Momordica cochinchinensis Spreng. seed extract suppresses breast cancer growth by inducing cell cycle arrest and apoptosis

Zheng,Lei; Zhang,Yanmin; Liu,Yanping; Yang,Xiaoyan  Ou; Zhan,Yingzhuan

doi:10.3892/mmr.2015.4186

Momordica cochinchinensis Spreng. seed extract suppresses breast cancer growth by inducing cell cycle arrest and apoptosis

Authors:
- Lei Zheng
- Yanmin Zhang
- Yanping Liu
- Xiaoyan Ou Yang
- Yingzhuan Zhan
View Affiliations

Affiliations: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: August 5, 2015 https://doi.org/10.3892/mmr.2015.4186
Pages: 6300-6310

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

The herb Momordica cochinchinensis has been used for a variety of purposes, and been shown to have anti‑cancer properties. The present study assessed the potency and the underlying mechanisms of action of the ethyl acetate extract of seeds of Momordica cochinchinensis (ESMC2) on breast cancer cells. Therefore, the effects of ESMC2 on the cell viability, cell cycle and apoptosis of MDA‑MB‑231 cells were investigated. The results showed that ESMC2 exerted a marked growth inhibitory effect on the cells. Cell cycle arrest in G2 phase following treatment with ESMC2 was associated with a marked increase in the protein levels of cyclin B1, cyclin E and cyclin-dependent kinase 1 and a decrease in cyclin D1 expression. In addition, ESMC2 dose‑dependently induced cell apoptosis, which was mediated via upregulation of the apoptosis-associated proteins p53, B-cell lymphoma 2 (Bcl‑2)‑associated X protein, Bcl-2 homologous antagonist killer and Bcl-2-associated death promoter expression, as well as downregulation of nuclear factor kappa B, Bcl‑2 and myeloid cell leukemia‑1. Furthermore, the activation of extracellular signal-regulated kinase 1/2, p38, c-Jun N-terminal kinase (JNK) and Akt phosphorylation were decreased by ESMC2 in a dose‑dependent manner, indicating that ESMC2 exerted its effects via the mitogen-activated protein kinase/JNK pathway. Furthermore, nude mouse xenotransplant models were used to evaluate the tumor growth inhibitory effects of ESMC2. The possible chemical components of ESMC2 were analyzed by gas chromatography-mass spectrometry, and 12 compounds were detected from the major peaks based on the similarity index with entries of a compound database. The results of the present study may aid in the development of novel therapies for breast cancer.

