Lipid cell membrane composition: A novel therapeutic target in cancer.

7062 Background: Cell membrane cholesterol, more specifically, the lipid composition of lipid rafts is associated with regulation of trans-membrane receptors. Methods: We tested the hypothesis that altering membrane cholesterols, via mevalonate pathway inhibitors, Ro 48-8071, TAK-475, BIBB-515 and YM-53601, may have differential effects on cancer cells in in-vitro models of Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia (CLL) cell lines and Peripheral blood lymphocytes of CLL patients. Results: In addition to chemo-sensitization of the cells, in-vitro results showed a statistically significant upregulation of cell surface proteins, CD20 and CD52. Treatment with cholesterol inhibitors resulted in significant upregulation of CD20 protein and glycosphingolipid-GM1 both by confocal microscopy and flow cytometry. Flow cytometry of MEC-2 and WAC-3 showed an upregulation of CD20 and CD52. Quantification of membrane lipids showed upregulation of glycosphingolipid-GM1. LysoPC (lysophosphatidylcholine) was an average of 0.0405 ± .0016 in controls was reduced to 0.0278 ± 0.0021 with BIBB-515 treatment and 0.0247 ± 0.0022 with YM-53601 treatment. PC (phosphatidylcholine) was upregulated from 1.0029 ± 0.02378 in controls to 1.0904 ± 0.04489 with BIBB-515 treatment and 1.1088 ± 0.02269 with YM-53601 treatment (P<0.05). Spingomyelin/Dihydrosphingomyelin (SM/DSM) was an average of 0.5863 ± 0.0113 in controls and was upregulated to 0.5997 ± 0.0294 with BIBB-515 treatment (P<.05) and 0.6735 ± 0.0159 in YM-53601 treatment (P<.001). Ether-linked Phosphatidylcholine (ePC) was upregulated from 0.2938 ± 0.0044 in controls to 0.3328 ± 0.0152 with BIBB-515 treatment and 0.3370 ± 0.0061 with YM-53601 treatment (P<.001). Treatment with BIBB-515 and YM-53601 did not affect membrane cholesterol levels significantly. Lovastatin significantly reduced membrane cholesterol from controls (P<0.05). Conclusions: Mevalonate pathway inhibitors lead to alterations in drug-resistant cancer cell membrane lipids by altering the cell surface receptor proteins CD 20 and upregulation of glycosphingolipid-GM1. A specific biochemical alteration in cancer cell membrane lipids represents a potential novel therapeutic approach to cancer.