Potential‐dependent permeabilization of the plasma membrane by antitumor polycation peptides

Abstract

Some polycation antimicrobial KLA peptides demonstrate pro‐apoptotic activity in tumor cells. Antitumor activity of one such KLA peptide, KLAKLAKKLAKLAK, has been strongly enhanced by its conjugation with a cell penetrating hepta‐arginine peptide. It was shown (Law et al., 2006) that cytotoxic activity of the peptide 7r‐kla, D‐form of conjugated peptide, is higher (IC50=3.54 uM) than that of 7R‐KLA (IC50=7.21 uM) and significantly higher than that of kla. Here we studied the capacity of 3.6 uM aforementioned peptides and of 0.36 uM antimicrobial peptide BTM‐P1 (Lemeshko et al., 2005) to permeabilize plasma membrane of red blood cells. Cell swelling was monitored by light dispersion. The membrane potential was monitored by fluorescent probe DioC6(3). The peptides did not permeabilize the plasma membrane with a physiological membrane potential value near ‐10 mV. In contrast, artificially generated potential of approximately ‐180 mV strongly increased the capacity of 7r‐kla and 7R‐KLA, but not of kla, to induce cell swelling that started with a half‐minute lag‐period after a fast drop of the induced membrane potential. The activity of 7r‐kla was almost double of 7R‐KLA, and significantly lower that that of BTM‐P1. Thus, the plasma membrane potential is likely an essential factor for the cell permeabilization by antitumor and antimicrobial polycation peptides. (Supported by Colciencias grant #111840820380).