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Cell Surface Binding and Lipid Interactions behind Chemotherapy-Drug-Induced Ion Pore Formation in Membranes.

ABSTRACT: Chemotherapy drugs (CDs) disrupt the lipid membrane's insulation properties by inducing stable ion pores across bilayer membranes. The underlying molecular mechanisms behind pore formation have been revealed in this study using several methods that confirm molecular interactions and detect associated energetics of drugs on the cell surface in general and in lipid bilayers in particular. Liposome adsorption and cell surface binding of CD colchicine has been demonstrated experimentally. Buffer dissolved CDs were considerably adsorbed in the incubated phospholipid liposomes, measured using the patented 'direct detection method'. The drug adsorption process is regulated by the membrane environment, demonstrated in cholesterol-containing liposomes. We then detailed the phenomenology and energetics of the low nanoscale dimension cell surface (membrane) drug distribution, using atomic force microscopy (AFM) imaging what addresses the surface morphology and measures adhesion force (reducible to adhesive energy). Liposome adsorption and cell surface binding data helped model the cell surface drug distribution. The underlying molecular interactions behind surface binding energetics of drugs have been addressed in silico numerical computations (NCs) utilizing the screened Coulomb interactions among charges in a drug-drug/lipid cluster. Molecular dynamics (MD) simulations of the CD-lipid complexes detected primarily important CD-lipid electrostatic and van der Waals (vdW) interaction energies. From the energetics point of view, both liposome and cell surface membrane adsorption of drugs are therefore obvious findings. Colchicine treated cell surface AFM images provide a few important phenomenological conclusions, such as drugs bind generally with the cell surface, bind independently as well as in clusters of various sizes in random cell surface locations. The related adhesion energy decreases with increasing drug cluster size before saturating for larger clusters. MD simulation detected electrostatic and vdW and NC-derived charge-based interactions explain molecularly of the cause of cell surface binding of drugs. The membrane binding/association of drugs may help create drug-lipid complexes with specific energetics and statistically lead to the creation of ion channels. We reveal here crucial molecular understanding and features of the pore formation inside lipid membranes that may be applied universally for most of the pore-forming existing agents and novel candidate drugs.

SUBMITTER: Ashrafuzzaman M

PROVIDER: S-EPMC8304557 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We recently published two novel findings where we found the chemotherapy drugs (CDs) thiocolchicoside (TCC) and taxol to induce toroidal type ion pores and the antimicrobial peptide gramicidin S (GS) to induce transient defects in model membranes. Both CD pores and GS defects were induced under the influence of an applied transmembrane potential (≈100 mV), which was inspected using the electrophysiology record of membrane currents (ERMCs). In this article, I address the regulation of the membrane adsorption and pore formation of CDs due to GS-induced possible alterations of lipid bilayer physical properties. In ERMCs, low micromolar (≥1 μM) GS concentrations in the aqueous phase were found to cause an induction of defects in lipid bilayers, but nanomolar (nM) concentration GS did nothing. For the binary presence of CDs and GS in the membrane-bathing aqueous phase, the TCC pore formation potency is found to increase considerably due to nM concentration GS in buffer. This novel result resembles our recently reported finding that due to the binary aqueous presence of two AMPs (gramicidin A or alamethicin and GS), the pore or defect-forming potency of either AMP increases considerably. To reveal the underlying molecular mechanisms, the influence of GS (0-400 nM) on the quantitative liposome (membrane) adsorption of CD molecules, colchicine and TCC, was tested. I used the recently patented direct detection method, which helps detect the membrane active agents directly at the membrane in the mole fraction relative to its concentrations in aqueous phase. We find that GS, at concentrations known to do nothing to the lipid bilayer electrical barrier properties in ERMCs, increases the membrane adsorption (membrane uptake) of CDs considerably. This phenomenological finding along with the GS effects on CD-induced membrane conductance increase helps predict an important conclusion. The binary presence of AMPs alongside CDs in the lipid membrane vicinity may work toward enhancing the physical adsorption and pore formation potency of CDs in lipid bilayers. This may help understand why CDs cause considerable cytotoxicity.

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Cell Surface Binding and Lipid Interactions behind Chemotherapy-Drug-Induced Ion Pore Formation in Membranes.

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