The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90.

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 suppressed 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.

• Authors: 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
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 26 Issue 22 (Nov 21 2021) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 34834129 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Quinones
• Reactive Oxygen Species
• xestoquinone

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• HSP90 Heat-Shock Proteins (metabolism)
• Humans
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Nude
• Mitochondria (drug effects, metabolism)
• Quinones (pharmacology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)