DNA topoisomerases as additional targets for anticancer monofunctional platinum(ii) complexes. Issue 1 (10th December 2020)

• Record Type: Journal Article
• Authors: Zhang, Hongmei; Yang, Tao; Wang, Yanqing; Wang, Zenghui; Zhu, Zhenzhu; Guo, Zijian; Wang, Xiaoyong
• Is Part Of: Dalton transactions. Volume 50:Issue 1(2020)
• Page Start: 304
• Page End: 310
• Publication Date: 2020-12-10
• Subjects: Chemistry, Inorganic -- Periodicals; Chemistry, Physical and theoretical -- Periodicals; Chemistry, Inorganic -- Periodicals; 546.05
• DOI: 10.1039/d0dt02608e
• Languages: English
• ISSNs: 1477-9226

Abstract

Abstract : Monofunctional platinum(ii ) complexes show significant inhibition to DNA topoisomerases I/IIα besides DNA-binding and mitochondrial targeting capabilities, thereby potentiating the cytotoxicity. Abstract : Topoisomerases are ubiquitous enzymes and important targets for DNA-oriented anticancer drugs. Two mitochondrion-targeted monofunctional platinum(ii ) complexes, [Pt( ortho -PPh3 CH2 Py)(NH3 )2 Cl](NO3 )2 (OPT) and [Pt( para -PPh3 CH2 Py)(NH3 )2 Cl](NO3 )2 (PPT; PPh3 = triphenylphosphonium, Py = pyridine), show significant inhibition towards the activity of DNA topoisomerases in addition to their DNA binding and mitochondrial targeting capabilities. OPT exhibits strong cytotoxicity toward the human renal clear cell carcinoma 786-O and the murine prostate cancer RM-1 cell lines. The complex could bind to the minor groove of DNA, as well as DNA topoisomerases I and IIα, thereby acting as an inhibitor of topoisomerase I/IIα and causing DNA damage. The damage was evidenced by the enhanced expression of γ-H2AX, Chk1/2 phosphorylation, p53 and cell cycle arrest in the G2/M phase. In contrast, the inhibitory effect of PPT on DNA topoisomerases was largely limited to the isolated enzymes. The results demonstrate that the cellular inhibition of the complex towards the DNA topoisomerases positively correlated with its mitochondrial accumulation. Molecular docking provided more detailed structural insights into the interactions of OPT or PPT with DNA and topoisomerase I/IIα. The binding sites of OPT and PPT in topoisomerase–DNA complexes are different from each other. Aside from previously revealed DNA and mitochondrial targets, this study discovered new evidence that DNA topoisomerases may also serve as targets of monofunctional platinum(ii ) complexes. For a multispecific platinum complex, strong DNA binding ability does not necessarily lead to potent cytotoxicity as other factors including the cell types, mitochondrial accumulation, and activity of DNA topoisomerases also affect the outcome of DNA damage.