A Novel Copper(II) Indenoisoquinoline Complex Inhibits Topoisomerase I, Induces G2 Phase Arrest, and Autophagy in Three Adenocarcinomas

Abstract

Topoisomerases, targets of inhibitors used in chemotherapy, induce DNA breaks accumulation leading to cancer cell death. A newly synthesized copper(II) indenoisoquinoline complex WN197 exhibits a cytotoxic effect below 0.5 µM, on MDA-MB-231, HeLa, and HT-29 cells. At low doses, WN197 inhibits topoisomerase I. At higher doses, it inhibits topoisomerase IIα and IIβ, and displays DNA intercalation properties. DNA damage is detected by the presence of γH2AX. The activation of the DNA Damage Response (DDR) occurs through the phosphorylation of ATM/ATR, Chk1/2 kinases, and the increase of p21, a p53 target. WN197 induces a G2 phase arrest characterized by the unphosphorylated form of histone H3, the accumulation of phosphorylated Cdk1, and an association of Cdc25C with 14.3.3. Cancer cells die by autophagy with Beclin-1 accumulation, LC3-II formation, p62 degradation, and RAPTOR phosphorylation in the mTOR complex. Finally, WN197 by inhibiting topoisomerase I at low concentration with high efficiency is a promising agent for the development of future DNA damaging chemotherapies.

Copper and Copper Complexes in Tumor Therapy

“…Furthermore, inhibiting topoisomerases I (Top1) and II (Top2) to disrupts the topology of DNA and therefore inducing severe DNA damages, cell cycle arrest and cell death is another important mechanism of anticancer activities of copper complexes. [65,66,[69][70][71] Topoisomerases play critical role in DNA replication and transcription via mediating DNA winding. [72] Top1 creates transient single-DNA nicks, while Top2 creates transient double-stranded DNA breaks.…”

New Cu+2 Complexes with N-Sulfonamide Ligands: Potential Antitumor, Antibacterial, and Antioxidant Agents

“…Current research focuses on the design and synthesis of new complex metal antitumor agents with better biological activity and selectivity, reduced toxicity, and mechanisms of action other than those of platinum compounds, capable of overcoming the unresolved clinical problems of analogue drugs of cisplatin (serious side effects, general toxicity, and resistance) [ 5 , 6 ]. In this context, Cu +2 complexes present encouraging prospects [ 7 , 8 , 9 , 10 , 11 ]. The differentiated response of normal and tumor cells to exposure to Cu +2 ions is the basis for the development of new copper compounds with antitumor properties.…”

“…The differentiated response of normal and tumor cells to exposure to Cu +2 ions is the basis for the development of new copper compounds with antitumor properties. Copper complexes known as “artificial nucleases” have been shown to possess in vitro cytotoxic activity and lower toxicity than platinum derivatives established as antitumor agents [ 8 , 9 , 10 ]. Many of them are active against tumor cell lines resistant to cisplatin and similar compounds.…”

Potential of Copper and Copper Compounds for Anticancer Applications

“…Topoisomerase (topo) is a crucial enzyme indispensable for cellular DNA replication or transcription and is widely found in living organisms. As the reverse rotation of DNA during replication can produce tangles, positive and negative superhelices, etc., which affect the replication of DNA, in order to ensure normal replication, it must rely on the participation of topo for DNA cleavage, gyration, and rejoining, so that the DNA can be successfully deconvoluted, replicated, and transcribed [ 78 ]. Compared to normal cells, topoisomerases exhibit high expression levels in tumor cells independent of other factors.…”