Scientists report that they have succeeded in sensitizing human leukemic cells to molecules that induce cell death by apoptosis. They did this by coupling the drug etoxomir with molecules that release proapoptotic proteins to inhibit a cellular pathway known as fatty acid oxidation.
Recent research has indicated that in the process of generating energy, leukemic cells use fatty acid oxidation rather than pyruvate oxidation as had been previously thought. The researchers, from the University of Texas M.D. Anderson Cancer Center and the University of Texas Houston Medical School, thus decided to inhibit fatty acid oxidation.
They used either etomoxir, a drug that was tested in clinical trials for the treatment of heart disease but never made it to market due to unacceptable toxicities, or ranolazine, a drug approved for the treatment of chronic angina. The investigators found that this inhibited human leukemic-cell proliferation in vitro. More importantly, etoxomir treatment sensitized human leukemic cells to the death-inducing compound ABT-737 both in vitro and in vivo, in a xenotransplant mouse model of leukemia. ABT-737 is a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737.
Etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human acute myeloid leukemia samples. When combined with either ABT-737 or cytosine arabinoside, it provided substantial therapeutic benefit in a murine model of leukemia.
The authors therefore conclude that fatty acid oxidation is essential for human leukemic cell survival and suggest that inhibitors of fatty acid oxidation might provide a new approach to treating leukemias. Their findings appear in the December 21 online edition of The Journal of Clinical Investigation in a paper titled “Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction.”