(S)-Erypoegin K, an isoflavone isolated from Erythrina poeppigiana, is a novel inhibitor of topoisomerase IIα: Induction of G2 phase arrest in human gastric cancer cells

  • Bioorg Med Chem. 2021 Jan 15:30:115904. doi: 10.1016/j.bmc.2020.115904.
Kiyomi Hikita  1 ,  Yuko Yamakage  1 ,  Honoka Okunaga  1 ,  Yui Motoyama  1 ,  Haruka Matsuyama  1 ,  Kenta Matsuoka  1 ,  Tomiyasu Murata  1 ,  Tomoki Nakayoshi  2 ,  Akifumi Oda  2 ,  Kuniki Kato  3 ,  Hitoshi Tanaka  4 ,  Naoki Asao  5 ,  Shingo Dan  6 ,  Norio Kaneda  7
Affiliations
  • 1. Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.
  • 2. Laboratory of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.
  • 3. Chubu TLO, Nagoya Industrial Science Research Institute, VBL, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan.
  • 4. Laboratory of Natural Product Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.
  • 5. Advanced Institute for Materials Research, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan; Division of Chemistry and Materials, Graduate School of Science and Technology, Shinshu University, Ueda, Nagano 386-8567, Japan.
  • 6. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
  • 7. Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan. Electronic address: [email protected].
PMID: 33341500 DOI: 10.1016/j.bmc.2020.115904
Abstract

Erypoegin K, an isoflavone isolated from the stem bark of Erythrina poeppigiana, has a single chiral carbon in its structure and exists naturally as a racemic mixture. Our previous study showed (S)-erypoegin K selectively exhibits potent anti-proliferative and apoptosis-inducing activity against human leukemia HL-60 cells. To identify the target molecule of (S)-erypoegin K, we employed the human Cancer cell panel analysis (termed JFCR39) coupled with a drug sensitivity database of pharmacologically well-characterized drugs for comparison using the COMPARE algorithm. (S)-erypoegin K exhibited a similar profile to that of etoposide, suggesting the molecular target for erypoegin K may be Topoisomerase II (Topo II). Subsequent experiments using purified human Topo IIα established that the (S)-isomer selectively stabilizes the cleavage complex composed of double-stranded plasmid DNA and the enzyme. Moreover, (S)-erypoegin K inhibited decatenation of kinetoplast DNA. Molecular docking studies clearly indicated specific binding of the (S)-isomer to the active site of Topo IIα involving hydrogen bonds that help stabilize the cleavage complex. (S)-erypoegin K displayed potent cytotoxic activity against two human gastric Cancer cells GCIY and MKN-1 with IC50 values of 0.270 and 0.327 μM, respectively, and induced enzyme activities of Caspase 3 and 9. Cell cycle analysis showed marked cell cycle arrest at G2 phase in both cell lines. (S)-erypoegin K also displayed significant antitumor activity toward GCIY xenografted mice. The present study suggests (S)-erypoegin K acts as a Topo II Inhibitor to block the G2/M transition of Cancer cells.

Keywords
Antitumor agent; Erypoegin K; G2 cell cycle arrest; Human gastric cancer cells; JFCR39 panel assay; Topoisomerase II inhibitor.