Effects of self-assembled cell-penetrating peptides and their nano-complexes on ABCB1 expression and activity

Objective(s): Doxorubicin (Dox) is one of the most wellknown chemotherapeutics that are commonly applied for a wide range of cancer treatments. However, in most cases, efflux pumps like Pglycoprotein (P-gp), expel the taken drugs out of the cell and decrease the Dox bioavailability. Expression of Pgp is associated with elevated mRNA expression of the ATPbinding cassette B1 (ABCB1) gene. Materials and Methods: In the current study, different sequences of cellpenetrating peptides (CPPs) containing tryptophan, lysine, and arginine and their nanocomplexes were synthesized and their impact on the expression and activity of the ABCB1 gene was evaluated in the A549 lung carcinoma cell line. Furthermore, the cellular uptake of designed CPPs in the A549 cell line was assessed. Results: The designed peptides, including [W4K4], [WR]3-QGR, R10, and K10 increased Dox cytotoxicity after 48 hr. Furthermore, argininerich peptides showed higher cellular uptake. Rhodamin123 accumulation studies illustrated that all the obtained peptides could successfully inhibit the Pgp pump. The designed peptides inhibited the ABCB1 gene expression, of which, [W4K4] resulted in the lowest expression ratio. Conclusion: [W4K4], [WR]3-QGR, R10, and K10 could successfully increase the Dox cytotoxicity by decreasing the efflux pump gene expression.