Antitumor studies evaluation of triphenylphosphine ruthenium complexes with 5,7-dihalo-substituted-8-quinolinoline targeting mitophagy pathways

Abstract

Both ruthenium-containing complexes and 8-quinolinoline compounds have emerged as a potential novel agent for malignant tumor therapy. Here, three triphenylphosphine ruthenium complexes, [Ru(ZW1)(PPh₃)₂Cl₂] (PPh₃ = triphenylphosphine) (RuZ1), [Ru(ZW2)(PPh₃)₂Cl₂] (RuZ2) and [Ru(ZW2)₂(PPh₃)Cl₂]·CH₂Cl₂ (RuZ3) bearing 5,7-dichloro-8-quinolinol (H-ZW1) and 5,7-dichloro-8-hydroxyquinaldine (H-ZW2), have been synthesized, characterized and tested for their anticancer potential. We showed that triphenylphosphine ruthenium complexes RuZ1–RuZ3 impaired the cell viability of ovarian adenocarcinoma cisplatin-resistant SK-OV-3/DDP (SKO3CR) and SK-OV-3 (SKO3) cancer cells with greater selectivity and specificity than cisplatin. In addition, RuZ1–RuZ3 show higher excellent cytotoxicity than cisplatin towards SKO3CR cells, with IC₅₀ values of 9.66 ± 1.08, 4.05 ± 0.67 and 7.18 ± 0.40 μM, respectively, in which the SKO3CR cells was the most sensitive to RuZ1–RuZ3. Depending on the substituent type, the antiproliferative ability of RuZ1–RuZ3 followed the trend: –CH₃ > –H. However, RuZ1–RuZ3 have no obvious toxicity to normal cell HL-7702. Besides, RuZ1 and RuZ2 could induce mitophagy related-apoptosis pathways through suppression of mitochondrial membrane potential (ΔΨm), accumulation of [Ca²⁺] and reactive oxygen species (ROS), and regulation of LC3 II/LC3 I, Beclin-1, P62, FUNDC1, PINK1, Parkin, cleaved-caspase-3, caspase-9 and cytochrome c signaling pathway, and hindering the preparation of mitochondrial respiration complexes I and IV and ATP levels. Mechanistic study revealed that RuZ1 and RuZ2 induce apoptosis in SKO3CR cells via mitophagy related-apoptosis pathways induction and energy (ATP) generation disturbance. Taken together, the studied triphenylphosphine ruthenium complexes RuZ1–RuZ3 are promising chemotherapeutic agents with high effectiveness and low toxicity.