Apoptosis at bay

Credit: © Dr Gopal Murti / Photo Researchers, Inc." /> Credit: © Dr Gopal Murti / Photo Researchers, Inc. The paper: M. Certo et al., "Mitochondria primed by death signals determine cellular addiction to anti-apoptotic BCL-2 family members," Cancer Cell, 9:351-65, 2006. (Cited in 116 papers) The finding: Anthony Letai's team at the Dana-Farber Cancer Institute

Elie Dolgin
Aug 1, 2008
<figcaption> Credit: © Dr Gopal Murti / Photo Researchers, Inc.</figcaption>
Credit: © Dr Gopal Murti / Photo Researchers, Inc.

The paper:

M. Certo et al., "Mitochondria primed by death signals determine cellular addiction to anti-apoptotic BCL-2 family members," Cancer Cell, 9:351-65, 2006. (Cited in 116 papers)

The finding:

Anthony Letai's team at the Dana-Farber Cancer Institute found an intermediate state in which cells are ready to die and need continuous anti-apoptotic protein function for survival - a state they called "primed for death." Letai used fluorescence-binding assays to show that anti-apoptotic BCL2-family proteins interact in a highly specific manner with related pro-apoptotic proteins that control apoptosis.

The impact:

The paper "provided a way to sort out which interactions are important and how to make use of that information in cancer cells," says Eileen White of Rutgers University. Based on the distinct binding patterns, Letai's team used the pro-apoptotic proteins' BH3 domains to infer the subset of anti-apoptotic proteins that...

The follow-up:

Last year, Letai's group used BH3 profiling on 18 lymphoma cell lines. They identified one class of cell lines that was primed for death and was the most sensitive to both ABT-737 - a compound that blocks anti-apoptotic protein function - and conventional chemotherapy agents.

The application:

ABT-737 is now in Phase I clinical trials for leukemia, Hodgkin lymphoma, and small-cell lung cancer (SCLC). Earlier this year, Charles Rudin of Johns Hopkins University and his colleagues showed that SCLC cell lines that acquire resistance to ABT-737 have lower levels of anti-apoptotic BL2 protein, indicating that they might no longer be primed for death.

Selective binding of "activator" pro-apoptotic proteins (Kd in nM)
Anti-apoptotic
Pro-apoptotic BCL-2 BCL-XL BCL-w MCL1 BFL1
BID 66 12 <10 <10 53
BIM <10 <10 38 <10 73