Experimental Cancer Drug Prevents Inhibition of Pro-Death Molecules

Cancer researchers have identified a class of peptides, BH3 domains, which trigger death of tumor cells by inhibiting the Bcl-2 family of anti-apoptotic proteins.

Bcl-2 is the prototype for a family of mammalian genes and the proteins they produce. They govern mitochondrial outer membrane permeabilization and can be either pro-apoptopic (Bax, Bak, and Bok among others) or anti-apoptopic (including Bcl-2, Bcl-xL, and Bcl-w, among an assortment of others). There are a total of 25 genes in the Bcl-2 family known to date. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described as a reciprocal gene translocation in chromosomes 14 and 18 in follicular lymphomas. The members of the Bcl-2 family share one or more of the four characteristic domains of homology called the Bcl-2 homology (BH) domains (named BH1, BH2, BH3, and BH4). The BH domains are known to be crucial for function, as deletion of these domains via molecular cloning affects survival/apoptosis rates.

In the current study, investigators at the Dana-Farber Cancer Institute (Boston, MA, USA) isolated mitochondria from chronic lymphocytic leukemia (CLL) cells growing in tissue culture. The mitochondria preparations were treated with peptides known to interact with survival molecules like Bcl-2 and with the experimental drug ABT-737, which mimics the BH3 domain.

Results published in the January 2007 issue of the Journal of Clinical Investigation revealed that ABT-737 successful induced cell death in CLL cells by preventing Bcl-2 from binding and inhibiting the pro-apoptotic protein Bim. ABT-737 displaced Bim from Bcl-2's BH3-binding pocket, allowing Bim to activate Bax, induce mitochondrial permeabilization, and rapidly commit the CLL cell to death.

"We have treated CLL samples from several dozen patients, and each has responded to a very low concentration of the drug,” said senior author Dr. Anthony Letai, assistant professor of medicine at Harvard Medical School (Boston, MA, USA). "We find it particularly interesting that the cells died within four hours. This is a totally new class of drugs and has the potential to be a major addition to how we treat cancer.”




Related Links:
Dana Farber Institute (Harvard Medical School)