The title Cu(ii) complexes of tropolone induce the apoptosis of MGC80-3 through a caspase-dependent mitochondrion pathway and can also induce autophagy.
The reactions of cis-Pt(DMSO) 2 Cl 2 and tropolone (HL) with 8-hydroxyquinoline (HQ) or 2-methyl-8-hydroxyquinoline (HMQ) gave [Pt(Q)(L)] ( 1) and [Pt(MQ)(L)] (2), which present mononuclear structures with their Pt(II) ions four-coordinated in square planar geometries. Their in vitro biological properties were evaluated by MTT assay, which showed a remarkable cytotoxic activity on the cancer cell lines. 1 shows higher cytotoxic activities on tumor cells such as T24, HeLa, A549, and NCI-H460 than complex 2 and cisplatin, with IC 50 values <16 μM. Among them, an IC 50 value of 3.6 ± 0.63 μM was found for complex 1 against T24 cells. It presented a tuning cytotoxic activity by substitution groups on 8-hydroxyquinoline skeleton. In our case, the substitution groups of −H are much superior to −CH 3 against tumor cells. It revealed that both complexes can induce cell apoptosis by decreasing the potential of a mitochondrial membrane, enhancing reactive oxygen species and increasing Ca 2+ levels of T24 cells. The T24 cell cycle can be arrested at G2 and G1 phases by complexes 1 and 2, respectively, with an upregulation for P21 and P27 expression levels and a down-regulation for cyclin A, CDK1, Cdc25A, and cyclin B expression levels. Furthermore, complex 1 exhibits satisfactory in vivo antitumor activity as revealed by the tumor inhibitory rate and the tumor weight change as well as by the cute toxicity assay and renal pathological examinations, which is close to cisplatin and much better than complex 2. All of these suggest that 1 might be a potential candidate for developing into a safe and effective anticancer agent.
Our previously reported copper-based complexes of tropolone show nice antitumor effects, but with high cytotoxicity to normal cells, which is presumably caused by copper ions. Here we managed to achieve this challenge by using other 3d metals to replace copper ions. We thus prepared four mononuclear 3d Metal complexes [M(phen)L2] (M = Mn, Co, Ni, Zn for 1–4, respectively). Complexes 1 and 4 show selectivity on different cancer cell lines with much lower cytotoxicity to normal cells than cisplatin. The anti-cancer effects for complexes 2 and 3 on the tested cancer cell lines are very poor. It revealed a tuning effect of different metal ions on the anti-cancer activities with that for Mn(II) and Zn(II) being much higher than that for Co(II) and Ni(II) in this system. Among of them, complex 1 presents a best anti-cancer effect on Hela cells comparable to cisplatin. It overcame the afore-mentioned shortage of high cytotoxicity to normal cells for the reported Cu(II) complexes. It revealed from the mechanistic studies that complex 1 mainly induces apoptosis through the mitochondrial pathway by increasing intracellular ROS, releasing Ca2+, activating Caspase 9 and pro-apoptotic gene Bax.
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