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Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer

Babcook, Melissa A.
http://rave.ohiolink.edu/etdc/view?acc_num=case1410439667

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Nutrition.
Docetaxel (DTX) remains the first-line chemotherapy for metastatic castration-resistant prostate cancer (CRPC), yet results in frequent occurrence of side-effects and DTX-resistant disease. A handful of other treatment options for metastatic CRPC pre- and post-DTX exist that modestly improve patient survival. More effective alternate treatments for metastatic CRPC that may provide longer progression-free and overall survival with less toxicity are being sought. CRPC cells acquire resistance to androgen-deprivation and chemotherapy in part due to acquisition of “Warburg effect”-promoting metabolic aberrations, including constitutive activation of Akt, loss of adenosine monophosphate-activated protein kinase (AMPK) activity, and over-expression and hyperactivity of fatty acid and cholesterol synthesis rate-limiting enzymes. By exploiting these metabolic aberrations to selectively target CRPC cells, we devised combination simvastatin (SIM) and metformin (MET) chemotherapy for CRPC. Our studies demonstrate that combination SIM and MET, within pharmacological dosages, ameliorated critical metabolic aberrations of C4-2B CRPC cells, synergistically and significantly decreased CRPC cell viability and metastatic properties, with minimal effect on normal prostate epithelial cells, and inhibited primary prostate tumor growth, metastasis, and biochemical failure in an C4-2B4 orthotopic NCr-nu/nu mouse model of metastatic CRPC, more effectively than DTX chemotherapy. Further elucidation of the cell death process showed that treatment of C4-2B cells with combination 4µM SIM and 2mM MET led to significant G1-phase cell cycle arrest and decrease in percentage of DNA-replicating cells in S-phase by 24h; arrest was sustained throughout 96h treatment. Combination SIM and MET treatment then led to receptor-interacting protein kinase-1 (Ripk1)- and Ripk3-dependent necrosis by 48-96h. C4-2B CRPC upregulated autophagy in attempt to withstand combination SIM and MET chemotherapy, but this survival mechanism was overcome by 96h treatment. Overall, our studies demonstrate that combination SIM and MET treatment is a promising treatment for apoptosis- and chemotherapy-resistant metastatic CRPC cells.
Danny Manor (Committee Chair)
Michelle Puchowicz (Committee Member)
Janos Kerner (Committee Member)
Paul Ernsberger (Committee Member)
David Danielpour (Committee Member)
Sanjay Gupta (Advisor)
261 p.
Biomedical Research; Pharmaceuticals
castration-resistant prostate cancer; simvastatin; metformin

Recommended Citations

Citations

  • Babcook, M. A. (2015). Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1410439667

    APA Style (7th edition)

  • Babcook, Melissa. Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1410439667.

    MLA Style (8th edition)

  • Babcook, Melissa. "Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1410439667

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.