Drug Combination Cures Myeloid Leukemia in Mouse Model

The combination of the vitamin A derivative ATRA (all-trans retinoic acid) with the monoamine oxidase inhibitior tranylcypromine (TCP) was shown to be an effective chemotherapeutic regimen for the treatment of acute myeloid leukemia (AML).

All-trans retinoic acid (ATRA, or tretinoin) is used to treat acute promyelocytic leukemia (APL) by causing the immature blood cells to differentiate. The pathology of the leukemia is due to the highly proliferative immature cells; retinoic acid drives these cells to develop into functional cells, which helps to alleviate the disease. However, among patients with non-APL AML, ATRA-based treatment has not been effective.

Investigators at the Institute of Cancer Research (Sutton, United Kingdom) looked for ways to extend the usefulness of ATRA treatment to the more common forms of AML.

They reported in the March 11, 2012, online edition of the journal Nature Medicine that inhibitors of the enzyme lysine-specific demethylase 1 (LSD1, also called KDM1A), including the antidepressant tranylcypromine (TCP), rendered non-APL AML cells susceptible to ATRA-driven therapy. As a monoamine oxidase inhibitor, tranylcypromine blocks the action of the enzyme monoamine oxidase and results in an increase in serotonin, adrenaline, and noradrenaline.

Initiation of ATRA plus TCP treatment 15 days after transplantation of human AML cells into mice revealed that the ATRA plus TCP drug combination had a potent anti-leukemic effect that was superior to treatment with either drug alone.

"Retinoids have already transformed one rare type of fatal leukemia into a curable disease. We have now found a way to harness these powerful drugs to treat far more common types of leukemia," said senior author Dr. Arthur Zelent, reader in biochemistry at the Institute of Cancer Research. "Until now, it has been a mystery why the other forms of AML do not respond to this drug. Our study revealed that there was a molecular block that could be reversed with a second drug that is already commonly used as an antidepressant. We think this is a very promising strategy, and if these findings can be replicated in patients the potential benefits are enormous."

Related Links:
Institute of Cancer Research