Enhanced breast cancer cell targeting: RGD integrin ligand potentiates RWQWRWQWR’s cytotoxicity and inhibits migration

A. Barragán-Cárdenas, Daniel Castellar-Almonacid, Yerly Vargas-Casanova, C. Parra-Giraldo, Adriana Umaña-Pérez, J. López-Meza, Z. Rivera-Monroy, J. García-Castañeda
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Abstract

Aim: Evaluate the selective cytotoxic effect of the palindromic sequence RWQWRWQWR and its analogues obtained by replacement of L-amino acids by D-amino acids or the functionalization by adding the RGD (integrin ligand motif) to the peptide. Methods: Peptides were obtained by SPPS, characterized by RP-HPLC and ESI-QTOF and its biological activity was evaluated using MTT assays. Evaluation of mechanism associated to the cytotoxic effect were carried out by flow cytometry, RT-qPCR, wound healing, transwell and zymography. Results: The peptides with replacements of D-amino acid showed a lesser cytotoxic effect against breast cancer cell lines, regardless it was one or several residues modified which suggested a possible specific interaction between the peptide and the cancer cell membrane besides its initial electrostatically contact. On the other hand, addition of the RGD sequence to the palindromic peptide in the N-terminal end resulted in a greater cytotoxic effect against cell lines derived from the three mainly diagnosed breast cancer molecular subtypes. An approximation on mechanisms associated to this effect was evaluated on MCF-7 cells, it shows that the peptide induced apoptosis by activating intrinsic and extrinsic pathway, which correlates with the possibility of a specific interaction, and induces mitochondrial depolarization with release of oxygen reactive species. Also, this peptide induces a reduction in migration and invasion associated with a diminish in metalloprotease 9 activity and a lesser release of IL-6, IL-10 and arginase cytokines. Conclusions: Our results suggest that this promising peptide can be considered for preclinical evaluation in the development of drugs to treat breast cancer and thus mitigate the impact of this disease.
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增强乳腺癌细胞靶向性:RGD 整合素配体可增强 RWQWRWQWR 的细胞毒性并抑制迁移
目的:评估回文序列 RWQWRWQWR 及其类似物的选择性细胞毒性作用,这些类似物是通过将 L-氨基酸替换为 D-氨基酸或在肽中添加 RGD(整合素配体基团)进行功能化而得到的。方法:通过 SPPS 获得多肽,用 RP-HPLC 和 ESI-QTOF 对其进行表征,并用 MTT 试验评估其生物活性。通过流式细胞术、RT-qPCR、伤口愈合、transwell 和酶图法评估与细胞毒性作用相关的机制。结果显示替换了 D-氨基酸的肽对乳腺癌细胞株的细胞毒性作用较弱,不管是修饰了一个残基还是多个残基,这表明除了最初的静电接触外,肽与癌细胞膜之间还可能存在特定的相互作用。另一方面,在 N 端添加 RGD 序列的回旋肽对来自三种主要诊断乳腺癌分子亚型的细胞株具有更大的细胞毒性作用。对 MCF-7 细胞进行的近似评估显示,该肽通过激活内在和外在途径诱导细胞凋亡,这与特异性相互作用的可能性有关,并诱导线粒体去极化,释放氧活性物质。此外,该肽还能降低金属蛋白酶 9 的活性,减少 IL-6、IL-10 和精氨酸酶等细胞因子的释放,从而减少肿瘤的迁移和侵袭。结论我们的研究结果表明,在开发治疗乳腺癌的药物时,可以考虑对这种有前景的多肽进行临床前评估,从而减轻这种疾病的影响。
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