Drug Combination Overwhelms Leukemia Cells

Cancer researchers have shown that a combination of two experimental drugs, ABT-737 and a mitogen-activated protein kinase (MAPK) inhibitor, effectively killed acute myeloid leukemia (AML) blast, progenitor, and stem cells without affecting normal hematopoietic cells.

ABT-737 is a small molecule that mimics the structure of BH3 protein and has been shown to be active against lymphoma and small-cell lung cancer in preclinical studies.

The BH3 proteins act as sentinels that selectively trigger apoptosis in response to developmental cues or stress-signals like DNA damage. Widely expressed mammalian BH3 proteins are thought to act by binding to and neutralizing their pro-survival counterparts. Activation of BH3 proteins directly or indirectly results in the activation of pro-apoptotic BAX and BAK to trigger cell death.

Bcl-2 is the prototype for a family of mammalian genes and the proteins they produce. They govern mitochondrial membrane permeabilization and can be either pro-apoptopic (tumor suppressing--Bax, Bak, and Bok among others) or anti-apoptopic (potentially carcinogenic--including Bcl-2, Bcl-xL, and Bcl-w, among an assortment of others). 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.

Investigators at the University of Texas M. D. Anderson Cancer Center (Houston, USA) worked with tissue cultures of normal cells and AML cells taken from cancer patients. They found that although ABT-737 was able to destroy AML cells that were resistant to other forms of chemotherapy, some cells were able to develop resistance to the drug. The AML cells that did not die were those where another anti-apoptotic protein, MCL-1, was over expressed. To render these cells sensitive to ABT-737 a MAP-kinase inhibitor was added in order to knock down MCL-1 expression.

Results published in the November 14, 2006, issue of Cancer Cell revealed that treatment of AML cells with the MAPK inhibitor restored ABT-737 sensitivity in those cells with phosphorylated BCL-2 or increased MCL-1.

"ABT-737 represents a completely new class of agents that could have a major impact on a number of cancers, and we have now seen that AML will likely be among them,” explained senior author Dr. Michael Andreeff, professor of oncology at the University of Texas M. D. Anderson Cancer Center. "ABT-737 had diminished effects against cells with phosphorylated BCL-2, which was restored by combination with a MAPK inhibitor. The combination of these two experimental drugs provides the highest synergistic action I have ever seen against acute myeloid leukemia cells. Most importantly, our results demonstrated killing of the progenitor and stem cells responsible for production of AML, which makes this a truly innovative treatment for different leukemias and cancer.”



Related Links:
University of Texas M. D. Anderson Cancer Center