Studies on mechanism of action of anticancer peptides by modulation of hydrophobicity within a defined structural framework.

In the present study, the hydrophobicity of a 26-residue α-helical peptide (peptide P) was altered to study the effects of peptide hydrophobicity on the mechanism of action of cationic anticancer peptides. Hydrophobicity of the nonpolar face of the peptides was shown to correlate with peptide helicity. The self-association ability of peptides in aqueous environment, determined by the reversed-phase high performance liquid chromatography temperature profiling, showed strong influence on anticancer activity. The peptide analogues with greater hydrophobicity showed stronger anticancer activity determined by IC(50) values with a necrotic-like membrane disruption mechanism. Peptide analogues exhibited high specificity against cancer cells and much higher anticancer activity than widely-used anticancer chemical drugs. The mechanism of action of anticancer peptides was also investigated. The hydrophobicity of peptides plays a crucial role in the mechanism of action against cancer cells, which could present a way, using a de novo design approach, to create anticancer peptides as potential therapeutics in clinical practices.