Antipsychotic medication can actively combat cells of difficult-to-treat form of ALL

Published on January 9, 2014 at 11:20 PM · No Comments

In zebrafish model, perphenazine activates therapeutic pathway for intractable leukemia, may hold promise for other tumors

In a prime example of finding new uses for older drugs, studies in zebrafish show that a 50-year-old antipsychotic medication called perphenazine can actively combat the cells of a difficult-to-treat form of acute lymphoblastic leukemia (ALL). The drug works by turning on a cancer-suppressing enzyme called PP2A and causing malignant tumor cells to self-destruct.

The findings suggest that developing medications that activate PP2A, while avoiding perphenazine's psychotropic effects, could help clinicians make much-needed headway against T-cell ALL, and perhaps other tumors as well.

A study team led by Alejandro Gutierrez, MD, and A. Thomas Look, MD, of Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and Jon Aster, MD, PhD, of Dana-Farber Cancer Institute and Brigham and Women's Hospital, reported the results Jan. 9 in the Journal of Clinical Investigation.

T-ALL is rarer and more aggressive than the B-cell form of ALL, and it has a relatively poor prognosis. Despite improvements in the treatments available, 20 percent of children and more than 50 percent of adults diagnosed with T-ALL succumb to it.

To identify possible new treatment options, Gutierrez, Look and their collaborators screened a library of 4,880 compounds-including FDA-approved drugs whose patents had expired, small molecules and natural products-in a model of T-ALL engineered using zebrafish.

Strategies that identify new uses for existing drugs have grown in popularity in recent years as a way of quickly developing new disease therapies. Zebrafish models are cost-effective platforms for rapidly conducting drug screens, as well as basic stem cell, genetic, cancer and developmental research.

"We wanted to see if there were drugs or known bioactive molecules that are active against T-ALL that hadn't been tested yet," Look explained. "There may be drugs available for other indications that could be readily repurposed if we can show activity."

One of the strongest hits in the zebrafish screen was the drug perphenazine. It is a member of the phenothiazines, a family of antipsychotic medications used for 50 years, because they can block dopamine receptors.

The team verified perphenazine's anti-leukemic potential in vitro in several mouse and human T-ALL cell lines. Biochemical studies indicated that perphenazine's anti-tumor activity is independent of its psychotropic activity, and that it attacks T-ALL cells by turning on PP2A.

The fact that perphenazine works by reactivating a protein shut down in cancer cells is itself novel in the drug development field.

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