The cytotoxic natural compound erianin binds to colchicine site of β-tubulin and overcomes taxane resistance.

Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE

Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.

Tubulin*/metabolism ; Tubulin*/chemistry ; Colchicine*/pharmacology ; Colchicine*/chemistry ; Colchicine*/metabolism ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/chemical synthesis ; Drug Screening Assays, Antitumor* ; Drug Resistance, Neoplasm*/drug effects ; Cell Proliferation*/drug effects; Humans ; Binding Sites ; Animals ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; Mice ; Apoptosis/drug effects ; Taxoids/pharmacology ; Taxoids/chemistry ; Tubulin Modulators/pharmacology ; Tubulin Modulators/chemistry ; Crystallography, X-Ray ; Bridged-Ring Compounds/chemistry ; Bridged-Ring Compounds/pharmacology ; Mice, Nude ; Cell Line, Tumor ; Biological Products/chemistry ; Biological Products/pharmacology ; Bibenzyls/chemistry ; Bibenzyls/pharmacology ; Phenol

Erianin, a natural compound derived from Dendrobium, has shown significant anticancer properties against a wide range of cancer cells. Despite the identification of multiple mechanisms of action for erianin, none of these mechanisms fully account for its broad-spectrum effect. In this study, we aimed to identify the cellular target and underlying mechanism responsible for the broad-spectrum antitumor effects of erianin. We found that erianin effectively inhibited tubulin polymerization in cancer cells and purified tubulin. Through competition binding assays and X-ray crystallography, it was revealed that erianin bound to the colchicine site of β-tubulin. Importantly, the X-ray crystal structure of the tubulin-erianin complex was solved, providing clear insight into the orientation and position of erianin in the colchicine-binding site. Erianin showed activity against paclitaxel-resistant cells, evidenced by G2/M cell cycle arrest, apoptosis-related PARP and Caspase-3 cleavage, and in vivo xenograft studies. The study concluded that erianin bound reversibly to the colchicine site of β-tubulin, inhibited tubulin polymerization, and displayed anticancer activity against paclitaxel-resistant cells, offering valuable insights for further exploration as potential anticancer agents.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)

Keywords: Colchicine site; Erianin; Microtubule; Paclitaxel resistant; Tubulin

0 (Tubulin)
0 (Erianin)
SML2Y3J35T (Colchicine)
0 (Antineoplastic Agents)
0 (Taxoids)
0 (Tubulin Modulators)
0 (Bridged-Ring Compounds)
1605-68-1 (taxane)
0 (Biological Products)
0 (Bibenzyls)
339NCG44TV (Phenol)

Date Created: 20240621 Date Completed: 20240719 Latest Revision: 20240722

20240722

10.1016/j.bioorg.2024.107569

38905886