Chemotherapy Drugs Form Ion Pores in Membranes Due to Physical Interactions with Lipids

Abstract

We demonstrate the effects on membrane of the tubulin-binding chemotherapy drugs: thiocolchicoside and taxol. Electrophysiology recordings across lipid membranes in aqueous phases containing drugs were used to investigate the drug effects on membrane conductance. Molecular dynamics simulation of the chemotherapy drug-lipid complexes was used to elucidate the mechanism at an atomistic level. Both drugs are observed to induce stable ion-flowing pores across membranes. Discrete pore current-time plots exhibit triangular conductance events in contrast to rectangular ones found for ion channels. Molecular dynamics simulations indicate that drugs and lipids experience electrostatic and van der Waals interactions for short periods of time when found within each other's proximity. The energies from these two interactions are found to be similar to the energies derived theoretically using the screened Coulomb and the van der Waals interactions between peptides and lipids due to mainly their charge properties while forming peptide-induced ion channels in lipid bilayers. Experimental and in silico studies together suggest that the chemotherapy drugs induce ion pores inside lipid membranes due to drug-lipid physical interactions. The findings reveal cytotoxic effects of drugs on the cell membrane, which may aid in novel drug development for treatment of cancer and other diseases.

Aptamers as Both Drugs and Drug-Carriers

“…With the absence of considerable binding with membrane the nanoparticles can easily diffuse to the cellular interior regions (for detailed theoretical analysis see above [46]). Induction of lipid-lined toroidal pores [13] may therefore be a mechanism for nanoparticle carrying delivery of drugs into cellular interior regions.…”

“…Various in silico techniques like molecular dynamic (MD) simulations, quantum mechanical (QM) calculations, and docking (see [2]) primarily detect candidate molecules for general binding to specific targets. These techniques fail to provide enough information on binding phenomena and energetics, though they may be utilized to address the distance dependent energy values as a result of molecular level physical interactions [13]. Further in vitro experiments validate the physical binding potency and thus drug molecules usually are ranked based on binding stability and energetics [13].…”

“…These techniques fail to provide enough information on binding phenomena and energetics, though they may be utilized to address the distance dependent energy values as a result of molecular level physical interactions [13]. Further in vitro experiments validate the physical binding potency and thus drug molecules usually are ranked based on binding stability and energetics [13]. There have been other traditional cell based dose-response techniques historically used.…”

“…The primary targets of these molecules are different or we can consider these molecules to be target specific. But occasionally they are found to show substantial off-target binding that accounts mainly for “drug cytotoxicity.” Due to cytotoxicity properties some molecules also show important off-target fractional binding specificity [13]. Thus same drug may appear as useful for other purposes.…”

Concentration effect of cimetidine with POPC bilayer: a molecular dynamics simulation study

“…Both experimental and in silico studies suggest that paclitaxel induce ion pores inside lipid membranes. [13] As paclitaxel is a hydrophobic drug, we wonder what effects of a hydrophilic drug cause with increased drug concentration. Cimetidine is an oral histamine H2-receptor antagonist, [14] whose structure is shown in Figure 1.…”