Journal
CANCER LETTERS
Volume 367, Issue 2, Pages 173-183Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2015.07.030
Keywords
Fisetin; Microtubules; Prostate cancer; Proliferation; Migration
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Funding
- United States Public Health Service [RO1 CA 160867, RO1 CA 160867 S1]
- Regione Autonoma della Sardegna within the frame of Legge regionale [CRP-25920, 7/2007]
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Microtubule targeting based therapies have revolutionized cancer treatment; however, resistance and side effects remain a major limitation. Therefore, novel strategies that can overcome these limitations are urgently needed. We made a novel discovery that fisetin, a hydroxyflavone, is a microtubule stabilizing agent. Fisetin binds to tubulin and stabilizes microtubules with binding characteristics far superior than paclitaxel. Surface plasmon resonance and computational docking studies suggested that fisetin binds to beta-tubulin with superior affinity compared to paclitaxel. Fisetin treatment of human prostate cancer cells resulted in robust up-regulation of microtubule associated proteins (MAP)-2 and -4. In addition, fisetin treated cells were enriched in alpha-tubulin acetylation, an indication of stabilization of microtubules. Fisetin significantly inhibited PCa cell proliferation, migration, and invasion. Nudc, a protein associated with microtubule motor dynein/dynactin complex that regulates microtubule dynamics, was inhibited with fisetin treatment. Further, fisetin treatment of a P-glycoprotein overexpressing multidrug-resistant cancer cell line NCI/ADR-RES inhibited the viability and colony formation. Our results offer in vitro proof-of-concept for fisetin as a microtubule targeting agent. We suggest that fisetin could be developed as an adjuvant for treatment of prostate and other cancer types. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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