Coadministration of the drugs gossypol and navitoclax may prove to be an effective way to destroy resistant chronic lymphocytic leukemia (CLL) cells in the lymph nodes and bone marrow.
A team led by Alan Eastman, PhD, a professor of pharmacology and toxicology at the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, found that the combination of gossypol and navitoclax targets the mechanism in CLL cells that make those cells resistant to standard treatment.
Both drugs belong to a class of compounds known as BH3 mimetics, noted Eastman and colleagues in their letter to the editor, published by the journal Leukemia. BH3 mimetics were developed to directly inhibit proteins in the BCL2 family. CLL is characterized by the deregulated accumulation and persistence of B lymphocytes in the blood; these cells manage to evade apoptosis (programmed cell death) with the help of BCL2 proteins.
As explained in a statement from Dartmouth-Hitchcock Medical Center, CLL cells in the lymph nodes have an increased level of the BCL-X protein. Gossypol likely inhibits this protein, allowing navitoclax to work more effectively to kill the cancer cells.
“Both drugs have been given to patients, but never in combination because no one had the mechanistic rationale for doing that,” pointed out Eastman in the statement. “Now we have what we think is the most promising drug combination so far for the treatment of CLL.”
The investigators found that gossypol sensitized human CLL cells to a navitoclax-like BCL inhibitor, increasing the rate of apoptosis, which gossypol alone was not able to achieve.
With both gossypol and navitoclax already having been tested in humans, Eastman’s group concludes the new data support the notion of a combination trial in persons with CLL. Although both drugs have demonstrated toxicity when administered on a chronic daily basis, the findings suggest acute treatment might be effective and would avoid the toxicity.