The B-cell lymphoma-2 (BCL-2) gene, abbreviated as BCL-2, is one of the most highly regarded oncogenes in apoptosis research.
Apoptosis is the autonomous, ordered death of cells, a death process that involves a series of proteins regulated to better adapt to the environment in which they live. Some of these proteins promote the event, called “pro-apoptotic proteins,” and some inhibit the process, called “apoptosis-inhibiting proteins. Under normal physiological conditions, pro-apoptotic genes and apoptosis-inhibiting molecules check and balance each other, allowing apoptosis to occur in an orderly fashion.
The physiological function of BCL-2 is to block apoptosis and prolong cell life, but overexpression of this part of the gene can cause uncontrolled cell growth and overproliferation, leading to tumorigenesis, and overactivation of BCL-2 has been found in many hematologic tumors. Therefore, BCL-2 is currently the main target molecule in hematologic tumor research, and the application of BCL-2 inhibitors inhibits the overactivation of BCL-2, allowing programmed death of tumor cells, thus achieving therapeutic goals.
Currently, the main applications of BCL-2 inhibitors in hematologic tumors are as follows:
- Venetoclax: was approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia with the 7p deletion mutation (del 17p) and those who have received at least one prior therapy [1]. It became the first Bcl-2 inhibitor to be marketed worldwide, officially opening up cancer therapy targeting the apoptosis pathway. In addition, venetoclax is in clinical trials as a single agent or in combination with other agents for the treatment of acute myeloid leukemia, multiple myeloma, and non-Hodgkin’s lymphoma.
- Obatoclax: entered clinical studies in 2005 because of platelet toxicity, with a focus on trials in combination therapy for chronic lymphocytic leukemia, Hodgkin lymphoma, myelofibrosis, and myelodysplastic syndromes.
- ABT-263 (navitoclax): is another inhibitor of BCL-2. Clinical trials are underway on single-agent or combination therapy for chronic lymphocytic leukemia, acute lymphocytic leukemia, and lymphoma.
- APG-2575: is a third-generation BCL-2 inhibitor, which selectively inhibits BCL-2 protein, mainly for hematologic tumors, and fundamentally addresses platelet toxicity in terms of target protein selectivity, and is currently in clinical trials.
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Dr. Xiao Dan, Department of Hematology, Shanghai Renji Hospital South Hospital, also contributed to this article