Based on this research, scientists at the Pennsylvania State (Penn State) University Cancer Institute in Hershey — led by Omer Kuzu, a postdoctoral fellow in pharmacology — set out to stop the movement of cholesterol within treatment-resistant cancer cells.
To do so, they turned to a class of drugs called functional inhibitors of acid sphingomyelinase (FIASMAs). Specifically, they tested 42 FIASMAs that were either antipsychotics or antidepressants and compared their effects with those of leelamine.
The findings were published in the British Journal of Cancer.
Using nanoparticles to deliver perphenazine
Kuzu and colleagues tested the drugs first in cell cultures, and then in mouse models of melanoma.
Of all the 42 drugs tested, perphenazine and fluphenazine were found to be just as effective as leelamine at killing cancer cells.
Then, the researchers administered these drugs orally to mice. They monitored the size and weight of the rodents' tumors.
Perphenazine reduced the size and weight of the malignancies, but only in high doses. Such a dosage made the rodents sleepy.
"Perphenazine was able to decrease tumor growth by shutting down cholesterol metabolism in cancer cells," explains lead study author Kuzu. "But the problem was that the drug concentrations required to do so led to sedative effects and loss of animal weight since mice were sleeping and not eating."
To bypass these side effects, the scientists used nanoparticles made of lipids, or fats, called nanoliposomes to deliver the drug.
Administered intravenously, these mini drug carriers destroyed the tumors without causing as many side effects. This was because the nanoparticles cannot permeate the blood-brain barrier, unlike the oral drugs.
"This study suggests that disruption of intracellular cholesterol transport by targeting ASM [acid sphingomyelinase] could be utilized as a potential chemotherapeutic approach for treating cancer," conclude the authors.
Senior study author Gavin Robertson, the director of the Penn State Melanoma and Skin Cancer Center, comments on the findings, saying, "This drug could be the first of a new class, disrupting the movement of cholesterol in cancer cells to inhibit disease development."
"It could lead to the repurposing of perphenazine to perform a new function in human medicine by encapsulating it into a nanoparticle, which reduces its capability of entering the brain so it can perform its new function to prevent cancer."
The scientists note that previous trials have tested the effects of antipsychotics in the fight against different types of cancer, but the results have been mixed.
Delivering the drugs via nanoliposomes could make the compounds safer and more effective.