Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies

Abstract

Despite doxorubicin being commonly used in chemotherapy there still remain significant holes in our knowledge regarding its delivery efficacy and an observed resistance mechanism that is postulated to involve the cell membrane. One possible mechanism is the efflux by protein P-gp, which is found predominantly in cholesterol enriched domains. Thereby, a hypothesis for the vulnerability of doxorubicin to efflux through P-gp is its enhanced affinity for the ordered cholesterol rich regions of the plasma membrane. Thus, we have studied doxorubicin’s interaction with model membranes in a cholesterol rich, ordered environment and in liquid-disordered cholesterol poor environment. We have combined three separate experimental protocols: UV-Vis spectrophotometry, fluorescence quenching and steady-state anisotropy and computational molecular dynamics modeling. Our results show that the presence of cholesterol induces a change in membrane structure and doesn’t impair doxorubicin’s membrane partitioning, but reduces drug’s influence on membrane fluidity without directly interacting with it. It is thus possible that the resistance mechanism that lowers the efficacy of doxorubicin, results from an increased density in membrane regions where the efflux proteins are present. This work represents a successful approach, combining experimental and computational studies of membrane based systems to unveil the behavior of drugs and candidate drug molecules.

Azurin interaction with the lipid raft components ganglioside GM-1 and caveolin-1 increases membrane fluidity and sensitivity to anti-cancer drugs

“…It was seen that this drug has a preference to locate in more ordered microdomains, where for example, P-glycoprotein is also preferentially located. For the authors, this could explain how the drug is available to be a substrate for efflux by this protein which is also located in these structures [44]. It is then possible that, by decreasing the more ordered domains, one of the mechanisms by which azurin enhances the activity of this drug is by perturbing this preferential localization of the drug reducing its availability to be efflux pumps.…”

Membrane Interactivity of Non-steroidal Anti-inflammatory Drugs: A Literature Review

“…Tamoxifen used to treat estrogen receptor-positive breast cancer has the property to decrease the membrane fluidity of human cancer cells and liposomes at relatively low concentrations [93,94]. Antineoplastic doxorubicin acts on human myeloid leukemia cells to decrease the fluidity of plasma membranes [95] and this drug is also effective in decreasing the fluidity of liposomal membranes by preferentially acting on lipid bilayers in the more fluid phase [96]. Cisplatin and other platinum (II) analogs used as anticancer drugs for a wide range of tumors not only form the adducts with genomic DNA but also interact with plasma membranes to change the membrane organization and fluidity [97].…”

A Role of Newly Found Auxiliary Site in Phospholipase A1 from Thai Banded Tiger Wasp (Vespa affinis) in Its Enzymatic Enhancement: In Silico Homology Modeling and Molecular Dynamics Insights

“…Various lipid molecules can then be considered as a potential representative to analyze Ves a 1 binding towards a phospholipid molecule. However, in this study, 1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) was chosen as a lipid representative since DMPC could well represent the phospholipid bilayer in both computational and experimental studies [14][15][16][17][18]. In this study, the lipid was docked into the 200-ns snapshot of Ves a 1 and the binding energy as well as conformation was obtained using SwissDock.…”