2. Academic Validation
  3. (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

(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

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: nkaneda@meijo-u.ac.jp.
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.

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