Niazi Mehri, Zakeri-Milani Parvin, Soleymani-Goloujeh Mehdi, Mohammadi Ali, Sarfraz Muhammad, Löbenberg Raimar, Najafi-Hajivar Saeedeh, Shahbazi-Mojarrad Javid, Farshbaf Masoud, Valizadeh Hadi
Student Research Committee, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Iran J Basic Med Sci. 2021 Mar;24(3):383-390. doi: 10.22038/ijbms.2021.51675.11727.
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 B1 (ABCB1) gene.
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 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.
The designed peptides, including [W4K4], [WR]3-QGR, R10, and K10 increased Dox cytotoxicity after 48 hr. Furthermore, arginine-rich peptides showed higher cellular uptake. Rhodamin123 accumulation studies illustrated that all the obtained peptides could successfully inhibit the P-gp pump. The designed peptides inhibited the ABCB1 gene expression, of which, [W4K4] resulted in the lowest expression ratio.
[W4K4], [WR]3-QGR, R10, and K10 could successfully increase the Dox cytotoxicity by decreasing the efflux pump gene expression.
阿霉素（Dox）是最著名的化疗药物之一，常用于多种癌症治疗。然而，在大多数情况下，像P-糖蛋白（P-gp）这样的外排泵会将摄入的药物排出细胞，降低阿霉素的生物利用度。P-gp的表达与ATP结合盒转运体B1（ABCB1）基因的mRNA表达升高有关。
在本研究中，合成了含有色氨酸、赖氨酸和精氨酸的不同序列的细胞穿透肽（CPPs）及其纳米复合物，并在A549肺癌细胞系中评估了它们对ABCB1基因表达和活性的影响。此外，还评估了设计的CPPs在A549细胞系中的细胞摄取情况。
设计的肽，包括[W4K4]、[WR]3-QGR、R10和K10，在48小时后增加了阿霉素的细胞毒性。此外，富含精氨酸的肽显示出更高的细胞摄取率。罗丹明123积累研究表明，所有获得的肽都能成功抑制P-gp泵。设计的肽抑制了ABCB1基因的表达，其中[W4K4]导致的表达率最低。
[W4K4]、[WR]3-QGR、R10和K10可通过降低外排泵基因表达成功增加阿霉素的细胞毒性。
