Understanding the anticancer potential of inhibitor of BCL2, Disarib in Oral Cancer Cells and its Toxicological Evaluation in Rodents

Abstract

Overexpression of BCL2 has been reported in several cancers, such as B-cell lymphomas, leukemias, colorectal adenocarcinoma, breast cancer, prostate cancer, and oral cancer, making it an excellent target for cancer treatment. We have identified a novel BCL2 inhibitor, Disarib, which primarily inhibits BCL2 by predominantly binding to its BH1 domain. Considering that Head and Neck cancer is the second most prevalent cancer in India with a high BCL2 expression, the anticancer potential of Disarib was explored in Head and Neck cancer. In the current study, we have evaluated through a series of in vitro efficacy and mechanistic studies, followed by in vivo efficacy assessments using Head and Neck xenograft mouse models, which revealed that Disarib administration can cause a significant reduction in the rate of tumor progression by killing the cancer cells via activation of the intrinsic pathway of apoptosis. Toxicological studies of Disarib, including the preclinical acute toxicity analysis of Disarib, revealed the safe use of Disarib for further evaluation. Evaluation of body weight, organ weight, food, and water consumption analysis, along with an evaluation of hematological parameters and kidney-liver function tests, following continuous 45 days of oral administration of Disarib showed no significant deviations when compared between the treated and the control group. Similarly, 90 days toxicity study revealed no observable toxicity in any of the parameters studied indicating the safer use of Disarib for long-term treatment. Hence, our results suggest no adverse preclinical observations in the toxicity profile of Disarib when administered orally in mice. Although Disarib has the potential to develop as an anticancer therapeutic drug, it is important to further derivatize it with better efficacy than Disarib. Therefore, we have derivatized and screened BCL2 inhibitors in BCL2 high and BCL2 low cell lines. Two compounds (DSR 43 and 4-O-CH 3 ), emerged with improved efficacy as compared to Disarib, encouraging further investigation for their potential. Taken together, our results suggest that Disarib has the potential to be developed as a cancer therapeutic against Head and Neck cancer. Besides, results of toxicity studies reveal no or limited toxicity against normal cells and may be safe to use for further preclinical studies in non-rodents.