Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo

Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators-prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of Cancer. We evaluated the Anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line-CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the Animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC₅₀ values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent Apoptosis and Autophagy. In the presence of chloroquine, an Autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of Autophagy. Our in vivo experiment reports tumor growth attenuation in Animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in Cancer development, these results have a significant impact and are worthy of further evaluation.

5-lipoxygenase; CT26CL25; Rev-5901; carboranes; colorectal carcinoma.