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Chemopreventive and Bioenergetic Signaling Effects of PDK1/Akt Pathway Inhibition in a Transgenic Mouse Model of Prostate Cancer

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Department of Veterinary Biosciences, College of Veterinary Medicine

Russell D. Klein

Department of Human Nutrition and Food Management-Chemoprevention and Support, College of Human Ecology

Robert C. Rengel

Department of Human Nutrition and Food Management-Chemoprevention and Support, College of Human Ecology

Steven K. Clinton

Division of Hematology and Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210-1291, USA

Samuel K. Kulp

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy

Yoko Kashida

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy

Mamoru Yamaguchi

Department of Veterinary Biosciences, College of Veterinary Medicine

Xingya Wang

Department of Human Nutrition and Food Management-Chemoprevention and Support, College of Human Ecology

Ching-Shih Chen

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, chen.844{at}osu.edu, Department of Veterinary Biosciences, College of Veterinary Medicine

The phosphoinositide-dependent kinase 1 (PDK1)/Akt pathway is an important regulator of multiple biological processes including cell growth, survival, and glucose metabolism. In light of the mechanistic link between Akt signaling and prostate tumorigenesis, we evaluated the chemopreventive relevance of inhibiting this pathway in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model with OSU03012, a celecoxib-derived, but COX-2-inactive, PDK1 inhibitor. Beginning at ten weeks of age when prostatic intraepithelial neoplasia (PIN) lesions are well developed, TRAMP mice received OSU03012 via daily oral gavage for 8 weeks. The drug treatment significantly decreased the weight of all 4 prostate lobes as well as the grade of epithelial proliferation in the dorsal and lateral lobes compared to vehicle-treated control mice. The incidences of carcinoma and metastasis were decreased, although not to statistically significant levels. Treated mice lost body fat and failed to gain weight independent of food intake. This change and periportal hepatocellular atrophy can be linked to sustained PDK1 inhibition through downstream inactivation of glycogen synthase. Centrilobular hepatocellular hypertrophy and necrosis of Type II skeletal myofibers were also compound-related effects. We conclude that targeting of the PDK1/Akt pathway has chemopreventive relevance in prostate cancer and causes other in vivo effects mediated in part by an alteration of bioenergetic signaling.

Key Words: OSU03012 • TRAMP • prostate • PDK1 • Akt • chemoprevention • myonecrosis.

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