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.
Highlights
Complex WN197 was synthesized by reacting methanolic solutions of indenoisoquinoline derivative WN170 and CuCl2
Copper(II) indenoisoquinoline complex WN197 displays an anticancerous activity at low doses inhibiting Top1
MDA-MB-231, HeLa, and HT-29, cancer cells accumulate DNA breaks and arrest in the G2 phase of the cell cycle. This arrest is characterized by the inactivation of the Cdc25C phosphatase through phosphorylation on serine 216 and binding to 14.3.3 that leaves in its inactive form the MPF
Summary
Current treatments include chemotherapy with agents that generate DNA damage to trigger cancer cell division arrest and associated programmed cell death of tumours [2, 3]. Inhibition of Top allows DNA cleavage, prevents the religation reaction, and leaves cancer cells with DNA breaks. Top and Top are mainly targeted due to their overexpression in many cancers including breast, cervix, and colorectal cancers [10,11,12,13]. DNA breaks further trigger the activation of DNA Damage Response (DDR) pathways, leading to cell cycle arrest and to death if DNA damage is too severe [19, 20]. Chk and Chk kinases are activated, inhibit phosphatase Cdc25 [23], and induce a cell cycle arrest followed in most cases by apoptosis [20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
