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Acute toxicity analysis of Disarib, an inhibitor of BCL2
Shivangi Sharma1, Kontham Kulangara Varsha1, Susmita Kumari1
1Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India.
Abstract:
Small molecule inhibitors targeting BCL2 are explored as anticancer therapeutics. Previously, we have reported identification and characterization of a novel BCL2 inhibitor, Disarib. Disarib induced cancer cell death in a BCL2 dependent manner in different cancer cell lines and mouse tumor models when it was administered intraperitoneally. In the present study, using two syngeneic mouse models, breast adenocarcinoma (EAC) and Dalton's lymphoma (DLA), we show that oral administration of Disarib resulted in significant tumor regression in a concentration dependent manner. Importantly, tumor developed in both female and male mice were equally sensitive to Disarib. Further, we have investigated the toxicity of Disarib in normal cells. Single dose toxicity analysis of Disarib in male and female mice after oral administration revealed no significant variations compared to control group for parameters such as body weight, food and water consumption and behavioural changes which were analysed for the entire period of study. Haematological and histopathological analyses also did not show any significant difference from the control groups. Thus, our results reveal safe use of Disarib as a small molecule inhibitor and provide the foundation for investigation of other preclinical studies.
Insights
Oral administration of Disarib, a novel BCL2 inhibitor, effectively reduced tumors in mouse models. This study confirms Disarib
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Small molecule inhibitors targeting BCL2 are investigated as anticancer agents.
- Disarib, a novel BCL2 inhibitor, previously demonstrated cancer cell death via BCL2-dependent mechanisms.
- Previous administration of Disarib was via intraperitoneal injection.
Purpose of the Study:
- To evaluate the efficacy of orally administered Disarib in preclinical cancer models.
- To assess the safety and toxicity profile of Disarib following oral administration.
- To determine if tumor sensitivity to Disarib differs between sexes.
Main Methods:
- Two syngeneic mouse models (EAC and DLA) were used to assess tumor regression after oral Disarib administration.
- Tumor regression was evaluated in a concentration-dependent manner.
- Toxicity was assessed through single-dose oral administration in male and female mice, monitoring body weight, consumption, behavior, and performing hematological and histopathological analyses.
Main Results:
- Oral Disarib administration led to significant, concentration-dependent tumor regression in both breast adenocarcinoma and Dalton's lymphoma models.
- Tumors in both male and female mice exhibited equal sensitivity to Disarib.
- No significant toxicity was observed in normal mice receiving a single oral dose of Disarib, with no adverse effects on body weight, consumption, behavior, hematology, or histology.
Conclusions:
- Disarib demonstrates significant anticancer efficacy when administered orally in preclinical models.
- Oral administration of Disarib is well-tolerated, showing a favorable safety profile.
- These findings support further preclinical development of Disarib as an oral anticancer therapeutic.
