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

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

Bibliographic Details
Main Author: Babcook, Melissa A.
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2015
Subjects:
Biomedical Research
Pharmaceuticals
castration-resistant prostate cancer
simvastatin
metformin
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1410439667
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case14104396672021-08-03T06:27:26Z Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer Babcook, Melissa A. Biomedical Research Pharmaceuticals castration-resistant prostate cancer simvastatin metformin 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. 2015-02-06 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1410439667 http://rave.ohiolink.edu/etdc/view?acc_num=case1410439667 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Biomedical Research
Pharmaceuticals
castration-resistant prostate cancer
simvastatin
metformin
spellingShingle Biomedical Research
Pharmaceuticals
castration-resistant prostate cancer
simvastatin
metformin
Babcook, Melissa A.
Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer
author Babcook, Melissa A.
author_facet Babcook, Melissa A.
author_sort Babcook, Melissa A.
title Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer
title_short Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer
title_full Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer
title_fullStr Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer
title_full_unstemmed Preclinical Development of Combination Simvastatin and Metformin Chemotherapy for Metastatic Castration-Resistant Prostate Cancer
title_sort preclinical development of combination simvastatin and metformin chemotherapy for metastatic castration-resistant prostate cancer
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2015
url http://rave.ohiolink.edu/etdc/view?acc_num=case1410439667
work_keys_str_mv AT babcookmelissaa preclinicaldevelopmentofcombinationsimvastatinandmetforminchemotherapyformetastaticcastrationresistantprostatecancer
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