The antileukemic effect of xestoquinone, a marine-derived polycyclic quinone-type metabolite, is mediated through ros-induced inhibition of hsp-90

Kuan Chih Wang, Mei Chin Lu, Kai Cheng Hsu, Mohamed El-Shazly, Shou Ping Shih, Ssu Ting Lien, Fu Wen Kuo, Shyh Chyun Yang, Chun Lin Chen, Yu Chen S.H. Yang

Research output: Contribution to journalArticlepeer-review

Abstract

Xestoquinone is a polycyclic quinone-type metabolite with a reported antitumor effect. We tested the cytotoxic activity of xestoquinone on a series of hematological cancer cell lines. The antileukemic effect of xestoquinone was evaluated in vitro and in vivo. This marine metabolite sup-pressed the proliferation of Molt-4, K562, and Sup-T1 cells with IC50 values of 2.95 ± 0.21, 6.22 ± 0.21, and 8.58 ± 0.60 µM, respectively, as demonstrated by MTT assay. In the cell-free system, it inhibited the activity of topoisomerase I (Topo I) and II (Topo II) by 50% after treatment with 0.235 and 0.094 µM, respectively. The flow cytometric analysis indicated that the cytotoxic effect of xestoquinone was mediated through the induction of multiple apoptotic pathways in Molt-4 cells. The pretreatment of Molt-4 cells with N-acetyl cysteine (NAC) diminished the disruption of the mitochondrial membrane potential (MMP) and apoptosis, as well as retaining the expression of both Topo I and II. In the nude mice xenograft model, the administration of xestoquinone (1 µg/g) significantly attenuated tumor growth by 31.2% compared with the solvent control. Molecular docking, Western blotting, and thermal shift assay verified the catalytic inhibitory activity of xestoquinone by high binding affinity to HSP-90 and Topo I/II. Our findings indicated that xestoquinone targeted leukemia cancer cells through multiple pathways, suggesting its potential application as an antileukemic drug lead.

Original languageEnglish
Article number7037
JournalMolecules
Volume26
Issue number22
DOIs
Publication statusPublished - Nov 1 2021

Keywords

  • Anticancer
  • Apoptosis
  • Heat shock protein 90 (HSP-90)
  • Polycyclic quinone
  • Reactive oxygen species (ROS)
  • Topoisomerase
  • Xestoquinone

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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