Tier 4 — mechanistic

Dietary flavonoid fisetin: a novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management

Adhami VM, Syed DN, Khan N, Mukhtar H
Biochemical Pharmacology 2012 Volume 84, issue 10, pages 1277–1281

Bibliography

PubMed
PMID 22842629
PubMed Central
PMC3813433
DOI
10.1016/j.bcp.2012.07.012
Funding
United States Public Health Service Grant RO1 CA 160867 to H Mukhtar (Department of Dermatology, University of Wisconsin-Madison).
Competing interests
The authors' original work summarised here was funded by the US National Institutes of Health. No commercial competing interests were declared in the manuscript. The review is written by the laboratory group whose own work forms the fisetin-mTOR hypothesis for prostate cancer, which should be noted when interpreting the review's framing.

Study snapshot

DesignNarrative review synthesising the authors' own cancer cell line and xenograft studies alongside the wider fisetin cancer literature.
ModelProstate cancer cell lines (LNCaP, CWR22Rv1, PC3, DU145), progression model prostate epithelial cells (RWPE-1 through WPE1-NB26), non-small cell lung cancer A549 cells and pancreatic cancer AsPC-1 cells; athymic nude mice bearing CWR22Rv1 prostate cancer xenografts.
SampleReview of approximately fifty published in vitro and animal cancer studies; no human data.
InterventionIn vitro fisetin exposure across reviewed studies typically 5–75 μM; xenograft dosing supported plasma sulphated/glucuronidated fisetin levels of ~10 μM sustained for over 24 hours.
DurationReviewed studies span acute cell-culture exposures of 24–72 hours to chronic xenograft dosing over several weeks.
EndpointsPI3K/Akt pathway phosphorylation; mTOR complex 1 and mTOR complex 2 assembly and downstream signalling; Androgen receptor signalling and serum PSA; Autophagic versus cytoprotective cell death in prostate cancer cells; Xenograft tumour growth in athymic nude mice

What the study showed, in plain terms

This is a narrative review from the University of Wisconsin dermatology group who first identified fisetin as an inhibitor of the PI3K/Akt and mTOR signalling pathways in cancer. It pulls together their in vitro and mouse xenograft findings alongside supporting work from other laboratories, with prostate cancer as the central case.

The mechanistic argument is straightforward. PI3K/Akt and mTOR sit at the heart of most advanced prostate tumours, and drugs that block mTOR alone tend to fail because they release a feedback brake that re-activates Akt. Fisetin appears to hit both arms of the loop at once — binding directly to mTOR at two sites, disrupting the mTORC1 and mTORC2 complexes, and separately inhibiting PI3K/Akt phosphorylation. In prostate cancer cell lines this triggers autophagic cell death rather than the protective autophagy that limits many cancer drugs.

The paper is not a clinical study. The evidence is entirely preclinical — cultured prostate, lung and pancreatic cancer cells plus one xenograft experiment in nude mice. It should be read as mechanistic rationale for further research, not as evidence that fisetin treats prostate cancer in people.

Key findings

  • Fisetin decreases viability of androgen-dependent (LNCaP), androgen-independent (CWR22Rv1, PC3) and DU145 prostate cancer cells with only minimal effect on normal prostate epithelial cells.
  • In silico modelling shows fisetin binds directly to mTOR at two distinct sites with binding energies of −7 to −8 kcal/mol, disrupting both mTORC1 and mTORC2 assembly and downregulating Raptor, Rictor, PRAS40 and GβL.
  • In PTEN-negative PC3 cells fisetin inhibits mTOR downstream targets p70-S6 kinase and 4E-BP1, suppresses cap-dependent translation, and induces autophagic cell death — not the cytoprotective autophagy that undermines many cancer drugs.
  • Fisetin also inhibits the PI3K/Akt arm, which is the feedback loop that undermines rapamycin-class mTOR inhibitors clinically. Simultaneous PI3K/Akt and mTOR blockade is the mechanistic rationale for developing fisetin as a dual inhibitor for advanced prostate cancer.
  • In athymic nude mice bearing AR-positive CWR22Rv1 xenografts, fisetin binds the androgen receptor ligand-binding domain, blocks AR-mediated transactivation of prostate-specific antigen, inhibits tumour growth and lowers serum PSA.
  • The same PI3K/Akt/mTOR inhibition is reproduced in non-small cell lung cancer A549 cells and in prostate epithelial cell progression models (RWPE-1 through WPE1-NB26), where cells with higher baseline mTOR signalling are more sensitive to fisetin.
  • Fisetin sensitises TRAIL-resistant LNCaP, DU145 and PC3 cells to TRAIL-induced apoptosis and enhances the effect of cisplatin and cyclophosphamide in combination studies — supporting a possible role as a chemotherapy adjuvant rather than as monotherapy.

What this study can and cannot tell us

This is a narrative review of in vitro cell line studies and one mouse xenograft experiment. It contains no human clinical trial data. The concentrations of fisetin used in the cell culture work (typically 5–75 μM) exceed what free fisetin ever reaches in human circulation after an oral dose; peak human plasma free fisetin after a 1000 mg oral dose is roughly 0.01 μg/mL, although sulphated and glucuronidated metabolites reach ~10 μM and persist for longer.

The review is written by the laboratory group whose own work forms the fisetin-mTOR hypothesis. It should therefore be read as an expert case for further research, not as an independent assessment of the field. Selection of supporting evidence is not systematic.

There is no direct evidence — in this paper or elsewhere at time of publication — that fisetin supplementation influences prostate cancer risk, progression or PSA in people. The clinical rationale rests entirely on preclinical mechanism plus favourable safety of the parent compound in animals.

Related papers in the corpus

Tier 4
Fisetin: A Dietary Antioxidant for Health Promotion
Khan N et al. · Antioxidants & Redox Signaling · 2013
Tier 4
Anti-cancer effects of fisetin on mammary carcinoma cells via regulation of the PI3K/Akt/mTOR pathway: In vitro and in vivo studies
Sun X et al. · International Journal of Molecular Medicine · 2018
Tier 4
Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells
Mukhtar E et al. · Cancer Letters · 2015

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