Targeting Bcl-2 in CLL

M.      Rogalinska; Z.M.      Kilianska

Abstract

Chronic lymphocytic leukemia (CLL) is a common adult leukemia in the Western world with an incidence of 4.2/100,000/year. The clinical course of disease is highly heterogenous; it affects people over 65-70 years of age. This hematologic cancer is characterized by the resistance to apoptosis stimuli predominantly associated with overexpression of antiapoptotic Bcl-2 family members. Therapeutic options for advanced CLL patients are limited. Thus there is an urgent need to discover a novel, less toxic, and much more effective agent(s) or drug combinations for CLL patients. Among chemotherapeutic(s) and immunotherapeutics currently in use, several enzyme inhibitors were tested to gain better results in CLL treatment. Here, we review the main achievements made on targeting of prosurvival Bcl-2 proteins through the use of different approaches, i.e. anti-sense methodology, small molecules that mimic the action of BH3 domain and microRNAs (mainly miRNA-15a and miRNA-16-1).

Keywords: Antileukemic therapy, antisense oligonucleotides, small molecular Bcl-2 inhibitors, BH3 domain mimetics, CLL, microRNA-15a/16-1, oblimersen, obatoclax, gossypol derivatives, ABT-737, ABT-263