Molecular mechanisms underlying mangiferin-induced apoptosis and cell cycle arrest in A549 human lung carcinoma cells

Shi,Wei; Deng,Jiagang; Tong,Rongsheng; Yang,Yong; He,Xia; Lv,Jianzhen; Wang,Hailian; Deng,Shaoping; Qi,Ping; Zhang,Dingding; Wang,Yi

doi:10.3892/mmr.2016.4947

Molecular mechanisms underlying mangiferin-induced apoptosis and cell cycle arrest in A549 human lung carcinoma cells

Authors:
- Wei Shi
- Jiagang Deng
- Rongsheng Tong
- Yong Yang
- Xia He
- Jianzhen Lv
- Hailian Wang
- Shaoping Deng
- Ping Qi
- Dingding Zhang
- Yi Wang
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Affiliations: Department of Pediatrics, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China, Guangxi Province Key Laboratory, Guangxi University of Chinese Medicine, Nanning, Guangxi 530200, P.R. China, Department of Pharmacy, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China, Institute of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
Published online on: February 29, 2016 https://doi.org/10.3892/mmr.2016.4947
Pages: 3423-3432
Copyright: © Shi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Mangiferin, which is a C‑glucosylxanthone (1,3,6,7-tetrahydroxyxanthone-C2-β-D-glucoside) purified from plant sources, has recently gained attention due to its various biological activities. The present study aimed to determine the apoptotic effects of mangiferin on A549 human lung adenocarcinoma cells. In vitro studies demonstrated that mangiferin exerted growth‑inhibitory and apoptosis-inducing effects against A549 cells. In addition, mangiferin exhibited anti-tumor properties in A549 xenograft mice in vivo. Mangiferin triggered G2/M phase cell cycle arrest via downregulating the cyclin-dependent kinase 1-cyclin B1 signaling pathway, and induced apoptotic cell death by inhibiting the protein kinase C-nuclear factor-κB pathway. In addition, mangiferin was able to enhance the antiproliferative effects of cisplatin on A549 cells, thus indicating the potential for a combined therapy. Notably, mangiferin exerted anticancer effects in vivo, where it was able to markedly decrease the volume and weight of subcutaneous tumor mass, and expand the lifespan of xenograft mice. The present study clarified the molecular mechanisms underlying mangiferin-induced antitumor activities, and suggested that mangiferin may be considered a potential antineoplastic drug for the future treatment of cancer.

