O‑desmethylangolensin inhibits the proliferation of human breast cancer MCF‑7 cells by inducing apoptosis and promoting cell cycle arrest

Choi,Eun   Jeong; Kim,Gun‑Hee

doi:10.3892/ol.2013.1601

O‑desmethylangolensin inhibits the proliferation of human breast cancer MCF‑7 cells by inducing apoptosis and promoting cell cycle arrest

Authors:
- Eun Jeong Choi
- Gun‑Hee Kim
View Affiliations

Affiliations: Plant Resources Research Institute, Duksung Women's University, Tobong‑ku, Seoul 132‑714, Republic of Korea
Published online on: October 1, 2013 https://doi.org/10.3892/ol.2013.1601
Pages: 1784-1788

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 aim of the present study was to investigate the anticancer effect of O‑desmethylangolensin (O‑DMA) by assessing cell proliferation, apoptosis and cell cycle distribution, as well as exploring the mechanisms underlying these effects in breast carcinoma MCF‑7 cells. The cells were exposed to O‑DMA (5‑200 µM) for 24, 48 and 72 h. The results revealed that cell proliferation was significantly inhibited in a dose‑dependent manner following treatment for 48 and 72 h, but not after 24 h, and resulted in the significant induction of apoptosis and the promotion of cell cycle arrest at the G1/S and G2/M phases. To elucidate these effects of O‑DMA, the expression levels of cell cycle regulators were measured in the cells exposed to O‑DMA at 150 µM for 72 h. Of the G1/S phase‑related proteins, O‑DMA modulated the cyclin‑dependent kinases (CDKs), with a decrease in CDK2 and CDK4 and an increase in CDK6, and downregulated cyclin D and E. With respect to the G2/M‑related proteins, O‑DMA caused a reduction in CDK1, together with a slight increase in cyclin A and B. In addition, O‑DMA downregulated p21Cip1 and p27Kip1, but not p16INK4a and p15INK4b, and interacted with the CDK6‑cyclin D and CDK1‑cyclin B complexes. In conclusion, these results indicate for the first time that the regulation of the CDK4/6‑cyclin D and CDK1‑cyclin B complexes may participate in the anticancer activity pathway of O‑DMA in MCF‑7 cells.

