Abstract
Cisplatin was the first metal-based therapeutic agent approved for the treatment of human cancers, but its clinical activity is greatly limited by tumor drug resistance. This work utilized the parent complex [Ru(phen)2(PIP)]2+ (1) to develop three Ru(II) complexes (2–4) with different positional modifications. These compounds exhibited similar or superior cytotoxicities compared to cisplatin in HeLa, A549 and multidrug-resistant (A549R) tumor cell lines. Complex 4, the most potent member of the series, was highly active against A549R cancer cells (IC50 = 0.8 μM). This complex exhibited 178-fold better activity than cisplatin (IC50 = 142.5 μM) in A549R cells. 3D multicellular A549R tumor spheroids were also used to confirm the high proliferative and cytotoxic activity of complex 4. Complex 4 had the greatest cellular uptake and had a tendency to accumulate in the mitochondria of A549R cells. Further mechanistic studies showed that complex 4 induced A549R cell apoptosis via inhibition of thioredoxin reductase (TrxR), elevated intracellular ROS levels, mitochondrial dysfunction and cell cycle arrest, making it an outstanding candidate for overcoming cisplatin resistance.
Highlights
Cisplatin is an effective antitumor agent that acts on DNA and is largely employed as the first metal-based therapeutic in the clinic against a wide spectrum of solid tumors[1,2]
Compounds 1–4 were evaluated against three tumor cell lines derived from different tissues, including the cervix (HeLa), lung (A549) and cisplatin-resistant lung (A549R) tissues
Remarkable differences were observed among the four complexes: the cyclometalated Ru(II) complex 4 exhibited much higher cytotoxicity (IC50 values ranged from 0.8 to 2.4 μ M) toward all the tested cancer cell lines compared to the other three Ru(II) complexes
Summary
Cisplatin is an effective antitumor agent that acts on DNA and is largely employed as the first metal-based therapeutic in the clinic against a wide spectrum of solid tumors[1,2]. Worldwide efforts to develop alternative organometallic drug designs that are distinct from cisplatin and have different targets have been directed toward overcoming this issue[9,10,11,12,13,14] Due to their octahedral geometry, ruthenium complexes are widely utilized to construct highly effective anticancer agents with high selectivity and fewer (and less severe) side effects compared to platinum drugs[15]. Some ruthenium complexes have been proven to be mitochondria-targeting anticancer drug candidates[21], which often induce redox reactions inside cancer cells resulting in an increase in reactive oxygen species (ROS)[22]. We synthesized four Ru(II) complexes with similar structures but distinctly different biological activities to verify that ruthenium cyclometalation in combination with trifluoromethyl and PIP ligands is a simple but competitive method to develop novel metallodrugs for the treatment of cancer. The results show that complex 4 can efficiently induce A549R cell apoptosis via multiple pathways
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