Evaluation of Drugs with Selective Inhibitors Targeting the Anti-Apoptotic Protein B-cell Lymphoma 2 (BCL-2) with Pro-Apoptotic and Antineoplastic Activities in Grade IV Glioblastoma.

Abstract

Aim: To systemically review the efficacy, safety, and clinical applications of B-cell lymphoma 2 (BCL-2) family inhibitors such as venetoclax (ABT-199), navitoclax (ABT-263), and obatoclax (GX15-070) across different malignancies.

Material and methods: A systematic search was conducted in the PubMed database following PRISMA guidelines. Studies evaluating the pharmacological effects, preclinical findings, and clinical trial data of venetoclax, navitoclax, and obatoclax were included in the analysis. Key outcomes, including efficacy, resistance mechanisms, and adverse effects, were synthesized from the analysis.

Results: Venetoclax demonstrated significant efficacy and a favorable safety profile in hematologic malignancies, particularly chronic lymphocytic leukemia and acute myeloid leukemia; however, no positive safety profile was observed in glioblastoma grade IV (GBM). Navitoclax combination treatments showed potential in various malignancies but were used in a limited manner due to dose-related thrombocytopenia. However, no clear data were available regarding its efficacy against GBM. Obatoclax demonstrated efficacy in preclinical studies; however, off-target effects and limited clinical success hindered its development. No clear data were available regarding its effectiveness against GBM. Resistance mechanisms, including upregulation of MCL-1 and BCL-xL, were commonly observed among these agents, highlighting the need for combination strategies.

Conclusion: Venetoclax, navitoclax, and obatoclax represented significant advances in apoptosis-targeted therapy, with venetoclax emerging as the most clinically successful agent. However, resistance mechanisms and side effects were significant challenges, necessitating further preclinical and clinical studies to optimize the therapeutic potential of these agents.