The combination of the two drugs nearly abolished Mcl-1 expression in AML cells, and in doing so unleashed Bax and Bak proteins. Bax and Bak are usually held in check by Mcl-1, and both help initiate apoptosis in cancer cells. Increased levels of Bim were also observed in treated cells. Bim is another pro-apoptotic protein that is often referred to as a "death trigger." Increased levels or activation of all three of these proteins contributed to the pronounced killing of AML cells.
Grant's team also observed protective mechanisms at play in the AML cells. The combination therapy induced autophagy, a process that diverts energy from less critical cellular constituents to enhance survival. Using chloroquine, a drug that suppresses immune responses and is typically used to treat malaria, the researchers were able to inhibit autophagy and increase AML cell death even further.
"When cancer cells are placed under stress, they seek any possible way to remain alive," says Grant. "The combination of these drugs served to block molecular 'escape routes,' leaving the cells no option other than suicide. Thus, it is theoretically possible that a third agent such as chloroquine may enhance the effectiveness of this regimen even further by reducing the cell's ability to induce autophagy."
Moving forward, Grant's team, led by Prithviraj Bose, M.D., assistant professor of internal medicine and hematologist-oncologist at Massey, is proposing a Phase I clinical trial testing this therapy in AML patients. The researchers are working with the involved drug companies, the National Cancer Institute and multiple potential collaborators to in
|Contact: John Wallace|
Virginia Commonwealth University