Effects of self-assembled cell-penetrating peptides and their nano-complexes on ABCB۱ expression and activity

Objective(s): Doxorubicin (Dox) is one of the most well-known chemotherapeutics that are commonly applied for a wide range of cancer treatments. However, in most cases, efflux pumps like P-glycoprotein (P-gp), expel the taken drugs out of the cell and decrease the Dox bioavailability. Expression of P-gp is associated with elevated mRNA expression of the ATP-binding cassette B۱ (ABCB۱) gene. Materials and Methods: In the current study, different sequences of cell-penetrating peptides (CPPs) containing tryptophan, lysine, and arginine and their nano-complexes were synthesized and their impact on the expression and activity of the ABCB۱ gene was evaluated in the A۵۴۹ lung carcinoma cell line. Furthermore, the cellular uptake of designed CPPs in the A۵۴۹ cell line was assessed. Results: The designed peptides, including [W۴K۴], [WR]۳-QGR, R۱۰, and K۱۰ increased Dox cytotoxicity after ۴۸ hr. Furthermore, arginine-rich peptides showed higher cellular uptake. Rhodamin۱۲۳ accumulation studies illustrated that all the obtained peptides could successfully inhibit the P-gp pump. The designed peptides inhibited the ABCB۱ gene expression, of which, [W۴K۴] resulted in the lowest expression ratio. Conclusion: [W۴K۴], [WR]۳-QGR, R۱۰, and K۱۰ could successfully increase the Dox cytotoxicity by decreasing the efflux pump gene expression.

کلیدواژه ها:

Cancer therapy CPPs Doxorubicin Multi ، drug resistance P ، gp