-1 study. J Clin Oncol. 2010;28:1645–51.PubMedCrossRefGoogle Scholar
- 9.Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.PubMedCrossRefGoogle Scholar
- 11.Von Hoff D, Ervin TJ, Arena FP, Chiorean EG, Infante JR, Moore MJ, Seay TE, Tjulandin S, Ma WW, Saleh MN: Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT): 2013 ASCO Gastrointestinal Cancers Symposium, Abstract, 2012, 148, pp 24–26Google Scholar
- 13.Xie XB, Yin JQ, Wen LL, Gao ZH, Zou CY, Wang J, et al. Critical role of heat shock protein 27 in bufalin-induced apoptosis in human osteosarcomas: a proteomic-based research. PLoS One. 2012;7:16.Google Scholar
- 16.Hsiao YP, Yu CS, Yu CC, Yang JS, Chiang JH, Lu CC, et al. Triggering apoptotic death of human malignant melanoma a375.S2 cells by bufalin: involvement of caspase cascade-dependent and independent mitochondrial signaling pathways. Evid Based Complement Alternat Med. 2012;591241:7.Google Scholar
- 21.Huang WW, Yang JS, Pai SJ, Wu PP, Chang SJ, Chueh FS, et al. Bufalin induces g(0)/g(1) phase arrest through inhibiting the levels of cyclin d, cyclin e, cdk2 and cdk4, and triggers apoptosis via mitochondrial signaling pathway in t24 human bladder cancer cells. Mutat Res. 2012;732:26–33.PubMedCrossRefGoogle Scholar
- 26.Kapranos N, Kominea A, Konstantinopoulos PA, Savva S, Artelaris S, Vandoros G, et al. Expression of the 27-kda heat shock protein (hsp27) in gastric carcinomas and adjacent normal, metaplastic, and dysplastic gastric mucosa, and its prognostic significance. J Cancer Res Clin Oncol. 2002;128:426–32.PubMedCrossRefGoogle Scholar
- 34.Baylot V, Andrieu C, Katsogiannou M, Taieb D, Garcia S, Giusiano S, et al. Ogx-427 inhibits tumor progression and enhances gemcitabine chemotherapy in pancreatic cancer. Cell Death Dis. 2011;20:104.Google Scholar
- 38.Zhu Z, Li E, Liu Y, Gao Y, Sun H, Ma G, et al. Inhibition of jak-stat3 pathway enhances bufalin-induced apoptosis in colon cancer sw620 cells. World J Surg Oncol. 2012;10:1477–7819.Google Scholar
- 47.Hardwick JM, Soane L. Multiple functions of bcl-2 family proteins. Cold Spring Harb Perspect Biol. 2013;5(2). doi: 10.1101/cshperspect.a008722.