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

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

  • Cancer Lett. 2015 Oct 28;367(2):173-83. doi: 10.1016/j.canlet.2015.07.030.
Eiman Mukhtar 1 Vaqar Mustafa Adhami 1 Mario Sechi 2 Hasan Mukhtar 3
Affiliations

Affiliations

  • 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.

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