Novel Tl(III) complexes containing pyridine-2,6-dicarboxylate derivatives with selective anticancer activity through inducing mitochondria-mediated apoptosis in A375 cells

Abstract

Three novel Tl(III) complexes (C1), (C2) and (C3) were synthesized using the one-pot reactions of pyridine dicarboxylic acid derivatives, 2-aminobenzimidazole and/or 4-aminopyridine, and also thallium(III) nitrate trihydrate metal salt. The structure of all three complexes was determined by the single-crystal X-ray diffraction. C1 and C2 were realized to be isostructural with disordered square anti-prismatic geometry and for C3 arrangement of the distorted tricapped triangular prism was proposed. Cyclic voltammetry measurements on the complexes exhibited that formal potential values are more positive for C1 (E0ˊ 0.109 V) and C3 (E0ˊ 0.244 V) compared to C2 (E0ˊ –0.051 V), versus Ag/AgCl under argon. Moreover, cytotoxicity of the compounds was evaluated in vitro against two cancer cell lines including a human melanoma (A375), a human colon adenocarcinoma (HT29), and also one normal cell human foreskin fibroblast (HFF). The selective and potent cytotoxicity effect was exhibited by C1 and C3 on cancer cell lines. The apoptosis through a caspase-dependent mitochondrion pathway was confirmed by ROS production, MMP reduction, p53 activation, Bax up-regulation, and Bcl-2 down-regulation, cytochrome c release, procaspase-9, and 3 expression, for A375 cells treated to C1 and C3. According to similar cellular uptake of the complexes in A375 cell line, the generation of ROS was considered as an effective agent to justify the inhibition effect C1 and C3 on mentioned cells. Furthermore, arresting the cell cycle in the G2-M phase and inducing apoptosis were indicated by these two complexes.

Thallium-induced DNA damage, genetic, and epigenetic alterations

“…The type of cell death induced in this cell line depicted increases in the late apoptosis pattern compared to Tl-untreated A375 cells. The suggested apoptotic pathway activated in this cell line was confirmed by western blotting assays which showed an increase in p53 protein, Bax upregulation, Bcl-2 down-regu ation, cytochrome c release, and augmented expression of procaspase-9, and 3 ( Abdolmaleki et al, 2021 ).…”

“…Regarding the antineoplastic effects induced by Tl compounds, it seems that the ROS levels generated by the administration of this metal induce more cytotoxic effects in neoplastic cells than in normal cells, suggesting that the cellular levels of ROS play a crucial role in inducing cancer cell death. Finally, it has been demonstrated that Tl has a special affinity for cancer cells likely due to the mimicry between Tl to potassium ( Abdolmaleki et al, 2021 ; Rangel-López et al, 2022 ). Considering its biochemical and physical properties, its effects on DNA damage, and the energetic requirements of neoplastic cells future studies should focus on strategies to reduce the toxic effects of Tl and to design novel thallium-based drugs to inhibit the development and progression of several cancer types.…”

“…In addition, secondary to increased ROS levels induced by intracellular Tl, damage to mitochondria ensues, including electron transport chain disruption. In turn, ATP levels decrease and Ca + cytoplasmic levels increase, leading to the release of cytochrome c and activation of apoptotic protease activating factor-1 (Apaf- 1) ( Fani et al, 2016 ; Abdolmaleki et al, 2021 ). At the nuclear level, Tl alters the expression of p21 which inhibits the cyclin/CDK complex, blocking the G1/S and G2/M transitions, thus disturbing the cell cycle ( Chia et al, 2005 ), In addition, Tl induces telomere shortening and modifies epigenetic patterns due the structural modifications of histones H3 and H4 from nucleosomes and the sites susceptible of methylations (ME), thus eliciting chromosomal aberrations ( Wu et al, 2021 ).…”

Synthesis and characterization of polyimidazolium species on silica nanoparticles: Study on cytotoxicity and removal of nitrate from water

“…Then, the cells were stained with 1 ml of JC‐1 stock solution (10 mg/ml). The assays were initiated by incubating HL60 cells with JC‐1 for 30 min at 37°C in the dark and detected using a fluorescence microscope 39 …”

“…The assays were initiated by incubating HL60 cells with JC-1 for 30 min at 37 C in the dark and detected using a fluorescence microscope. 39…”