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Suppression of Carcinogenesis and Tumor Progression by an Energy Restriction-Mimetic Agent in Murine Models of Prostate Cancer
Berman-Booty, Lisa Danielle

2013, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Cancer cells preferentially utilize glycolysis to generate energy even in the presence of sufficient oxygen for oxidative phosphorylation. This shift in energy metabolism, termed the Warburg effect, is responsible for cancer cells’ high metabolic rate. Therapies that inhibit cancer cell energy metabolism have proved effective in vitro, and dietary caloric restriction is a valuable experimental chemotherapeutic strategy. While animal studies utilizing caloric restriction typically restrict the experimental group’s caloric intake by 20-40%, this degree of caloric restriction is not realistic for human cancer patients. Therefore, agents that can induce a response similar to that of glucose restriction in vitro and caloric restriction in vivo are needed. These agents are termed energy-restriction mimetic agents (ERMAs) and include 2-deoxyglucose, resveratrol, and the thiazolidinedione derivatives OSU-CG12 and OSU-CG5. Here, we characterized OSU-CG5’s mechanism of action in vitro and its chemotherapeutic and chemopreventive activities in vivo. Specifically, we evaluated OSU-CG5’s activity in three different human prostate cancer cell lines that range from androgen-dependent (LNCaP) to castration-resistant (LNCaP-abl and PC3). OSU-CG5 was cytotoxic and induced a response similar to that of glucose deprivation in these cell lines. Additionally, treatment with OSU-CG5 resulted in decreased expression of genes that promote the Warburg effect, namely, those for glucose transporter 1 (GLUT1) and a number of metabolic enzymes. Regarding its in vivo chemotherapeutic activity, 100 mg/kg/day of OSU-CG5 administered via daily oral gavage suppressed the growth of LNCaP-abl xenograft tumors by 81%. Tumor growth suppression was associated with decreased tumor cell proliferation, as determined by proliferating cell nuclear antigen (PCNA) levels, and modulation of intratumoral biomarkers associated with cell survival, growth, and metabolism, including insulin like growth factor 1 (IGF-1) and its receptor IGF-1R, Myc, the androgen receptor (AR), and cyclins D1 and E. OSU-CG5’s activity was also investigated using transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Treatment of 6-week-old TRAMP mice with 100 mg/kg/day of OSU-CG5 via oral gavage for 4 weeks significantly reduced absolute and relative urogenital tract weights, as well as the weights of the individual lobes of the prostate. Reductions in lobe weight were associated with decreased cell proliferation within prostatic intraepithelial neoplasia (PIN) lesions, as determined by immunostaining for Ki67 and western blotting for PCNA. OSU-CG5 also decreased the levels of the AR, phosphorylated Akt (p-Akt), and IGF-1R within the prostates of these mice. When 6-week-old, intact, male TRAMP mice were fed an AIN-76A diet containing 1286 ppm of OSU-CG5 for approximately 18 weeks, prostate tumor development was not suppressed or significantly delayed. However, the tumors that developed in OSU-CG5-treated mice were 54.6% smaller by volume and 54.1% smaller by mass than the control mouse tumors. Decreased tumor size was associated with decreased tumor cell proliferation, as determined by Ki67 immunostaining, and reductions in the AR and p-Akt. Collectively, these studies demonstrate OSU-CG5’s efficacy as a chemotherapeutic agent. OSU-CG5 mediated this effect by reducing tumor cell proliferation and modulating pro-growth and pro-survival biomarkers.
Ching-Shih Chen, PhD (Advisor)
Steven Clinton, MD, PhD (Committee Member)
Robert Brueggemeier, PhD (Committee Member)
Thomas Rosol, DVM, PhD (Committee Member)
214 p.

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Berman-Booty, L. (2013). Suppression of Carcinogenesis and Tumor Progression by an Energy Restriction-Mimetic Agent in Murine Models of Prostate Cancer. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/

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Berman-Booty, Lisa. "Suppression of Carcinogenesis and Tumor Progression by an Energy Restriction-Mimetic Agent in Murine Models of Prostate Cancer." Electronic Thesis or Dissertation. Ohio State University, 2013. OhioLINK Electronic Theses and Dissertations Center. 21 Sep 2017.

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Berman-Booty, Lisa "Suppression of Carcinogenesis and Tumor Progression by an Energy Restriction-Mimetic Agent in Murine Models of Prostate Cancer." Electronic Thesis or Dissertation. Ohio State University, 2013. https://etd.ohiolink.edu/

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