2. Academic Validation
  3. Mechanism of action of non-camptothecin inhibitor Genz-644282 in topoisomerase I inhibition

Mechanism of action of non-camptothecin inhibitor Genz-644282 in topoisomerase I inhibition

  • Commun Biol. 2022 Sep 16;5(1):982. doi: 10.1038/s42003-022-03920-w.
Masahiro Nishida  # 1,  Takeshi Terabayashi  # 2,  Shigeru Matsuoka 3,  Tomoko Okuma 4,  Sawako Adachi 4,  Tadashi Tomo 1,  Masanori Kawano 5,  Kazuhiro Tanaka 5,  Hiroshi Tsumura 5,  Hirofumi Anai 1,  Toshimasa Ishizaki 2,  Yoshihiro Nishida 6,  Katsuhiro Hanada 7
Affiliations

Affiliations

  • 1 Clinical Engineering Research Centre, Oita University, Yufu, Oita, Japan.
  • 2 Department of Pharmacology, Oita University, Yufu, Oita, Japan.
  • 3 Department of Clinical Pharmacology & Therapeutics, Oita University, Yufu, Oita, Japan.
  • 4 Department of Obstetrics and Gynecology, Oita University, Yufu, Oita, Japan.
  • 5 Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Yufu, Oita, Japan.
  • 6 Department of Obstetrics and Gynecology, Oita University, Yufu, Oita, Japan. ynishida@oita-u.ac.jp.
  • 7 Clinical Engineering Research Centre, Oita University, Yufu, Oita, Japan. hanada@oita-u.ac.jp.
  • # Contributed equally.
PMID: 36114357 DOI: 10.1038/s42003-022-03920-w
Abstract

Topoisomerase I (TOP1) controls the topological state of DNA during DNA replication, and its dysfunction due to treatment with an inhibitor, such as camptothecin (CPT), causes replication arrest and cell death. Although CPT has excellent cytotoxicity, it has the disadvantage of instability under physiological conditions. Therefore, new types of TOP1 inhibitor have attracted particular attention. Here, we characterised the effect of a non-camptothecin inhibitor, Genz-644282 (Genz). First, we found that treatment with Genz showed cytotoxicity by introducing double-strand breaks (DSBs), which was suppressed by co-treatment with aphidicolin. Genz-induced DSB formation required the functions of TOP1. Next, we explored the advantages of Genz over CPT and found it was effective against CPT-resistant TOP1 carrying either N722S or N722A mutation. The effect of Genz was also confirmed at the cellular level using a CPT-resistant cell line carrying N722S mutation in the TOP1 gene. Moreover, we found arginine residue 364 plays a crucial role for the binding of Genz. Because tyrosine residue 723 is the active centre for DNA cleavage and re-ligation by TOP1, asparagine residue 722 plays crucial roles in the accessibility of the drug. Here, we discuss the mechanism of action of Genz on TOP1 inhibition.

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