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Investigation of the pleiotrophic effects of a series of isoflavonoid analogues in hormone dependent and hormone independent breast cancer cells

Davis, Danyetta Denise
http://rave.ohiolink.edu/etdc/view?acc_num=osu1180124283

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Genistein, the predominant isoflavone, has several interesting properties including and not limited to cell cycle arrest, induction of apoptosis, tyrosine kinase inhibition, and effecting cell signaling transduction pathways. To enhance the anti-cancer activity of genistein, a series of novel isoflavone analogs were synthesized based on the isoflavone skeleton backbone and the side chain of raloxifene. The synthetic isoflavone analogs were shown to be effective antiproliferative, cytotoxic, and apoptosis agents in both hormone-dependent and hormone-independent breast cancer cell lines. We also determined that the MDA-MB-231 cell line was more sensitive to the cytotoxic and apoptosis inducing ability of the isoflavone analogs. Flow cytometry analysis revealed that selected isoflavone analogs arrested breast cancer cells at the G1 to S transition with concomitant increase in the endogenous cdk inhibitors (p21 and p27). Of this series, compound 5 showed selectivity in its mechanism of action for the MDA-MB-231 cell line, suggesting that its activity was not strictly mediated through estrogen-dependent pathways. Potential cell death mediated targets in the apoptosis pathway were furtherd explored. A 48 hour treatment with 5 and 10 mM of compound 5 resulted in a significant increase in Bax expression in both breast cancer cell lines. Additionally, the Bax/Bcl-2 ratio was significantly increased in the MDA-MB-231 breast cancer cell line. Also, treatment with compound 5 in the MDA-MB-231 breast cancer cell line resulted in decreased expression of activated Akt at Serine-473. High-throughput analysis revealed an increase in gene expression of the caspase-dependent, TNF/FAS-mediated, and death domain related families following treatment with compound 5 in the MDA-MB-231 breast cancer cell line. Gene expression was validated by real time PCR, western blotting of relevant caspase proteins, and decrease in apoptosis in the presence of the general caspase inhibitor, z-VAD-fmk. A series of nimesulide analogs were also examined and not found to induce apoptosis in SK-BR-3 cells, which supports their further exploration as novel aromatase suppression modulators in breast cancer cells. These findings provide important insights into the potential molecular targets of a novel series of synthetic isoflavone analogs, with valuable implications that can impact the overall etiology and treatment of breast cancer.
Robert Brueggemeier (Advisor)
177 p.
Genistein; Synthetic Isoflavonoids; Breast Cancer; Apoptosis

Recommended Citations

Citations

  • Davis, D. D. (2007). Investigation of the pleiotrophic effects of a series of isoflavonoid analogues in hormone dependent and hormone independent breast cancer cells [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1180124283

    APA Style (7th edition)

  • Davis, Danyetta. Investigation of the pleiotrophic effects of a series of isoflavonoid analogues in hormone dependent and hormone independent breast cancer cells. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1180124283.

    MLA Style (8th edition)

  • Davis, Danyetta. "Investigation of the pleiotrophic effects of a series of isoflavonoid analogues in hormone dependent and hormone independent breast cancer cells." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1180124283

    Chicago Manual of Style (17th edition)

osu1180124283
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© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.