Ak-i-190, a new catalytic inhibitor of topoisomerase ii with anti-proliferative and pro-apoptotic activity on androgen-negative prostate cancer cells

Kyung Hwa Jeon, Seojeong Park, Hae Jin Jang, Soo Yeon Hwang, Aarajana Shrestha, Eung Seok Lee, Youngjoo Kwon

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Castration-resistant prostate cancer (CRPC) is a clinical challenge in treatment because of its aggressive nature and resistance to androgen deprivation therapy. Topoisomerase II catalytic inhibitors have been suggested as a strategy to overcome these issues. We previously reported AK-I-190 as a novel topoisomerase II inhibitor. In this study, the mechanism of AK-I-190 was clarified using various types of spectroscopic and biological evaluations. AK-I-190 showed potent topoiso-merase II inhibitory activity through intercalating into DNA without stabilizing the DNA-enzyme cleavage complex, resulting in significantly less DNA toxicity than etoposide, a clinically used topoisomerase II poison. AK-I-190 induced G1 arrest and effectively inhibited cell proliferation and colony formation in combination with paclitaxel in an androgen receptor–negative CRPC cell line. Our results confirmed that topoisomerase II catalytic inhibition inhibited proliferation and induced apoptosis of AR-independently growing prostate cancer cells. These findings indicate the clinical relevance of topoisomerase II catalytic inhibitors in androgen receptor-negative prostate cancer.

Original languageEnglish
Article number11246
JournalInternational Journal of Molecular Sciences
Volume22
Issue number20
DOIs
StatePublished - 1 Oct 2021

Bibliographical note

Funding Information:
Funding: This work was supported by grants from National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (2018R1A5A2025286, 2019R1I1A1A01050921 and 2020R1A4A4079494) and by Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Education (2021R1A6C101A442).

Publisher Copyright:
© 2021 by the authors. Li-censee MDPI, Basel, Switzerland.

Keywords

  • CRPC
  • DNA intercalator
  • Topoisomerase II inhibitor

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