Tier 3 — preclinical

Fisetin, a dietary flavonoid, induces apoptosis of cancer cells by inhibiting HSF1 activity through blocking its binding to the hsp70 promoter

Kim JA, Lee S, Kim DE, Kim M, Kwon BM, Han DC
Carcinogenesis 2015 36(6):696-706

Bibliography

PubMed
PMID 25840992
DOI
10.1093/carcin/bgv045
Funding
Not explicitly stated in the reviewed sections; conducted at the Korea Research Institute of Bioscience and Biotechnology. Authors disclosed no potential conflicts of interest.
Competing interests
The authors declare there are no potential conflicts of interest.

Study snapshot

DesignCell-based screening of a 716-compound natural chemical library identified fisetin as an inhibitor of heat shock factor 1 (HSF1). Mechanistic follow-up used a p(HSE)4-TA-Luc reporter assay, Western blot, ChIP assay (HSF1 binding to the hsp70 promoter), qRT-PCR, cell proliferation (WST-1) and FACS assays across HCT-116 and other cancer cell lines, plus an HCT-116 nude mouse xenograft model for in vivo tumour growth.
ModelHCT-116 (colon), SW620 (colon), Mia-PaCa-2 (pancreatic), MDA-MB-231 (breast), PC-3, DU-145, LNCaP (prostate) human cancer cell lines in vitro; HCT-116 xenografts in nude mice in vivo.
SampleCell-based assays performed in the stated cell lines with standard replicate designs; xenograft study group sizes not stated in the reviewed sections.
InterventionFisetin in vitro (IC50 14 μM for heat-shock-induced luciferase activity; GI50 23 μM for HCT-116 proliferation); fisetin 30 mg/kg intraperitoneal in the nude mouse xenograft model.
DurationIn vitro assays over standard 24-48 h timeframes; in vivo xenograft growth followed over the treatment course (exact duration not stated in reviewed sections).
EndpointsHeat-shock-induced luciferase reporter activity (HSF1 activity, IC50); HCT-116 cell proliferation (GI50); HSP70, HSP27, BAG3 protein induction after heat shock; Bcl-2, Bcl-xL, Mcl-1 protein levels; Chromatin immunoprecipitation: HSF1 binding to the hsp70 promoter; Cell cycle distribution (FACS); In vivo tumour volume/growth inhibition in nude mouse xenografts

What the study showed, in plain terms

Cancer cells often rely on a stress-response protein called HSF1 to survive treatment, making it an attractive drug target. This study screened hundreds of natural compounds to find one that could block HSF1, and found fisetin.

Korean researchers showed that fisetin blocked HSF1 from turning on heat-shock protein genes, reduced the levels of survival proteins (HSP70, HSP27, BAG3, Bcl-2, Bcl-xL, Mcl-1) that those genes produce, and directly prevented HSF1 from attaching to the hsp70 gene's promoter region — then confirmed the effect shrank tumours in mice.

Fisetin inhibited HSF1-driven luciferase activity (IC50 14 μM) and HCT-116 colon cancer cell growth (GI50 23 μM) in vitro, and a 30 mg/kg intraperitoneal dose reduced tumour growth by 35.7% in a nude mouse xenograft model.

Bottom line: a mechanistically detailed cancer-biology study identifying a specific molecular target (HSF1) through which fisetin may promote cancer cell death, backed by an in vivo tumour-growth result — but this is intraperitoneal dosing in a mouse xenograft model, not evidence relevant to oral supplementation in healthy people.

Key findings

Fisetin inhibited heat-shock-induced HSF1 transcriptional activity (IC50 14 μM) and HCT-116 cell proliferation (GI50 23 μM), reduced HSP70/HSP27/BAG3 induction and downstream Bcl-2, Bcl-xL and Mcl-1 levels, and blocked HSF1 binding to the hsp70 gene promoter (by ChIP assay), inducing apoptosis; intraperitoneal fisetin (30 mg/kg) produced a 35.7% reduction in tumour growth in an HCT-116 nude mouse xenograft model.

What this study can and cannot tell us

Cancer cell-line and xenograft model only; intraperitoneal dosing at 30 mg/kg does not reflect oral supplement use. HSF1 inhibition is a cancer-therapeutic mechanism studied in the context of tumour cell survival, not directly generalisable to fisetin's effects in non-cancerous tissue or to longevity/senotherapeutic claims.

Editorial review

Reviewed by the Biohack Blueprint research team

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology