Castellar-Almonacid Daniel Alejandro, Barragán-Cárdenas Andrea Carolina, Rodríguez-Mejia Karla Geraldine, Maldonado-Sanabria Laura Angélica, Ardila-Chantré Natalia, Mendoza-Mendoza Jose David, Parra-Giraldo Claudia Marcela, Rivera-Monroy Jhon Erick, Rivera-Monroy Zuly Jenny, García-Castañeda Javier Eduardo, Fierro-Medina Ricardo
Departamento de Farmacia-Facultad de Ciencias, Universidad Nacional de Colombia-Sede Bogotá Bogotá D.C. Colombia
Instituto de Biotecnología-Facultad de Ciencias, Universidad Nacional de Colombia-Sede Bogotá Bogotá D.C. Colombia.
RSC Med Chem. 2025 Jul 11. doi: 10.1039/d5md00476d.
Previous studies have shown that the palindromic peptide RWQWRWQWR derived from bovine lactoferricin (LfcinB) has exhibited selective cytotoxic effects against multiple cancer cells such as cervical, breast, and prostate cancer. We designed and synthesized peptides based on this palindromic sequence conjugated with non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen and ibuprofen to obtain novel hybrid peptides that could trigger inflammatory processes within cancer cells. Incorporating the non-natural amino acid ornithine as a spacer was done to improve the aqueous solubility of the NSAID-peptide conjugates. The antibacterial activity of the conjugated peptides was evaluated, and these peptides showed significant activity against strain ATCC 25922, with MIC values of 12 μM. Cytotoxicity was assessed in human cervical cancer cells (HeLa) and human melanoma cells (A375), showing that the NSAID-conjugated peptides retained and even exhibited better anticancer activity compared to the palindromic peptide from which they were derived. The NSAID-LfcinB conjugates showed good selectivity towards cancer cells in the concentration ranges evaluated, being non-hemolytic. The cytotoxic effect of the IBU-Orn-1 and NAP-Orn-1 peptides was rapid and selective, inducing severe morphological changes, including rounding, shrinkage, and vacuole formation, which are associated with apoptosis. Flow cytometry assays revealed that the ibuprofen-conjugated palindromic sequence induced apoptosis independently of peptide concentration and treatment duration. These results suggest that the palindromic peptide RWQWRWQWR could be used for new applications in cancer research, such as delivering small molecules with anti-inflammatory activity in tumoral environments. The conjugation of NSAIDs to anticancer peptide sequences is a novel, viable, and rapid strategy that facilitates the synthesis of hybrid peptides with enhanced anticancer activity, thereby expanding the pool of promising molecules for preclinical and clinical studies in cancer therapy development.
先前的研究表明,源自牛乳铁蛋白(LfcinB)的回文肽RWQWRWQWR对多种癌细胞,如宫颈癌、乳腺癌和前列腺癌,表现出选择性细胞毒性作用。我们基于此回文序列设计并合成了与非甾体抗炎药(NSAIDs)如萘普生和布洛芬偶联的肽,以获得能够引发癌细胞内炎症过程的新型杂合肽。引入非天然氨基酸鸟氨酸作为间隔基,以提高NSAID-肽缀合物的水溶性。评估了缀合肽的抗菌活性,这些肽对ATCC 25922菌株表现出显著活性,最低抑菌浓度(MIC)值为12μM。在人宫颈癌细胞(HeLa)和人黑色素瘤细胞(A375)中评估了细胞毒性,结果表明,与它们所衍生的回文肽相比,NSAID缀合肽保留了甚至表现出更好的抗癌活性。在评估的浓度范围内,NSAID-LfcinB缀合物对癌细胞表现出良好的选择性,且无溶血作用。IBU-Orn-1和NAP-Orn-1肽的细胞毒性作用迅速且具有选择性,诱导严重的形态学变化,包括细胞变圆、收缩和空泡形成,这些变化与细胞凋亡相关。流式细胞术分析显示,布洛芬缀合的回文序列诱导细胞凋亡,与肽浓度和处理持续时间无关。这些结果表明,回文肽RWQWRWQWR可用于癌症研究的新应用,如在肿瘤环境中递送具有抗炎活性的小分子。将NSAIDs与抗癌肽序列偶联是一种新颖、可行且快速的策略,有助于合成具有增强抗癌活性的杂合肽,从而扩大了癌症治疗开发临床前和临床研究中有前景分子的范围。