Epigenetic Modulation of the Biophysical Properties of Drug-Resistant Cell Lipids to Restore Drug Transport and Endocytic Functions

Abstract

In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane’s biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug, 5-aza-2′-deoxycytidine (decitabine), significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

Nanomedicine of synergistic drug combinations for cancer therapy – Strategies and perspectives

“…Hypomethylation of the gene MDR1 promoter in addition to acetylation of histone 3 induce overexpression of P-gp resulting in a broad spectrum of anticancer drug resistance [132]. Hypermethylation of the gene for enzyme sphingomyelinase alters lipid biosynthesis in cancer membrane and reduces the membrane fluidity preventing anticancer drugs from passive diffusion into cancer cells [133]. …”

“…Decitabine (DAC) is a DNMT inhibitor, which exerts its antineoplastic effects via direct incorporation into DNA and inhibition of DNMT, resulting in demethylation of DNA. Epigenetic disruption has been suggested to involve in early stage of breast cancer cell transformation in multidrug resistance [133, 135]. Sequential treatment of DAC and DOX exhibited synergistic anticancer effect against resistant MCF-7/Adr cancer cells via enhanced DOX accumulation.…”

Nutrient-Gene Interaction in Colon Cancer, from the Membrane to Cellular Physiology

“…Multidrug-resistance cancer cells have unique plasma membrane lipid composition and organization, specifically increased sphingomyelin and rigidity (213, 224). Increased rigidity is associated with increased lipid rafts, which typically facilitate efficient cellular signaling.…”

Photothermal ablation of inflammatory breast cancer tumor emboli using plasmonic gold nanostars

“…39 Vijayaraghavalu et al investigated the use of Doxil ® , the liposomal formulation of doxorubicin, in delivering doxorubicin to resistant breast cancer cells. 40 The compact and rigid nature of drug-resistant cell membranes resulted in impaired endocytic function that inhibited intracellular drug delivery using Doxil. Although the study was carried out using the encapsulated formulation Doxil, issues of endocytic transport in drug-resistant cells could potentially exist with other PEGylated nanocarrier systems, such as the nanoparticles used in this study.…”