Experiments in zebrafish have shown that a 50-year-old antipsychotic medication called perphenazine can actively combat T-cell acute lymphoblastic leukemia (T-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-ALL and perhaps other tumors as well.
Alejandro Gutierrez, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues detailed this research in The Journal of Clinical Investigation.
The researchers screened a library of 4880 compounds—including FDA-approved drugs whose patents had expired, small molecules, and natural products—in a model of T-ALL engineered using zebrafish.
One of the strongest hits in the zebrafish screen was perphenazine. The drug is a member of the phenothiazines family of antipsychotic medications, which can block dopamine receptors.
The investigators 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 novel in the drug development field.
“We rarely find potential drug molecules that activate an enzyme,” Dr Gutierrez explained. “Most new drugs deactivate some protein or signal that the cancer cell requires to survive. But, here, perphenazine is restoring the activity of PP2A in the T-ALL cell.”
The researchers are now working to better understand the interactions between PP2A and perphenazine. They also want to search for or develop molecules that bind to and activate the enzyme more tightly and specifically to avoid perphenazine’s psychiatric effects.
“The challenge is to use medicinal chemistry to develop new PP2A inhibitors similar to perphenazine and the other phenothiazines, but to dial down dopamine interactions and accentuate those with PP2A,” said study author A. Thomas Look, MD, also of Dana-Farber.
He added that future PP2A inhibitors could be important additions to the oncologist’s arsenal. When used in combination with other drugs, the inhibitors might “make a real difference” for patients with T-ALL.
The investigators also believe the benefits of PP2A-activating drugs could extend beyond T-ALL.
“The proteins that PP2A suppresses, such as Myc and Akt, are involved in many tumors,” Dr Look noted. “We are optimistic that PP2A activators will have quite broad activity against different kinds of cancer, and we’re anxious to study the pathway in other malignancies as well.”