View Figures

View References

1	Amin AR, Kucuk O, Khuri FR and Shin DM: Perspectives for cancer prevention with natural compounds. J Clin Oncol. 27:2712–2725. 2009. View Article : Google Scholar : PubMed/NCBI
2	Li M, Hou X-F, Zhang J, Wang S-C, Fu Q and He L-C: Applications of HPLC/MS in the analysis of traditional Chinese medicines. J Pharm Anal. 1:81–91. 2011. View Article : Google Scholar
3	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
4	Parks SE, Murray CT, Gale DL, Al-Khawaldeh B and Spohr LJ: Propagation and production of Gac (Momordica cochinchinensis Spreng), a greenhouse case study. Experimental Agriculture. 49:234–243. 2012. View Article : Google Scholar
5	Tsoi AY, Ng TB and Fong WP: Immunomodulatory activity of a chymotrypsin inhibitor from Momordica cochinchinensis seeds. J Pept Sci. 12:605–611. 2006. View Article : Google Scholar : PubMed/NCBI
6	Kubola J and Siriamornpun S: Phytochemicals and antioxidant activity of different fruit fractions (peel, pulp, aril and seed) of Thai gac (Momordica cochinchinensis Spreng). Food Chem. 127:1138–1145. 2011. View Article : Google Scholar : PubMed/NCBI
7	Wong RC, Fong WP and Ng TB: Multiple trypsin inhibitors from Momordica cochinchinensis seeds, the Chinese drug mubiezhi. Peptides. 25:163–169. 2004. View Article : Google Scholar : PubMed/NCBI
8	Chang F, Steelman LS, Shelton JG, Lee JT, Navolanic PM, Blalock WL, Franklin R and McCubrey JA: Regulation of cell cycle progression and apoptosis by the Ras/Raf/MEK/ERK pathway (Review). Int J Oncol. 22:469–480. 2003.PubMed/NCBI
9	Harbour JW and Dean DC: Rb function in cell-cycle regulation and apoptosis. Nat Cell Biol. 2:E65–E67. 2000. View Article : Google Scholar : PubMed/NCBI
10	Yao Y, Zhang YW, Sun LG, Liu B, Bao YL, Lin H, Zhang Y, Zheng LH, Sun Y, Yu CL, et al: Juglanthraquinone C, a novel natural compound derived from Juglans mandshurica Maxim, induces S phase arrest and apoptosis in HepG2 cells. Apoptosis. 17:832–841. 2012. View Article : Google Scholar : PubMed/NCBI
11	Morgan DO: Principles of CDK regulation. Nature. 374:131–134. 1995. View Article : Google Scholar : PubMed/NCBI
12	Gross A, McDonnell JM and Korsmeyer SJ: BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13:1899–1911. 1999. View Article : Google Scholar : PubMed/NCBI
13	Kang S, Dong SM, Kim BR, Park MS, Trink B, Byun HJ and Rho SB: Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis. 17:989–997. 2012. View Article : Google Scholar : PubMed/NCBI
14	Rasul A, Ding C, Li X, Khan M, Yi F, Ali M and Ma T: Dracorhodin perchlorate inhibits PI3K/Akt and NF-κB activation, up-regulates the expression of p53 and enhances apoptosis. Apoptosis. 17:1104–1119. 2012. View Article : Google Scholar : PubMed/NCBI
15	Chuang SM, Wang IC and Yang JL: Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium. Carcinogenesis. 21:1423–1432. 2000. View Article : Google Scholar : PubMed/NCBI
16	Wada T and Penninger JM: Mitogen-activated protein kinases in apoptosis regulation. Oncogene. 23:2838–2849. 2004. View Article : Google Scholar : PubMed/NCBI
17	Yang XH, Zhou GY, Ren T, Li H, Zhang Y, Yin D, Qian H and Li Q: β-Arrestin prevents cell apoptosis through pro-apoptotic ERK1/2 and p38 MAPKs and anti-apoptotic Akt pathways. Apoptosis. 17:1019–1026. 2012. View Article : Google Scholar : PubMed/NCBI
18	Zachary I: VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochem Soc Trans. 31:1171–1177. 2003. View Article : Google Scholar : PubMed/NCBI
19	Fridman JS and Lowe SW: Control of apoptosis by p53. Oncogene. 22:9030–9040. 2003. View Article : Google Scholar : PubMed/NCBI
20	Shen HM and Tergaonkar V: NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy. Apoptosis. 14:348–363. 2009. View Article : Google Scholar : PubMed/NCBI
21	Vogelstein B, Lane D and Levine AJ: Surfing the p53 network. Nature. 408:307–310. 2000. View Article : Google Scholar : PubMed/NCBI
