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Cancer Lett. 2015 Oct 28;367(2):173-83. doi: 10.1016/j.canlet.2015.07.030. Epub 2015 Jul 30.

Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells.

Author information

1
Department of Dermatology, University of Wisconsin-Madison, 1300 University Avenue, 4385 Medical Sciences Center, Madison, WI 53706, USA.
2
Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy.
3
Department of Dermatology, University of Wisconsin-Madison, 1300 University Avenue, 4385 Medical Sciences Center, Madison, WI 53706, USA. Electronic address: hmukhtar@wisc.edu.

Abstract

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 β-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 α-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.

KEYWORDS:

Fisetin; Microtubules; Migration; Proliferation; Prostate cancer

PMID:
26235140
PMCID:
PMC4570246
DOI:
10.1016/j.canlet.2015.07.030
[Indexed for MEDLINE]
Free PMC Article

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