In a revival of a 50-year-old antipsychotic treatment, scientists have found the drug perphenazine to successfully fight cancer cells by turning on an enzyme that causes the cells to essentially self-destruct.

Published in The Journal of Clinical Investigation, the study highlights the importance of revisiting drugs whose FDA patents have already expired and finding new ways to utilize them for modern diseases. If scientists can harness the drug’s effects on the specific enzyme, known as PP2A, without exploiting it for its psychotropic effects, they may be able to develop much-needed drug therapies for a rare form of cancer called acute lymphoblastic leukemia (ALL).

ALL actually comes in a number of forms, which vary in aggressiveness and rarity. The rarer, more aggressive form is called T-cell ALL, or simply T-ALL, which poses a 20 percent mortality risk for children and just over a 50 percent risk for adults. Basically, in this form of cancer the body’s T cells, which come in several variants and generally help regulate a person’s immune system without the aid of antibodies, succumb to proliferation of cancer cells. When this cancer is present, the cells stop producing the protein PP2A. Current research into zebrafish — cost-effective models for performing drug screenings — now show that perphenazine can restart that production.

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

The team combed through a library of 4,880 compounds in their zebrafish model before arriving at perphenazine as the desired drug target. These compounds included FDA-approved drugs whose patents had expired, small molecules, and natural products. As an antipsychotic drug, perphenazine works by blocking the brain’s dopamine receptors. Researchers say the drug’s new application is novel in that it can reactivate a protein shut down by cancer cells.

"We rarely find potential drug molecules that activate an enzyme," study leader Dr. Alejandro 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." In other words, while most drug therapies for cancer treatment suppress a certain function, the new finding returns the body to its natural state, instead suppressing the cancer cells themselves.

From here, Gutierrez and his colleagues say the necessary next step is deactivating the dopaminergic pathways to a greater extent. Since the drug’s original use was as an antipsychotic, the zebrafish model has been imperfect in the sense that the originally intended effects tend to spill over. And while doctors won’t feasibly rely on the PP2A route entirely, the team says the target can be an important addition in the oncologist’s arsenal.

Alternatively, they point out, scientists may seek to develop other PP2A-targeting drugs that don’t rely on the pathways at all. "We are optimistic that PP2A activators will have quite broad activity against different kinds of cancer,” Look concluded, “and we're anxious to study the pathway in other malignancies as well."

 

Source: Gutierrez A, Pan L, Groen R, et al. Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. The Journal of Clinical Investigation. 2014.