Disruption of Intracellular Cholesterol Transport: Potential Approach to Treating Melanoma
Posted: Wednesday, August 22, 2018
Results from a recently published study suggest that disruption of intracellular cholesterol transport by targeting acid sphingomyelinase (ASM) deficiency may be utilized as a potential chemotherapeutic approach for treating cancer, such as melanoma. The study, published in the British Journal of Cancer, centers on the hypothesis that the demand for cholesterol is high in certain cancers, making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis.
Omer F. Kuzu, MD, of the Pennsylvania State University College of Medicine, Hershey, and colleagues, studied the effect of functional ASM inhibitors on intracellular cholesterol levels, cholesterol homoeostasis, cellular endocytosis, and signaling cascades. Two tested ASM inhibitors, perphenazine and fluphenazine (also clinically used as antipsychotics), were effective in inhibiting xenografted tumor growth. The investigators also noted that targeting intracellular cholesterol transport with leelamine has been shown to retard melanoma tumor growth.
In the study, ASM inhibitors were effective at killing cancer cells, depending on the genetic background. Melanoma cell lines harboring activating BRAFmutations and loss of functional PTEN required twofold to fivefold lower concentrations of ASM inhibitors than normal skin cells or melanoma cells lacking these genetic alterations.
To measure the chemotherapeutic potential of ASM inhibition, the efficacy of perphenazine, nortriptyline, and desipramine was tested on xenografted melanoma tumor development. Oral administration of perphenazine reduced tumor growth by 60%, whereas the use of nortriptyline and desipramine led to 50% and 30% tumor inhibition, respectively. The investigators also commented that nanoliposomal encapsulation of perphenazine reduced side effects while enhancing chemotherapeutic efficacy.
“Certain ASM compounds with well-known toxicity profiles might be repurposed for use as anticancer agents by reformulation into nanoparticles,” noted the researchers.