Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung cancer cells

Zhang,Meng; Bian,Zhi-Gang; Zhang,Yi; Wang,Jia-He; Kan,Liang; Wang,Xin; Niu,Hui-Yan; He,Ping

doi:10.3892/mmr.2014.2581

Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung cancer cells

Authors:
- Meng Zhang
- Zhi-Gang Bian
- Yi Zhang
- Jia-He Wang
- Liang Kan
- Xin Wang
- Hui-Yan Niu
- Ping He
View Affiliations

Affiliations: Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China, Department of Otolaryngology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: September 18, 2014 https://doi.org/10.3892/mmr.2014.2581
Pages: 2905-2911
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Natural products are a great source of cancer chemotherapeutic agents. The present study was conducted to investigate whether cucurbitacin B (CuB), one of the most potent and widely used cucurbitacins, inhibits proliferation and induces apoptosis in the A549 lung cancer cell line. Furthermore, CuB induced apoptosis of A549 cells in a concentration-dependent manner, as determined by fluorescence microscopy, flow cytometry and transmission electron microscopy. The present study also demonstrated that CuB dose-dependently inhibited lung cancer cell proliferation, with cell cycle inhibition and cyclin B1 downregulation. Apoptosis induced by CuB was shown to be associated with cytochrome c release, B-cell lymphoma 2 downregulation and signal transducer and activator of transcription 3 pathway inhibition. CuB may prove to be a useful approach for the chemotherapy of lung cancer.

View Figures

View References

1	Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 346:92–98. 2002. View Article : Google Scholar
3	Zhang Y, Zhang GB, Xu XM, et al: Suppression of growth of A549 lung cancer cells by waltonitone and its mechanisms of action. Oncol Rep. 28:1029–1035. 2012.PubMed/NCBI
4	Reyes-Zurita FJ, Rufino-Palomares EE, Lupiañez JA and Cascante M: Maslinic acid, a natural triterpene from Olea europaea L., induces apoptosis in HT29 human colon-cancer cells via the mitochondrial apoptotic pathway. Cancer Lett. 273:44–54. 2009.PubMed/NCBI
5	Liu T, Zhang M, Zhang H, et al: Combined antitumor activity of cucurbitacin B and docetaxel in laryngeal cancer. Eur J Pharmacol. 587:78–84. 2008. View Article : Google Scholar : PubMed/NCBI
6	Jayaprakasam B, Seeram NP and Nair MG: Anticancer and antiinflammatory activities of cucurbitacins from Cucurbita andreana. Cancer Lett. 189:11–16. 2003. View Article : Google Scholar : PubMed/NCBI
7	Kongtun S, Jiratchariyakul W, Kummalue T, et al: Cytotoxic properties of root extract and fruit juice of Trichosanthes cucumerina. Planta Med. 75:839–842. 2009. View Article : Google Scholar : PubMed/NCBI
8	Zhang M, Zhang H, Sun C, et al: Targeted constitutive activation of signal transducer and activator of transcription 3 in human hepatocellular carcinoma cells by cucurbitacin B. Cancer Chemother Pharmacol. 63:635–642. 2009. View Article : Google Scholar : PubMed/NCBI
9	Hsu HF, Houng JY, Kuo CF, Tsao N and Wu YC: Glossogin, a novel phenylpropanoid from Glossogyne tenuifolia, induced apoptosis in A549 lung cancer cells. Food Chem Toxicol. 46:3785–3791. 2008.PubMed/NCBI
10	Magesh V, Lee JC, Ahn KS, et al: Ocimum sanctum induces apoptosis in A549 lung cancer cells and suppresses the in vivo growth of Lewis lung carcinoma cells. Phytother Res. 23:1385–1391. 2009. View Article : Google Scholar
11	Thoennissen NH, Iwanski GB, Doan NB, et al: Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells. Cancer Res. 69:5876–5884. 2009. View Article : Google Scholar
12	Liu T, Zhang M, Zhang H, Sun C and Deng Y: Inhibitory effects of cucurbitacin B on laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol. 265:1225–1232. 2008. View Article : Google Scholar : PubMed/NCBI
13	Chan KT, Meng FY, Li Q, et al: Cucurbitacin B induces apoptosis and S phase cell cycle arrest in BEL-7402 human hepatocellular carcinoma cells and is effective via oral administration. Cancer Lett. 294:118–124. 2010. View Article : Google Scholar
14	Xu X, Zhang Y, Qu D, Jiang T and Li S: Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway. J Exp Clin Cancer Res. 30:332011. View Article : Google Scholar : PubMed/NCBI
15	Jackman M, Lindon C, Nigg EA and Pines J: Active cyclin B1-Cdk1 first appears on centrosomes in prophase. Nat Cell Biol. 5:143–148. 2003. View Article : Google Scholar : PubMed/NCBI
16	Yasuda S, Yogosawa S, Izutani Y, et al: Cucurbitacin B induces G2 arrest and apoptosis via a reactive oxygen species-dependent mechanism in human colon adenocarcinoma SW480 cells. Mol Nutr Food Res. 54:559–565. 2010. View Article : Google Scholar : PubMed/NCBI
17	Yang L, Wu S, Zhang Q, Liu F and Wu P: 23,24-Dihydrocucurbitacin B induces G2/M cell-cycle arrest and mitochondria-dependent apoptosis in human breast cancer cells (Bcap37). Cancer Lett. 256:267–278. 2007. View Article : Google Scholar : PubMed/NCBI
18	Braun F, de Carne Trecesson S, Bertin-Ciftci J and Juin P: Protect and serve: Bcl-2 proteins as guardians and rulers of cancer cell survival. Cell Cycle. 12:2937–2947. 2013. View Article : Google Scholar : PubMed/NCBI
19	Yang J, Liu X, Bhalla K, et al: Prevention of apoptosis by Bcl-2: release of cytochrome C from mitochondria blocked. Science. 275:1129–1132. 1997. View Article : Google Scholar : PubMed/NCBI
20	Hu Y, Benedict MA, Ding L and Nuñez G: Role of cytochrome C and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J. 18:3586–3595. 1999. View Article : Google Scholar : PubMed/NCBI
21	Malladi S, Challa-Malladi M, Fearnhead HO and Bratton SB: The Apaf-1^*procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer. EMBO J. 28:1916–1925. 2009.
22	Inoue S, Browne G, Melino G and Cohen GM: Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway. Cell Death Differ. 16:1053–1061. 2009. View Article : Google Scholar : PubMed/NCBI
23	Niu G, Wright KL, Huang M, et al: Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 21:2000–2008. 2002. View Article : Google Scholar : PubMed/NCBI
24	Diaz N, Minton S, Cox C, et al: Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin Cancer Res. 12:20–28. 2006. View Article : Google Scholar
25	Yeh HH, Chang WT, Lu KC, et al: Upregulation of tissue factor by activated Stat3 contributes to malignant pleural effusion generation via enhancing tumor metastasis and vascular permeability in lung adenocarcinoma. PLoS One. 8:e752872013. View Article : Google Scholar
26	Chan KS, Sano S, Kiguchi K, et al: Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest. 114:720–728. 2004. View Article : Google Scholar : PubMed/NCBI
27	Yu H and Jove R: The STATs of cancer - new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI