Department of Chemistry.
Translational Research Core Facility, The H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Anticancer Drugs. 2019 Jan;30(1):65-71. doi: 10.1097/CAD.0000000000000694.
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 cm, they were either treated with ICA-1s or left as control and measured for 30 days or until the tumor reached 2 cm. 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.
蛋白激酶 C-ι（PKC-ι）是一种癌基因，在许多癌细胞中过度表达，包括前列腺癌、乳腺癌、卵巢癌、黑色素瘤和神经胶质瘤。之前的体外研究表明，5-氨基-1-((1R,2S,3S,4R)-2,3-二羟基-4-甲基环戊基)-1H-咪唑-4-甲酰胺（ICA-1s），一种 PKC-ι 特异性抑制剂，通过降低细胞生长和诱导细胞凋亡对一些癌细胞系有效。为了评估 ICA-1s 作为一种潜在的治疗方法，在使用小鼠模型的体内研究中进行了研究。在血液血清中测试了 ICA-1s 的稳定性，结果表明，在 25 和 37°C 下，在 2 小时的过程中，ICA-1s 在人血浆中稳定。测试了 ICA-1s 的急性和亚急性暴露毒性。急性暴露显示，在 5 至 5000mg/kg 的剂量下，患者在 48 小时后存活。亚急性试验使患者接受 14 天的治疗，并随后收集血清和组织。通过测量血清中天冬氨酸氨基转移酶、碱性磷酸酶、γ-谷氨酰转肽酶、肌钙蛋白和 C 反应蛋白的水平来评估器官功能。在口服和静脉治疗的过程中，24 小时内测量了血浆血清中的 ICA-1s。分析心、肝、肾和脑组织中 ICA-1s 的积累。最后，将无胸腺裸鼠异种移植 DU-145 前列腺癌细胞。当肿瘤达到约 0.2cm 时，用 ICA-1s 治疗或作为对照，测量 30 天或直到肿瘤达到 2cm。结果表明，治疗小鼠的肿瘤生长速度几乎是未治疗肿瘤的一半，表明肿瘤生长明显减少。总之，ICA-1s 稳定、毒性低，是前列腺癌肿瘤的潜在治疗药物。
