Gossypol possesses anticancer activities against a variety of tumor cell lines, and (-)-gossypol is more potent than racemic gossypol. (-)-Gossypol-enriched cottonseed oil [(-)-GPCSO] is more practicable to be developed as a chemo-preventive agent, but, the effects of (-)-GPCSO on human breast cancer cells are still not clear. Our experiments found that (-)-GPCSO inhibited estrogen receptor α (ERα) positive MCF-7 cells, ER α negative MDA-MB-231 cells, multi-drug resistant human breast cancer cell line, MCF-7/Adr cells, and primary cultured human breast cancer epithelial cell (PCHBCEC) with a dose dependent manner; (-)-GPCSO decreased the growth stimulatory effects of 17β-Estradiol (E 2) and Zeranol (Z) in MCF-7 and MCF-7Adr cells; the combination of (-)-GPCSO with tamoxifen (Tam), ICI 182 780 (ICI) and adriamycin (Adr) increased the inhibitory effects on proliferation in MCF-7/Adr cells and PHBCEC. The inhibitory effects of (-)-GPCSO on human breast cancer cells might be involved in the regulation of cell cycle related genes. The results of our experiment illustrated that (-)-GPCSO up-regulated tumor suppressor genes p53 and p21 expression in both mRNA level and protein level; it significantly decreased cyclin D1 expression in both mRNA and protein level.
(-)-GPCSO induced apoptosis in several human breast cancer cells. It induced DNA fragmentation in MCF-7 and MCF-7/Adr. The induction of apoptotic effects in these cells might be mediated by increasing pro-apoptotic Bcl-2 family members Bax and Bak and decreasing anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-xL in both mRNA and protein levels.
(-)-GPCSO increased Adr accumulation in MCF-7/Adr cells, and this effect might be mediated by (-)-GPCSO inhibiting MDR1 and P-gp expression in MCF-7/Adr cells; (-)-GPCSO can suppress DNMT1 mRNA and protein expression in MCF-7/Adr cells and PCHBCEC. It decreases the percent of global DNA methylation; our methylation-specific PCR and bisulfate sequencing PCR indicates that (-)-GPCSO can reduce the methylation of CpG dinucleotide in MDR1 gene.
Collectively, these studies provides solid evidences in vitro that (-)-GPCSO may be developed as an chemopreventive agent, and widely used breast cancer patients and general population. Further study still need to be done in both in vivo and in vitro.
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Apoptosis, Breast cancer chemoprevention, Cell cycle regualtion, Dna methylation, Multidrug resistance|
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