Ku70
protein and topoisomerase IIα (
Topo IIα) are promising targets of anticancer drugs, which play critical roles in DNA repair and replication processes. Three
platinum(II) complexes, [PtCl(NH3)2(9-(pyridin-2-ylmethyl)-9H-
carbazole)]NO3 (OPPC), [PtCl(NH3)2(9-(pyridin-3-ylmethyl)-9H-
carbazole)]NO3 (
MPPC), and [PtCl(NH3)2(9-(pyridin-4-ylmethyl)-9H-
carbazole)]NO3 (PPPC), were designed as inhibitors of Ku70 and
Topo IIα. Their antitumor activity and inhibitory efficacy on Ku70 and
Topo IIα were investigated on cellular and molecular levels. OPPC exhibited high antiproliferative activity against various
cancer cell lines, with acute toxicity to mice being lower than that of
cisplatin. Moreover, OPPC could enter
cancer cells effectively and cause DNA damage, which was evidenced by the enhanced expression of γ-H2AX, Chk1/2 phosphorylation, p53 and cell cycle arrest. OPPC also downregulated the DNA damage repair
protein Ku70 and inhibited the formation of Ku70 foci-the central points or loci of Ku70, which would suppress DNA repair and induce a nonhomologous end joining response in
cancer cells. More importantly, these complexes showed inhibition towards
Topo IIα; in particular, OPPC was more effective than
MPPC and PPPC. In the
Topo IIα knockdown cells, Ku70 and
Topo IIα were directly associated with the DNA damage and apoptotic response. The molecular docking provided detailed structural insights into the interactions of the complexes with
Topo IIα. This study demonstrates that the cytotoxicity of these complexes is associated with the DNA damage and repair pathways mediated by Ku70 and
Topo IIα; OPPC is an effective inhibitor of Ku70 and
Topo IIα and restrains
cancer cells via a mechanism utterly distinct from that of
cisplatin.