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1	Sánchez GM, Re L, Giuliani A, Núñez-Sellés AJ, Davison GP and León-Fernández OS: Protective effects of Mangifera indica L. extract, mangiferin and selected antioxidants against TPA-induced biomolecules oxidation and peritoneal macrophage activation in mice. Pharmacol Res. 42:565–573. 2000. View Article : Google Scholar : PubMed/NCBI
2	Dar A, Faizi S, Naqvi S, Roome T, Zikr-ur-Rehman S, Ali M, Firdous S and Moin ST: Analgesic and antioxidant activity of mangiferin and its derivatives: The structure activity relationship. Biol Pharm Bull. 28:596–600. 2005. View Article : Google Scholar : PubMed/NCBI
3	Guha S, Ghosal S and Chattopadhyay U: Antitumor, immunomodulatory and anti-HIV effect of mangiferin, a naturally occurring glucosylxanthone. Chemotherapy. 42:443–451. 1996. View Article : Google Scholar : PubMed/NCBI
4	Duang XY, Wang Q, Zhou XD and Huang DM: Mangiferin: A possible strategy for periodontal disease to therapy. Med Hypotheses. 76:486–488. 2011. View Article : Google Scholar : PubMed/NCBI
5	García-Rivera D, Delgado R, Bougarne N, Haegeman G and Berghe WV: Gallic acid indanone and mangiferin xanthone are strong determinants of immunosuppressive anti-tumour effects of Mangifera indica L. bark in MDA-MB231 breast cancer cells. Cancer Lett. 305:21–31. 2011. View Article : Google Scholar : PubMed/NCBI
6	Noratto GD, Bertoldi MC, Krenek K, Talcott ST, Stringheta PC and Mertens-Talcott SU: Anticarcinogenic effects of polyphenolics from mango (Mangifera indica) varieties. J Agric Food Chem. 58:4104–4112. 2010. View Article : Google Scholar : PubMed/NCBI
7	Chieli E, Romiti N, Rodeiro I and Garrido G: In vitro effects of Mangifera indica and polyphenols derived on ABCB1/P-glycoprotein activity. Food Chem Toxicol. 47:2703–2710. 2009. View Article : Google Scholar : PubMed/NCBI
8	Cheng P, Peng ZG, Yang J and Song SJ: The effect of mangiferin on telomerase activity and apoptosis in leukemic K562 cells. Zhong Yao Cai. 30:306–309. 2007.In Chinese. PubMed/NCBI
9	Peng ZG, Luo J, Xia LH, Chen Y and Song SJ: CML cell line K562 cell apoptosis induced by mangiferin. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 12:590–594. 2004.In Chinese. PubMed/NCBI
10	Percival SS, Talcott ST, Chin ST, Mallak AC, Lounds-Singleton A and Pettit-Moore J: Neoplastic transformation of BALB/3T3 cells and cell cycle of HL-60 cells are inhibited by mango (Mangifera indica L.) juice and mango juice extracts. J Nutr. 136:1300–1304. 2006.PubMed/NCBI
11	Chari NS, Pinaire NL, Thorpe L, Medeiros LJ, Routbort MJ and McDonnell TJ: The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death. Apoptosis. 14:336–347. 2009. View Article : Google Scholar : PubMed/NCBI
12	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
13	Hartwell LH and Kastan MB: Cell cycle control and cancer. Science. 266:1821–1828. 1994. View Article : Google Scholar : PubMed/NCBI
14	Vermeulen K, Van Bockstaele DR and Berneman ZN: The cell cycle: A review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 36:131–149. 2003. View Article : Google Scholar : PubMed/NCBI
15	Malumbres M and Barbacid M: Cell cycle, CDKs and cancer: A changing paradigm. Nat Rev Cancer. 9:153–166. 2009. View Article : Google Scholar : PubMed/NCBI
16	Goldstein JC, Waterhouse NJ, Juin P, Evan GI and Green DR: The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol. 2:156–162. 2000. View Article : Google Scholar : PubMed/NCBI
17	Li CY, Wang Y, Wang HL, Shi Z, An N, Liu YX, Liu Y, Zhang J, Bao JK and Deng SP: Molecular mechanisms of Lycoris aurea agglutinin-induced apoptosis and G2/M cell cycle arrest in human lung adenocarcinoma A549 cells, both in vitro and in vivo. Cell Prolif. 46:272–282. 2013. View Article : Google Scholar : PubMed/NCBI
18	Sarkar A, Sreenivasan Y, Ramesh GT and Manna SK: beta-D-Glucoside suppresses tumor necrosis factor-induced activation of nuclear transcription factor kappaB but potentiates apoptosis. J Biol Chem. 279:33768–33781. 2004. View Article : Google Scholar : PubMed/NCBI
19	Rajendran P, Ekambaram G and Sakthisekaran D: Protective role of mangiferin against Benzo(a)pyrene induced lung carcinogenesis in experimental animals. Biol Pharm Bull. 31:1053–1058. 2008. View Article : Google Scholar : PubMed/NCBI
20	Touny LH and Banerjee PP: Identification of both Myt-1 and Wee-1 as necessary mediators of the p21-independent inactivation of the cdc-2/cyclin B1 complex and growth inhibition of TRAMP cancer cells by genistein. Prostate. 66:1542–1555. 2006. View Article : Google Scholar : PubMed/NCBI
21	Hoffmann TK, Trellakis S, Okulicz K, Schuler P, Greve J, Arnolds J, Bergmann C, Bas M, Lang S, Lehnerdt G, et al: Cyclin B1 expression and p53 status in squamous cell carcinomas of the head and neck. Anticancer Res. 31:3151–3157. 2011.PubMed/NCBI
22	Chen H, Huang Q, Dong J, Zhai DZ, Wang AD and Lan Q: Overexpression of CDC2/CyclinB1 in gliomas, and CDC2 depletion inhibits proliferation of human glioma cells in vitro and in vivo. BMC Cancer. 8:292008. View Article : Google Scholar : PubMed/NCBI
23	Vairapandi M, Balliet AG, Hoffman B and Liebermann DA: GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J Cell Physiol. 192:327–338. 2002. View Article : Google Scholar : PubMed/NCBI
24	Chen H, Huang Q, Dong J, Zhai DZ, Wang AD and Lan Q: Overexpression of CDC2/CyclinB1 in gliomas, and CDC2 depletion inhibits proliferation of human glioma cells in vitro and in vivo. BMC Cancer. 8:292008. View Article : Google Scholar : PubMed/NCBI
25	Reyland ME: Protein kinase Cdelta and apoptosis. Biochem Soc Trans. 35:1001–1004. 2007. View Article : Google Scholar : PubMed/NCBI
26	Mezzano S, Aros C, Droguett A, Burgos ME, Ardiles L, Flores C, Schneider H, Ruiz-Ortega M and Egido J: NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy. Nephrol Dial Transplant. 19:2505–2512. 2004. View Article : Google Scholar : PubMed/NCBI