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Preclinical testing of 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide: a potent protein kinase C-ι inhibitor as a potential prostate carcinoma therapeutic

Apostolatos, André H.a,*; Apostolatos, Christopher A.a,*; Ratnayake, Wishrawana S.a; Neuger, Anthonyc; Sansil, Samerc; Bourgeois, Marieb; Acevedo-Duncan, Mildreda

doi: 10.1097/CAD.0000000000000694
Preclinical report: PDF Only

Protein kinase C-iota (PKC-ι) is an oncogene overexpressed in many cancer cells including prostate, breast, ovarian, melanoma, and glioma. Previous in-vitro studies have shown that 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1s), a PKC-ι specific inhibitor, is effective against some cancer cell lines by decreasing cell growth and inducing apoptosis. To assess ICA-1s as a possible therapeutic, in-vivo studies using a murine model were performed. ICA-1s was tested for stability in blood serum and results demonstrated that ICA-1s was stable in human plasma at 25 and 37°C over a course of 2 h. Toxicity of ICA-1s was tested for both acute and subacute exposure. The acute exposure showed patient surviving after 48 h of doses ranging from 5 to 5000 mg/kg. Subacute tests exposed the patients to 14 days of treatment and were followed by serum and tissue collection. Aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, troponin, and C-reactive protein serum levels were measured to assess organ function. ICA-1s in plasma serum was measured over the course of 24 h for both oral and intravenous treatments. Heart, liver, kidney, and brain tissues were analyzed for accumulation of ICA-1s. Finally, athymic nude mice were xenografted with DU-145 prostate cancer cells. After tumors reached ~0.2 cm2, they were either treated with ICA-1s or left as control and measured for 30 days or until the tumor reached 2 cm2. Results showed tumors in treated mice grew at almost half the rate as untreated tumors, showing a significant reduction in growth. In conclusion, ICA-1s is stable, shows low toxicity, and is a potential therapeutic for prostate carcinoma tumors.

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aDepartment of Chemistry

bCollege of Public Health, University of South Florida

cTranslational Research Core Facility, The H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

*André H. Apostolatos and Christopher A. Apostolatos contributed equally to the writing of this article.

Correspondence to Mildred Acevedo-Duncan, PhD, Research Professor, University of South Florida, 4202 E. Fowler Ave., CHE 205 Tampa, FL 33620, USA Tel: +1 813 748 4715; fax: +1 813 974 3203; e-mail:

Received May 23, 2018

Accepted August 20, 2018

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