Preclinical testing of 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide
Autor: | Samer S. Sansil, Christopher Apostolatos, Anthony Neuger, Mildred Acevedo-Duncan, Wishrawana S. Ratnayake, Andre H. Apostolatos, Marie Bourgeois |
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Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine Cancer Research kinase inhibitor Mice Nude Pharmacology Mice 03 medical and health sciences Prostate cancer 0302 clinical medicine Blood serum Prostate Cell Line Tumor Glioma Animals Humans Preclinical Reports Medicine Pharmacology (medical) Protein Kinase Inhibitors Protein Kinase C Oncogene business.industry Imidazoles Prostatic Neoplasms prostate cancer medicine.disease Xenograft Model Antitumor Assays 3. Good health Isoenzymes 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Toxicity Cancer cell protein kinase C-iota Alkaline phosphatase business PRKCI |
Zdroj: | Anti-Cancer Drugs |
ISSN: | 0959-4973 |
DOI: | 10.1097/cad.0000000000000694 |
Popis: | 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. |
Databáze: | OpenAIRE |
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