Exploring the molecular targets of dietary flavonoid fisetin in cancer

Syed, Deeba N.; Adhami, Vaqar M.; Khan, Naghma; Khan, Mohammad Imran; Mukhtar, Hasan

doi:10.1016/j.semcancer.2016.04.003

Cited by 68 publications

(42 citation statements)

References 90 publications

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“…These activities are regulated by many factors such as the BCL-2 family, Bax and PARP. It is well-known that fisetin interacts with many different signaling cascades to regulate critical cellular processes (24,36). Fisetin has been reported to induce cell-cycle arrest (37), induce apoptosis via inhibiting anti-apoptotic proteins, and impair phosphorylation of MEK and AKT in various cancer cells (23).…”

Section: Discussionmentioning

confidence: 99%

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

Mukhtar

Adhami

Siddiqui

et al. 2016

Molecular Cancer Therapeutics

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Although treatment of prostate cancer (PCa) has improved over the past several years, taxanes such as cabazitaxel remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant PCa. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule stabilizing agent and inhibits PCa cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 μM) enhances cabazitaxel (5nM) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in inhibition of tumor growth, invasion and metastasis when assessed in two in-vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced PCa through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant PCa and possibly other cancer types.

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Section: Discussionmentioning

confidence: 99%

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

Mukhtar

Adhami

Siddiqui

et al. 2016

Molecular Cancer Therapeutics

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“…(tomatoes, onions, and cucumbers), nuts, and wine 12,13 . Fis has attracted attention for its multi-functional therapeutic activities that include anti-cancer 14 , anti-diabetic 15 , and neuroprotective 16 effects in cell culture and in animal models relevant to human diseases. Fis has a remarkable spectroscopic attribute of an exquisitely sensitive intrinsic 'two colour' fluorescence, which arises due to a photoinduced excited state intramolecular proton transfer (ESIPT) reaction (Scheme 1) 17,18 .…”

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confidence: 99%

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

Takahashi

Bhattacharjee

Ghosh

et al. 2020

Sci Rep

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The relationship of i-motif DNAs with cancer has prompted the development of specific ligands to detect and regulate their formation. Some plant flavonols show unique fluorescence and anti-cancer properties, which suggest the utility of the theranostics approach to cancer therapy related to i-motif DNA. We investigated the effect of the plant flavonol, fisetin (Fis), on the physicochemical property of i-motif DNAs. Binding of Fis to the i-motif from the promoter region of the human vascular endothelial growth factor (VEGF) gene dramatically induced the excited state intramolecular proton transfer (ESIPT) reaction that significantly enhanced the intensity of the tautomer emission band of Fis. This unique response was due to the coincidence of the structural change from i-motif to the hairpin-like structure which is stabilized via putative Watson-Crick base pairs between some guanines within the loop region of the i-motif and cytosines in the structure. As a result, the VEGF i-motif did not act as a replication block in the presence of fis, which indicates the applicability of fis for the regulation of gene expression of VEGF. The fluorescence and biological properties of Fis may be utilised for theranostics applications for cancers related to a specific cancer-related gene, such as VEGF. Besides the canonical right-handed DNA double helix, DNA sequences can adopt non-canonical structures, including G-quadruplexes (G4s) and i-motifs, that are stabilised by non-Watson-Crick base pairing 1. G4 structures are formed from guanine (G)-rich sequences, whereas i-motifs are formed from the cytosine (C)-rich sequences. The i-motif structure consists of two parallel duplexes that intercalate with each other in an antiparallel orientation (Fig. 1A). The parallel duplexes are held together via hydrogen bonding between a neutral cytosine (C) and a protonated cytosine (C +) (Fig. 1B) 2. The formation of an i-motif structure occurs more readily in an acidic condition because protonation of cytosine is required to form a hemiprotonated CC + base pair. However, there is increasing evidence to suggest that the i-motif structures can also form at neutral pH 3,4 and even in the nuclei of living mammalian cells 5,6. The i-motif forming sequences are found in or near the promoter regions of >40% of all human genes, which can regulate the expressions of genes like Bcl2 7,8 and HRAS 9. Furthermore, the i-motif along the cancer-related DNA sequences strongly inhibits DNA replication 10. Therefore, i-motif DNAs are attractive targets for the diagnosis of cancer risk and to treat cancer by the modulation of gene transcription and replication. Considering the use of specific targeted therapy based on specific targeted test (i.e., theranostics) for both diagnosis and therapeutics, some ligands that both emit a fluorescent signal upon binding to a specific i-motif and regulate the transcription or replication of the target gene are required. Currently, no ligands have such dual functions for i-motif DNAs. Flavonols and other related compounds o...

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“…Fisetin is a natural product, which is readily available. Fisetin is a potent antioxidant and is thought to exert its antioxidant effect by activating heme oxygenase-I (HO-I) under oxidative stress conditions 22 . It has also been shown that fisetin suppresses NFκB signaling pathway and MAPKs.…”

Section: Discussionmentioning

confidence: 99%

Orally administered fisetin as an immuno-modulatory and therapeutic agent in a mouse model of chronic allergic airway disease

et al. 2019

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Introduction: Allergic asthma is a prevalent disorder, in which eosinophilic inflammation is involved in the lungs. Asthma affects people all over the world, regardless of the country's level of development. Chronic allergen-induced fibrotic damage of the lungs is stimulated in 55 days, which results in significant tissue destruction constitutive to pulmonary tissues, in addition to extensive oxidative & inflammation-induced damage of small and large airways. To date, there is no cure for asthma, and symptoms are controlled using corticosteroids, which may cause systemic side effects. Flavonoids, like fisetin, are a class of secondary metabolites produced by plants, which are known to have numerous beneficial effects. Previous report demonstrated that fisetin has beneficial effects against various diseases such as cancers, tumors, diabetes, and alcohol-induced liver injury. Methods: In the present study, chronic allergic disease (asthma) was developed in C57BL/6J mice, using intraperitoneal injection of ovalbumin for 54 days together with orally administered fisetin as a treatment strategy. Fisetin was administered 1 hour before intratracheal treatment. On day 55, treated animals were sacrificed, and tissues were collected for various assays. Results: Fisetin was found to reduce the symptoms of asthma significantly. Reduction in total cell infiltration, eosinophil count, and the levels of serum IgE were observed. There was a down regulation in CD3+CD4+ TH cells, and a decrease in the deposition of collagen in the lung and airways. Conclusion: From these observations, we conclude that fisetin is effective in the treatment of asthma, and a pathway by which fisetin acts was hypothesized.

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Exploring the molecular targets of dietary flavonoid fisetin in cancer

Cited by 68 publications

References 90 publications

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

Orally administered fisetin as an immuno-modulatory and therapeutic agent in a mouse model of chronic allergic airway disease

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