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Fisetin as a chemoprotective and chemotherapeutic agent: mechanistic insights and future directions in cancer therapy

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Abstract

Cancer remains a leading cause of mortality globally, characterized by the uncontrolled proliferation of abnormal cells, invasion of healthy tissues, and potential metastasis. Natural compounds have become a focus in cancer research due to their potential therapeutic roles. Among these, fisetin, a dietary flavonoid, demonstrates notable anti-cancer properties through various molecular mechanisms. This review evaluates the chemoprotective and chemotherapeutic potential of fisetin, focusing on its mechanisms of action against cancer and its capacity to enhance cancer treatment. A systematic literature search was conducted across PubMed, Web of Science, and Scopus databases using keywords related to fisetin and cancer. The review synthesizes findings from in vitro and in vivo studies examining fisetin’s effects on signaling pathways, apoptosis induction, oxidative stress modulation, and synergistic potential with chemotherapeutic agents. Fisetin has shown the ability to suppress tumor growth and metastasis by modulating critical signaling pathways, including PI3K/Akt/mTOR, NF-κB, and MAPK. It induces apoptosis in cancer cells through mitochondrial and endoplasmic reticulum stress responses and demonstrates antioxidative properties by reducing reactive oxygen species. Additionally, fisetin enhances the efficacy of conventional chemotherapies, indicating its role as a potential adjuvant in cancer treatment. Fisetin presents a promising natural compound with diverse anti-cancer effects, impacting cell cycle arrest, apoptosis, and oxidative stress pathways. Further clinical studies are warranted to fully elucidate its therapeutic potential and to optimize its delivery for improved bioavailability in cancer patients.

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Data availability

No datasets were generated or analyzed during the current study.

Abbreviations

5-FU:

5-Fluorouracil

Akt:

Protein kinase B

ALT:

Alanine transaminase

AMPK:

Adenosine monophosphate-activated protein kinase

AP-1:

Activator protein 1

AST:

Aspartate transaminase

ATM:

Ataxia telangiectasia mutated

AUC:

Area under the curve

BaP:

Benzo(a)pyrene

BAX:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma 2

Bcl-xl:

B-cell lymphoma-extra large

Bcl2l2:

B-cell lymphoma-2-like 2

BIRC8:

Baculoviral IAP repeat-containing 8

BUB1:

Budding uninhibited by benzimidazoles 1

BubR1:

Budding uninhibited by benzimidazoles 1-related 1

CAT:

Catalase

CDK:

Cyclin-dependent kinase

Cdc2:

Cell division cycle 2

Cdc25:

Cell division cycle 25

Cenp-F:

Centromere protein F

Chk1:

Checkpoint kinase 1

COX-2:

Cyclooxygenase-2

CRP:

C-reactive protein

DMBA:

7,12-Dimethylbenz[a]anthracene

DNA:

Deoxyribonucleic acid

DR4/DR5:

Death receptor 4 / Death receptor 5

ELISA:

Enzyme-linked immunosorbent assay

eNOS:

Endothelial nitric oxide synthase

ERK:

Extracellular signal-regulated kinase

FAK:

Focal adhesion kinase

FADD:

Fas-associated death domain

GADD45A/B:

Growth arrest and DNA damage-inducible proteins

GPx:

Glutathione peroxidase

GRP78:

Glucose-regulated protein 78

GSK-3β:

Glycogen synthase kinase 3 beta

GSH:

Glutathione

GSSG:

Oxidized glutathione

GST:

Glutathione-S-transferase

H2O2:

Hydrogen peroxide

HO-1:

Heme oxygenase-1

HRAS1/HRAS2:

Harvey rat sarcoma viral oncogenes

HSF-1:

Heat shock factor 1

IC50:

Inhibitory concentration 50%

IGF1R:

Insulin-like growth factor 1 receptor

IL-1β:

Interleukin-1 beta

IL-6:

Interleukin-6

IL-8:

Interleukin-8

IL-10:

Interleukin-10

JNK:

C-Jun N-terminal kinase

LLC:

Lewis lung carcinoma

MAPK:

Mitogen-activated protein kinase

Mcl-1:

Myeloid cell leukemia sequence 1

MEK1/2:

Mitogen-activated protein kinase kinase 1/2

MMP2/9:

Matrix metalloproteinases 2 and 9

Mitf:

Microphthalmia-associated transcription factor

mTOR:

Mammalian target of rapamycin

MTT assay:

Diphenyl-2H-tetrazolium bromide assay

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor kappa B

NHEKs:

Normal human epidermal keratinocytes

Nrf2:

Nuclear factor erythroid 2-related factor 2

NQO1:

NAD(P)H quinone dehydrogenase 1

OSCC:

Oral squamous cell carcinoma

PARP:

Poly (ADP-ribose) polymerase

PCNA:

Proliferating cell nuclear antigen

PI3K:

Phosphatidylinositol-3-kinase

PKC:

Protein kinase C

PSA:

Prostate-specific antigen

p53:

Tumor protein p53

RB-1:

Retinoblastoma 1

rRNA:

Ribosomal RNA

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TGF-β1:

Transforming growth factor beta 1

TNF-α:

Tumor necrosis factor alpha

TSC1/2:

Tuberous sclerosis complex 1 and 2

TUNEL assay:

Terminal deoxynucleotidyl transferase dUTP nick-end labeling assay

uPA:

Urokinase-type plasminogen activator

VEGF:

Vascular endothelial growth factor

Wnt:

Wingless-related integration site

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Acknowledgements

The authors would like to express their gratitude to: Dr. Irina Zamfir, MD, RCP London, Basildon University Hospital UK for providing professional English editing of this manuscript and for editorial support.

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  1. Rabab Fatima and Priyal Soni equal contribution.

Authors and Affiliations

  1. Department of Chemistry, UPES, Dehradun, 248007, India

    Rabab Fatima & Parteek Prasher

  2. Amity Institute of Pharmacy, Amity University, Lucknow, 226010, India

    Priyal Soni

  3. Department of Chemistry, Uttaranchal University, Dehradun, 248007, India

    Mousmee Sharma

  4. Department of Pharmacology, Nitte (Deemed to Be University), NGSM Institute of Pharmaceuticals, Mangaluru, India

    Rajesh Kaverikana

  5. Department of Chemistry, Nitte (Deemed to Be University), NMAM Institute of Technology, Nitte, Karkala, India

    Shivaprasad Shetty Mangalpady

  6. Universidad Espíritu Santo, Samborondón, Ecuador

    Javad Sharifi-Rad

  7. Centro de Estudios Tecnológicos y Universitarios del Golfo, Veracruz, Mexico

    Javad Sharifi-Rad

  8. Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea

    Javad Sharifi-Rad

  9. Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania

    Daniela Calina

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RF, PS, MS, PP, RK, SSM, JS-R, DC made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas. That is revising or critically reviewing the article; giving final approval of the version to be published; agreeing on the journal to which the article has been submitted; and, confirming to be accountable for all aspects of the work.

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Fatima, R., Soni, P., Sharma, M. et al. Fisetin as a chemoprotective and chemotherapeutic agent: mechanistic insights and future directions in cancer therapy. Med Oncol 42, 104 (2025). https://doi.org/10.1007/s12032-025-02664-x

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