Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis.
This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition. The lead ERMA in this class, OSU-CG5, decreases the production of ATP and NADH in LNCaP prostate cancer cells. In this study, we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal, lateral, and anterior prostatic lobes relative to vehicle controls. The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen (PCNA) expression in the prostate. OSU-CG5 treatment was not associated with evidence of systemic toxicity. Microarray analysis indicated a central role for Akt, and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt, Src, androgen receptor, and insulin-like growth factor-1 receptor in prostate lobes. These findings support further investigation of OSU-CG5 as a potential chemopreventive agent.
Written by:
Berman-Booty LD, Chu PC, Thomas-Ahner JM, Bolon B, Wang D, Yang T, Clinton SK, Kulp SK, Chen CS. Are you the author?
Division of Medicinal Chemistry, College of Pharmacy; Department of Veterinary Biosciences, College of Veterinary Medicine; Division of Medical Oncology, Department of Internal Medicine, College of Medicine; Comparative Pathology & Mouse Phenotyping Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; and Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan.
Reference: Cancer Prev Res (Phila). 2013 Feb 6. (Epub ahead of print)
PubMed Abstract
PMID: 23275006
