Fisetin, a dietary flavonoid, increases the sensitivity of chemoresistant head and neck carcinoma cells to cisplatin possibly through HSP90AA1/IL‐17 pathway

Abstract

Cisplatin (DDP) resistance is a bottleneck in the treatment of head and neck cancer (HNC), leading to poor prognosis. Fisetin, a dietary flavonoid, has low toxicity and high antitumor activity with unclear mechanisms. We intended to predict the targets of fisetin for reversing DDP‐resistance and further verify their expressions and roles. A network pharmacology approach was applied to explore the target genes. The hub genes were screened out and subjected to molecular docking and experimental verification (in vivo and in vitro). Thirty‐two genes common to fisetin and DDP‐resistance were screened, including three hub genes, namely HSP90AA1, PPIA, and PTPRS. Molecular docking suggested that fisetin and the candidate proteins could bind tightly. HSP90AA1 was identified as the key gene. Administration of fisetin increased the sensitivity of chemoresistant cells (Cal27/DDP and FaDu/DDP) to DDP, accompanied by the downregulation of HSP90AA1 and IL‐17. HSP90AA1 silencing increases the sensitivity of DDP‐resistant cells to DDP, which was mediated by IL‐17. In summary, fisetin might inhibit the chemoresistance of HNC cells to DDP by targeting the HSP90AA1/IL‐17 pathway. Several hub genes might be the targets of fisetin for reversing DDP‐resistance in HNC cells and might also serve as prognostic factors and therapeutic targets for HNC.

A comprehensive prognostic score for head and neck squamous cancer driver genes and phenotype traits

“…HSP90AA1 was highly expressed in various tumors and significantly correlated with poor prognosis [ 45 ]. HSP90AA1/IL-17 signaling pathway was associated with cisplatin resistance in head and neck squamous carcinoma [ 46 ]. MAP2K1 activation is implicated in several malignancies and is a therapeutic target in HNSCC [ 47 ].…”

The Role of IL-17 in the Pathogenesis of Oral Squamous Cell Carcinoma

“…The low-dose irradiation induces expression of IL-17 in tumor beds and enhances the growth of subsequently implanted tumor cells, while treatment with anti-IL-17 antibody abolished the acceleration of tumor growth, confirming the key role of IL-17 in enhancing tumor growth in pre-irradiated tumor beds [ 170 ]. Interleukin-17 plays a role in restoration of the damaged epithelia in radiation induced oral mucositis and attenuates epithelial damage [ 171 ], which imply that a similar IL-17 mediated process could contribute to better recovery of OSCC cells after radiotherapy and eventually chemotherapy and subsequently contribute to resistance of oral squamous cancer to therapy. Flavonoid induced better sensitivity of chemo-resistant OSCC cells to cisplatin is accompanied by the downregulation of IL-17 [ 171 ].…”

“…Interleukin-17 plays a role in restoration of the damaged epithelia in radiation induced oral mucositis and attenuates epithelial damage [ 171 ], which imply that a similar IL-17 mediated process could contribute to better recovery of OSCC cells after radiotherapy and eventually chemotherapy and subsequently contribute to resistance of oral squamous cancer to therapy. Flavonoid induced better sensitivity of chemo-resistant OSCC cells to cisplatin is accompanied by the downregulation of IL-17 [ 171 ]. Moreover, in the mouse model of OSCC, it has been shown that inhibition of IL-17A combined with the PD-1 blockade delayed the development of precancerous and cancerous lesions and prolonged the survival of 4NQO-treated mice, suggesting the IL-17A blockade as a potential approach to augment the tumor eliminating effects of anti-PD-1 therapy [ 92 ].…”

Extraction of Cynaroside from Honeysuckle by Nonionic Surfactant-mediated Aqueous Extraction with Cloud Point Enrichment and Purification by Metal Complexation

“…These compounds are frequently found in combination with sugars, forming glycosides. Over the years, avonoids have been extensively investigated for potential applications in medicines (Zhang and Yan 2023) and pharmaceuticals (Johan et al 2023), as well as natural health foods and beverages (Oei et al 2023), because they have demonstrated anti-in ammatory, antiviral, antioxidant, and anticancer properties and are nontoxic (Ling et al 2023;Peng et al 2023). They are also utilized in agricultural production and animal husbandry (Schnarr et al 2022;Lin et al 2022).…”