Anti-tumor and cellular mechanisms of HfIV tetra-(8-hydroxyquinolinato) complexes

Abstract

Three 8-hydroxyquinoline-stabilized hafnium complexes, [Hf^IV(oxinate)₄], were synthesized with good aqueous stability and solubility by reacting Hf^IVCl₄ with 8-hydroxyquinoline (HL₁), 2-methyl-8-hydroxyquinoline (HL₂) and 5-chloro-8-hydroxyquinoline (HL₃) in THF, achieving high yields. Among the synthesized complexes, [Hf^IV(L₁)₄] and [Hf^IV(L₃)₄] exhibited potent inhibitory activity against human liver (Hep G2), cervical (HeLa S3) and lung (PC9) cancer cell lines, while showing low toxicity against non-tumorigenic murine epithelial AML12 cells. Notably, [Hf^IV(L₁)₄] demonstrated the most potent activity, with an IC₅₀ value of 0.8 ± 0.3 μM against Hep G2 cells, which is 17 times lower than that of cisplatin (IC₅₀ = 13.8 ± 1.3 μM). Mechanistic cell studies revealed that [Hf^IV(L₁)₄] could effectively inhibit cell migration, induce reactive oxygen species generation and cause mitochondrial membrane potential disruption. Furthermore, [Hf^IV(L₁)₄] blocked the cell cycle progression at the G2/M phase and led almost exclusively to early apoptosis in Hep G2 cells. Western blot analysis revealed that in Hep G2 cells [Hf^IV(L₁)₄] could upregulate the expression of caspase-3 and Bax proteins while downregulating the expression of the anti-apoptotic Bcl-2 protein, highlighting the apoptotic pathway as a key mechanism of action. Comparisons are made with previously reported [Zr^IV(L₁)₄], which shows higher cytotoxicity, cellular uptake, reactive oxygen species generation, mitochondrial damage and stronger inhibition of antioxidant enzymes' activity. However, [Hf^IV(L₁)₄] induces primarily early apoptosis, which is advantageous. Overall, these rare earth complexes, particularly [Hf^IV(L₁)₄] and [Zr^IV(L₁)₄], demonstrate promising potential as novel anticancer agents with significant efficacy against human liver cancer cells and favourable selectivity profiles for further therapeutic development.