A novel topoisomerase I inhibitor DIA-001 induces DNA damage mediated cell cycle arrest and apoptosis in cancer cell

Jiaqi Liu; Guohe Geng; Guang Liang; Ling Wang; Kuntian Luo; Jian Yuan; Shiguang Zhao

doi:10.21037/atm.2019.12.138

A novel topoisomerase I inhibitor DIA-001 induces DNA damage mediated cell cycle arrest and apoptosis in cancer cell

Ann Transl Med. 2020 Feb;8(4):89. doi: 10.21037/atm.2019.12.138.

Authors

Jiaqi Liu¹, Guohe Geng², Guang Liang², Ling Wang³, Kuntian Luo^{4

5}, Jian Yuan^{4

5}, Shiguang Zhao¹

Affiliations

¹ Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
² School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
³ Department of Pharmacy, Fujian Provincial Hospital, Provincial Clinical College of Fujian Medical University, Fuzhou 350001, China.
⁴ Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
⁵ Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.

Abstract

Background: DNA topoisomerase enzyme plays an essential role in controlling the DNA topology structure by binding to DNA and cutting the phosphate backbone of either one or both of the DNA strands. Here, we have identified a small molecule inhibitor, DIA-001, that directly binds to Topoisomerase 1 (Topo I) and promotes the Topo I-DNA adducts.

Methods: In this study, we investigated the antitumor effects of DIA-001 using MTS assay and colony formation. We examined cell cycle of tumor cells with DIA-001 treatment in vitro by flow cytometry. And we investigated DNA damage and cell cycle marker protein after treatment with DIA-001 at different concentration and time point by western blot. Immunofluorescence was performance to detect the nuclear foci. The effects of DIA-001 on Topo I and Topo II activities were examined by DNA relaxation assays.

Results: We demonstrate that DIA-001 inhibit DNA replication and arrest cell cycle progression at the G2/M phase by directly binds to Topo I and promotes the Topo I-DNA adducts. In addition, DIA-001 can activate the DNA damage response signaling cascade, resulting in apoptosis in treated cells.

Conclusions: Our findings show a novel compound for treatment of cancer cells with the potential as a chemotherapy candidate that is less toxic to normal cells.

Keywords: Topoisomerase I; apoptosis; cell cycle arrest; chemotherapy.