View Figures

View References

1	Adlercreutz H, Musey PI, Fotsis T, et al: Identification of lignans and phytoestrogens in urine of chimpanzees. Clin Chim Acta. 158:147–154. 1896. View Article : Google Scholar : PubMed/NCBI
2	L’homme R, Brouwers E, Al-Maharik N, et al: Time-resolved fluoroimmunoassay of plasma and urine O-desmethylangolensin. J Steroid Biochem Mol Biol. 81:353–361. 2002.PubMed/NCBI
3	Arai Y, Uehara M, Sato Y, et al: Comparison of isoflavones among dietary intake, plasma concentration and urinary excretion for accurate estimation of phytoestrogen intake. J Epidemiol. 10:127–135. 2000. View Article : Google Scholar : PubMed/NCBI
4	Frankenfeld CL, McTiernan A, Aiello EJ, et al: Mammographic density in relation to daidzein-metabolizing phenotypes in overweight, postmenopausal women. Cancer Epidemiol Biomarkers Prev. 13:1156–1162. 2004.PubMed/NCBI
5	Kelly GE, Joannou GE, Reeder AY, et al: The variable metabolic response to dietary isoflavones in humans. Proc Soc Exp Biol Med. 208:40–43. 1995. View Article : Google Scholar : PubMed/NCBI
6	Setchell KD, Brown NM and Lydeking-Olsen E: The clinical importance of the metabolite equol - a clue to the effectiveness of soy and its isoflavones. J Nutr. 132:3577–3584. 2002.PubMed/NCBI
7	Bushinsky DA, Sessler NE and Krieger NS: Greater unidirectional calcium efflux from bone during metabolic, compared with respiratory, acidosis. Am J Physiol. 262:F425–F431. 1992.PubMed/NCBI
8	Jackman KA, Woodman OL and Sobey CG: Isoflavones, equol and cardiovascular disease: pharmacological and therapeutic insights. Curr Med Chem. 14:2824–2830. 2007. View Article : Google Scholar : PubMed/NCBI
9	Nagata C: Factors to consider in the association between soy isoflavone intake and breast cancer risk. J Epidemiol. 20:83–89. 2010. View Article : Google Scholar : PubMed/NCBI
10	Messina M, Nagata C and Wu AH: Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer. 55:1–12. 2006. View Article : Google Scholar : PubMed/NCBI
11	Jin S, Zhang QY, Kang XM, et al: Daidzein induces MCF-7 breast cancer cell apoptosis via the mitochondrial pathway. Ann Oncol. 21:263–268. 2010. View Article : Google Scholar : PubMed/NCBI
12	Chang WH, Liu JJ, Chen CH, et al: Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by fermented soy milk. Nutr Cancer. 43:214–226. 2002. View Article : Google Scholar : PubMed/NCBI
13	Constantinou AI, Kamath N and Murley JS: Genistein inactivates bcl-2, delays the G2/M phase of the cell cycle, and induces apoptosis of human breast adenocarcinoma MCF-7 cells. Eur J Cancer. 34:1927–1934. 1998. View Article : Google Scholar : PubMed/NCBI
14	Choi EJ and Kim GH: Daidzein causes cell cycle arrest at the G1 and G2/M phases in human breast cancer MCF-7 and MDA-MB-453 cells. Phytomedicine. 15:683–690. 2008. View Article : Google Scholar : PubMed/NCBI
15	Balabhadrapathruni S, Thomas TJ, Yurkow EJ, et al: Effects of genistein and structurally related phytoestrogens on cell cycle kinetics and apoptosis in MDA-MB-468 human breast cancer cells. Oncol Rep. 7:3–12. 2000.PubMed/NCBI
16	Guo JM, Xiao BX, Liu DH, et al: Biphasic effect of daidzein on cell growth of human colon cancer cells. Food Chem Toxicol. 42:1641–1646. 2004. View Article : Google Scholar : PubMed/NCBI
17	Tang BY and Adams NR: Effect of equol on oestrogen receptors and on synthesis of DNA and protein in the immature rat uterus. J Endocrinol. 85:291–297. 1980. View Article : Google Scholar : PubMed/NCBI
18	Shutt DA and Cox RI: Steroid and phyto-oestrogen binding to sheep uterine receptors in vitro. J Endocrinol. 52:299–310. 1972. View Article : Google Scholar : PubMed/NCBI
19	Pfitscher A, Reiter E and Jungbauer A: Receptor binding and transactivation activities of red clover isoflavones and their metabolites. J Steroid Biochem Mol Biol. 112:87–94. 2008. View Article : Google Scholar : PubMed/NCBI
20	Casagrande F and Darbon JM: Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1. Biochem Pharmacol. 61:1205–1215. 2001. View Article : Google Scholar : PubMed/NCBI
21	Woo HH, Jeong BR and Hawes MC: Flavonoids: from cell cycle regulation to biotechnology. Biotechnol Lett. 27:365–374. 2005. View Article : Google Scholar : PubMed/NCBI
22	Singh RP and Agarwal R: Natural flavonoids targeting deregulated cell cycle progression in cancer cells. Curr Drug Targets. 7:345–354. 2006. View Article : Google Scholar : PubMed/NCBI
23	Graña X and Reddy EP: Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene. 11:211–219. 1995.PubMed/NCBI
24	Collins I and Garrett MD: Targeting the cell division cycle in cancer: CDK and cell cycle checkpoint kinase inhibitors. Curr Opin Pharmacol. 5:366–373. 2005. View Article : Google Scholar : PubMed/NCBI
25	Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI
26	Zhang Z, Li M, Rayburn ER, et al: Oncogenes as novel targets for cancer therapy (part IV): regulators of the cell cycle and apoptosis. Am J Pharmacogenomics. 5:397–407. 2005. View Article : Google Scholar : PubMed/NCBI
27	Lee B, Kim CH and Moon SK: Honokiol causes the p21WAF1-mediated G(1)-phase arrest of the cell cycle through inducing p38 mitogen activated protein kinase in vascular smooth muscle cells. FEBS Lett. 580:5177–5184. 2006. View Article : Google Scholar : PubMed/NCBI
28	Deng C, Zhang P, Harper JW, et al: Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 82:675–684. 1995. View Article : Google Scholar : PubMed/NCBI
29	Sherr CJ and Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13:1501–1512. 1999. View Article : Google Scholar : PubMed/NCBI
30	Abbas T and Dutta A: p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 9:400–414. 2009. View Article : Google Scholar : PubMed/NCBI
31	Takizawa CG and Morgan DO: Control of mitosis by changes in the subcellular location of cyclin-B1-Cdk1 and Cdc25C. Curr Opin Cell Biol. 12:658–665. 2000. View Article : Google Scholar : PubMed/NCBI
32	Porter LA and Donoghue DJ: Cyclin B1 and CDK1: nuclear localization and upstream regulators. Prog Cell Cycle Res. 5:335–347. 2003.PubMed/NCBI