Membrane ordering effects of the anticancer agent VM-26

Area of Science:

• Biochemistry
• Membrane Biophysics
• Pharmacology

Background:

• Anticancer agents often target nuclear DNA.
• Cellular membranes play crucial roles in drug transport and cellular signaling.
• Understanding drug interactions with membranes is vital for drug development.

Purpose of the Study:

• To investigate the effect of the anticancer agent VM-26 on the acyl chain order of cellular and model membranes.
• To compare the membrane-ordering effects of VM-26 with its congener VP-16 and cholesterol.

Main Methods:

• Electron spin resonance (ESR) spectroscopy was employed to measure membrane order.
• Paramagnetic probe 5-doxyl stearate was used to assess acyl chain order.
• Experiments were conducted on fluid-phase (DMPC) and gel-phase (DPPC) liposomes, asolectin liposomes, and intact cancer cells (Ehrlich ascites and CCRF-CEM).

Main Results:

• VM-26 incorporation increased the order parameter of 5-doxyl stearate in both DMPC and DPPC liposomes.
• VM-26 exhibited a greater ordering effect on DMPC membranes than cholesterol on an equimolar basis.
• The less cytotoxic congener, VP-16, showed significantly less membrane-ordering activity compared to VM-26.
• Increased order parameters were observed in VM-26-treated asolectin liposomes and cancer cell lines.

Conclusions:

• VM-26 possesses significant membrane-associated activity, influencing membrane acyl chain order.
• This membrane activity is distinct from its established nuclear effects.
• The findings suggest that VM-26's therapeutic efficacy may be partly attributed to its interaction with cellular membranes.