22	Luque de Castro MD and Garcia-Ayuso LE: Soxhlet extraction of solid materials: an outdated technique with a promising innovative future. Anal Chim Acta. 369:1–10. 1998. View Article : Google Scholar
23	Luque de Castro MD and Priego-Capote F: Soxhlet extraction: Past and present panacea. J Chromatogr A. 1217:2383–2389. 2010. View Article : Google Scholar
24	Zheng L, He X, Ma W, Dai B, Zhan Y and Zhang Y: Ta1722, an anti-angiogenesis inhibitor targeted on VEGFR-2 against human hepatoma. Biomed Pharmacother. 66:499–505. 2012. View Article : Google Scholar : PubMed/NCBI
25	Li DD, Guo JF, Huang JJ, Wang LL, Deng R, Liu JN, Feng GK, Xiao DJ, Deng SZ, Zhang XS, et al: Rhabdastrellic acid-A induced autophagy-associated cell death through blocking Akt pathway in human cancer cells. PLoS One. 5:e121762010. View Article : Google Scholar : PubMed/NCBI
26	Zhang Y, Zhang J, Dai B, Wang N and He L: Anti-proliferative and apoptotic effects of the novel taspine derivative tas41 in the Caco-2 cell line. Environ Toxicol Pharmacol. 31:406–415. 2011. View Article : Google Scholar : PubMed/NCBI
27	Li T, Zhu J, Guo L, Shi X, Liu Y and Yang X: Differential effects of polyphenols-enriched extracts from hawthorn fruit peels and fleshes on cell cycle and apoptosis in human MCF-7 breast carcinoma cells. Food Chem. 141:1008–1018. 2013. View Article : Google Scholar : PubMed/NCBI
28	Zhan Y, Zhang Y, Liu C, et al: A novel taspine derivative, HMQ1611, inhibits breast cancer cell growth via estrogen receptor α and EGF receptor signaling pathways. Cancer Prev Res (Phila). 5:864–873. 2012. View Article : Google Scholar
29	Berdowska I, Zielinski B, Fecka I, Kulbacka J, Saczko J and Gamian A: Cytotoxic impact of phenolics from Lamiaceae species on human breast cancer cells. Food Chemistry. 141:1313–1321. 2013. View Article : Google Scholar : PubMed/NCBI
30	Zhou Y, Luo W, Zheng L, Li M and Zhang Y: Construction of recombinant FGFR1 containing full-length gene and its potential application. Plasmid. 64:60–67. 2010. View Article : Google Scholar : PubMed/NCBI
31	Zhang Y, Zheng L, Zhang J, Dai B, Wang N, Chen Y and He L: Antitumor activity of taspine by modulating the EGFR signaling pathway of Erk1/2 and Akt in vitro and in vivo. Planta Med. 77:1774–1781. 2011. View Article : Google Scholar : PubMed/NCBI
32	King KL and Cidlowski JA: Cell cycle regulation and apoptosis. Annu Rev Physiol. 60:601–617. 1998. View Article : Google Scholar : PubMed/NCBI
33	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
34	Kastan MB and Bartek J: Cell-cycle checkpoints and cancer. Nature. 432:316–323. 2004. View Article : Google Scholar : PubMed/NCBI
35	Farhana L, Dawson M, Rishi AK, Zhang Y, Van Buren E, Trivedi C, Reichert U, Fang G, Kirschner MW and Fontana JA: Cyclin B and E2F-1 expression in prostate carcinoma cells treated with the novel retinoid CD437 are regulated by the ubiquitin-mediated pathway. Cancer Res. 62:3842–3849. 2002.PubMed/NCBI
36	Lu HF, Chen YS, Yang JS, Chen JC, Lu KW, Chiu TH, Liu KC, Yeh CC, Chen GW, Lin HJ, et al: Gypenosides induced G0/G1 arrest via inhibition of cyclin E and induction of apoptosis via activation of caspases-3 and -9 in human lung cancer A-549 cells. In Vivo. 22:215–222. 2008.PubMed/NCBI
37	Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W and Xu T: Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat Genet. 21:177–181. 1999. View Article : Google Scholar : PubMed/NCBI
38	Liu Q, Fu HJ, Sun F, Zhang H, Tie Y, Zhu J, Xing R, Sun Z and Zheng X: miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes. Nucleic Acids Res. 36:5391–5404. 2008. View Article : Google Scholar : PubMed/NCBI
39	King KL and Cidlowski JA: Cell cycle regulation and apoptosis. Ann Rev Physiol. 60:601–617. 1998. View Article : Google Scholar
40	Jonsson P, Gullberg J, Nordström A, Kusano M, Kowalczyk M, Sjöström M and Moritz T: A strategy for identifying differences in large series of metabolomic samples analyzed by GC/MS. Anal Chem. 76:1738–1745. 2004. View Article : Google Scholar : PubMed/NCBI