Abstract
Three new oxoaporphine Co(II), Ni(II) and Zn(II) complexes 1–3 have been synthesized and fully characterized. 1–3 have similar mononuclear structures with the metal and ligand ratio of 1:2. 1–3 exhibited higher cytotoxicity than the OD ligand and cisplatin against HepG2, T-24, BEL-7404, MGC80–3 and SK-OV-3/DDP cells, with IC50 value of 0.23−4.31 μM. Interestingly, 0.5 μM 1–3 significantly caused HepG2 arrest at S-phase, which was associated with the up-regulation of p53, p21, p27, Chk1 and Chk2 proteins, and decrease in cyclin A, CDK2, Cdc25A, PCNA proteins. In addition, 1–3 induced HepG2 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by p53 activation, ROS production, Bax up-regulation and Bcl-2 down-regulation, mitochondrial dysfunction, cytochrome c release, caspase activation and PARP cleavage. Furthermore, 3 inhibited tumor growth in HepG2 xenograft model, and displayed more safety profile in vivo than cisplatin.
Highlights
Many efforts have been made on the development of new effective antitumor metal complexes via variation of coordination modes, metals or ligands, to trigger apoptosis
The ligand oxoaporphine derivative (OD) was synthesized according to the previously reported methods (Fig. 1)[26], in which (+)-boldine was used as the starting material
The results indicated that [1,2,3] induced the reduction of Membrane Potential (MMP), which facilitated the apoptosis of HepG2 cells[50]
Summary
Synthesis and Structural Characterization of OD and 1–3. The ligand OD was synthesized according to the previously reported methods (Fig. 1)[26], in which (+)-boldine was used as the starting material. Taken 3 as an example (Fig. 5), significant increase in the expression levels of Chk[1] and Chk[2] were observed in 3-treated HepG2 cells, which indicated that 3 induced DNA damage and the S-phase checkpoints were activated[35,36] It caused a concentration-dependent increase in the expression of CDKs inhibitor proteins p21 and p27, comparing to the control group. The DNA damage signaling translated to the downstream effector proteins, Cdc25A, cyclin-dependent kinases (cyclin A2) and CDK2, which culminated in the S-phase arrest of cell cycle progression[37,39] All these results demonstrated that [1,2,3] caused S-phase arrest via the activation of ATM-Chk2-Cdc25A-Cdk[2] and ATR-Chk1-Cdc25A-Cdk[2] pathways, very similar to other oxoaporphine or oxoisoaporphine alkaloid-metal complexes[23,25,26]. The length of the tail reflects the DNA damage in cells
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