Abstract 2458: Targeting membrane fluidity as a therapeutic strategy in cancer using BPM 31510

Abstract

Abstract Cancer cells membranes are relatively more fluid compared to healthy cells. Higher fluidity in cancer cells closely relate to their invasive potential, proliferation, and metastatic ability. Pharmacological modulation of membrane fluidity as a novel therapeutic strategy for potential treatment of cancer is investigated in this study. BPM 31510, a proprietary CoQ10 based liposomal formulation currently in clinical trials affects cell membrane fluidity to influence cancer cell survival. To study the effect of BPM 31510 on biophysical parameters of membrane structure in cancer cells, the CoQ10 concentration in the liposomes was systematically increased and the membrane rigidity (Fluorescence Anisotropy) as function of temperature was measured. A progressive (significant, p<0.05) increase in rigidity of liposomal membranes was observed with increase in CoQ10 concentration to a maxima, after which any further increase in CoQ10 concentration resulted in decreases in membrane rigidity. Interestingly, the local maxima in rigidity matched with the concentration of CoQ10 in BPM 31510 formulation. A spectrum of cell lines including cancer of breast, pancreas, liver, prostate, ovarian cell lines and corresponding healthy non-disease control cell lines including fibroblast, smooth muscles, primary prostate were treated with BPM 31510. For all cell lines, there was a temporal increase in cell membrane rigidity between 0-8 hours following treatment with BPM 31510. The magnitude of increase in membrane rigidity was higher for cells with higher initial membrane fluidity for cancer cells compared to healthy cells. Further, magnitude and rate of this reorganization of cell lipid and protein profile, bioenergetics and metabolic state as a maladaptive response of cells to BPM 31510 correlated with the magnitude of change in cell membrane rigidity. Finally, decrease in cell viability was higher for cells with higher membrane fluidity compared to cells with rigid membrane after 48 hours of treatment of BPM 31510. In in vivo preclinical animal model of cancer, there was a strong correlation between BPM 31510 in-plane rigidity measurements to observed bio-distribution and efficacy. This work provides profound insight into CoQ10 effect on cell membrane dynamics and mechanism of action of BPM 31510. The study provides compelling evidence in support of targeting membrane fluidity characteristics in cancer cells as a novel modality with therapeutic potential in the treatment of cancer. Citation Format: Sumit Garg, Sirisha Dhavala, Katerina Krumova, Vivek K. Vishnudas, Joaquin J. Jimenez, Michael Kiebish, Rangaprasad Sarangarajan, Niven R. Narain. Targeting membrane fluidity as a therapeutic strategy in cancer using BPM 31510. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2458. doi:10.1158/1538-7445.AM2015-2458