Anticancer drug development based on modulation of the Bcl-2 family core apoptosis mechanism.

Abstract:

:Cancer cells generally maintain their survival by suppressing apoptosis. Mitochondrial mechanisms are involved in most forms of apoptosis (referred to as mitochondrial apoptosis), and the Bcl-2 family controls apoptosis at the mitochondrion via a balance of the effects of pro- and antiapoptotic members. Antiapoptotic molecules such as Bcl-2 and Bcl-x(L) are often overexpressed in cancer cells and their inhibition is an attractive target for selective killing of tumor cells via induction of apoptosis. Reduction of the levels of these proteins with antisense molecules has shown encouraging experimental and clinical results and there has been some success in developing small-molecule inhibitors. These are likely to be the most productive drug development approaches in the near future. However, growing understanding of the molecular mechanisms involved has identified other potential targets. Cardiolipin is important for the proapoptotic activity of Bcl-2 family members such as Bid, Bax and Bak, and modulation of its metabolism and translocation in mitochondrial membranes could potentially have a strong influence on apoptosis. Post-translational modifications strongly influence the activity of Bcl-2 family members. Several molecules have been identified that bind to Bcl-2 family members and could be intracellular control mechanisms. These mechanisms may yield several drug development targets for the induction of apoptosis. Further research will qualify these targets and, in the longer term, could lead to a more specific means of inducing apoptosis in cancer cells.

authors

Gardner CR

doi

10.1586/14737140.4.6.1157

keywords:

subject

Has Abstract

pub_date

2004-12-01 00:00:00

pages

1157-77

issue

6

eissn

1473-7140

issn

1744-8328

pii

ERA040618

journal_volume

4

pub_type

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