Department of Biochemistry, School of Medicine, Autonomous University of Madrid (UAM), 28029 Madrid, Spain.
Instituto de Investigaciones Biomédicas "Sols-Morreale" (IIBM), CSIC-UAM, 28029 Madrid, Spain.
Int J Mol Sci. 2024 Jul 15;25(14):7739. doi: 10.3390/ijms25147739.
Gastric cancer prognosis is still notably poor despite efforts made to improve diagnosis and treatment of the disease. Chemotherapy based on platinum agents is generally used, regardless of the fact that drug toxicity leads to limited clinical efficacy. In order to overcome these problems, our group has been working on the synthesis and study of trans platinum (II) complexes. Here, we explore the potential use of two phosphine-based agents with the general formula -[Pt(amine)Cl(PPh)], called P1 and P2 (with dimethylamine or isopropylamine, respectively). A cytotoxicity analysis showed that P1 and especially P2 decrease cell viability. Specifically, P2 exhibits higher activity than cisplatin in gastric cancer cells while its toxicity in healthy cells is slightly lower. Both complexes generate Reactive Oxygen Species, produce DNA damage and mitochondrial membrane depolarization, and finally lead to induced apoptosis. Thus, an intrinsic apoptotic pathway emerges as the main type of cell death through the activation of BAX/BAK and BIM and the degradation of MCL1. Additionally, we demonstrate here that P2 produces endoplasmic reticulum stress and activates the Unfolded Protein Response, which also relates to the impairment observed in autophagy markers such as p62 and LC3. Although further studies in other biological models are needed, these results report the biomolecular mechanism of action of these Pt(II)-phosphine prototypes, thus highlighting their potential as novel and effective therapies.
尽管在提高胃癌的诊断和治疗水平方面做出了努力，但胃癌的预后仍然很差。通常使用基于铂类药物的化疗，尽管药物毒性导致临床疗效有限。为了克服这些问题，我们小组一直在研究反式铂（II）配合物的合成和研究。在这里，我们探索了两种膦基配体[Pt（胺）Cl（PPh）]的通用公式 - [Pt（胺）Cl（PPh）]的潜在用途，称为 P1 和 P2（分别为二甲胺或异丙胺）。细胞毒性分析表明，P1 和特别是 P2 降低细胞活力。具体来说，P2 在胃癌细胞中比顺铂具有更高的活性，而其在健康细胞中的毒性略低。两种复合物都会产生活性氧，导致 DNA 损伤和线粒体膜去极化，最终导致诱导细胞凋亡。因此，通过 BAX/BAK 和 BIM 的激活以及 MCL1 的降解，内在凋亡途径成为细胞死亡的主要类型。此外，我们在这里证明 P2 会产生内质网应激并激活未折叠蛋白反应，这也与自噬标志物如 p62 和 LC3 观察到的损伤有关。尽管还需要在其他生物模型中进行进一步的研究，但这些结果报告了这些 Pt(II)-膦原型的生物分子作用机制，从而突出了它们作为新型有效治疗方法的潜力。
