Combinatorial use of Lovastatin and FTI‐277 to alter Ras membrane association in A375 melanoma cells

Abstract

In 2018, 9,000 of those people will die from melanoma (American Cancer Society, 2018). In melanoma like many cancers, a mutation in the Ras protein has been implicated in excessive cell proliferation. A farnesyl transferase inhibitor, FTI‐277, has shown the ability to lower Ras membrane association by disrupting Ras prenylation. Additionally, Lovastatin, a cholesterol lowering drug, is associated with decreased Ras membrane association. Unprenylated Ras cannot attached to the cell membrane or initiate signals in downstream effector proteins. Previous studies have shown that these two drugs cannot kill melanoma tumors individually, but the combinatorial effects have not been examined. We hypothesize that FTI‐277 will be a more potent inhibitor of Ras prenylation/activation than Lovastatin due to Lovastatin's high cytotoxicity. A metastatic melanoma cell line (A375) was treated and Ras prenylation and membrane association examined using immunofluorescence. Flow cytometry showed that the minimum concentration of 10 mM of each drug individually and in combination did not result in more than 30% cell death. Results showed that high concentrations of both drugs induced cell toxicity and at 10 mM Lovastatin was more cytotoxic than FTI‐277 (mean= 30.67%, 10.69% respectively, p=0.017). Cell image analysis showed that the average corrected total cell fluorescence for individual treatment with each drug was significantly lower than both the vehicle control and treatment with both drugs (p<0.05). Together this shows that treatment with these drugs is efficacious for melanoma due to their abilities to induce apoptosis and alter Ras membrane association.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.