Anticancer Activity of a Combination of Cisplatin and Fisetin in Embryonal Carcinoma Cells and Xenograft Tumors

Abstract

Use of chemotherapeutic drug cisplatin is limited because of its toxicity. Therefore, efforts continue for the discovery of novel combination therapies with cisplatin to reduce its effective treatment dose. This study evaluates the potential of fisetin, a flavonoid, to increase cisplatin cytotoxicity in human embryonal carcinoma NT2/D1 cells. Addition of fisetin to cisplatin enhanced cisplatin cytoxicity in vitro at four times lower dose than that required by cisplatin monotherapy for similar cytotoxic effects. Cisplatin, fisetin monotherapy, and addition of fisetin to cisplatin in a combination increased FasL expression. Cisplatin and fisetin as single agents activated caspases-8 and -3 and caspases-9 and -7, respectively, whereas combination treatment activated all 4 caspases. Increases in p53 and p21 and decreases in cyclin B1 and survivin occurred, all effects being more exaggerated with the combination. Fisetin, with or without cisplatin, increased expression of proapoptotic protein Bak and induced its mitochondrial oligomerization. Bid truncation and mitochondrial translocation of Bid and p53 was induced by fisetin in the presence or absence of cisplatin. Downregulation of p53 by short hairpin RNA during drug treatment decreased p21 levels but caused survivin increase, thus reducing cell death. Upstream to p53, inhibition of p38 phosphorylation reduced p53 phosphorylation and cell death. In a NT2/D1 mouse xenograft model, combination therapy was most effective in reducing tumor size. In summary, findings of this study suggest that addition of fisetin to cisplatin activates both the mitochondrial and the cell death receptor pathway and could be a promising regimen for the elimination of embryonal carcinoma cells. Mol Cancer Ther; 10(2); 255-68. Ó2011 AACR.

Cardamonin enhances the anti-proliferative effect of cisplatin on ovarian cancer

“…Thus, improving the antitumor efficiency of cisplatin is an essential way for patients with ovarian cancer. A number of flavonoid compounds, including baicalein, apigenin and fisetin may enhance the cytotoxicity of cisplatin in head and neck squamous cell carcinoma, embryonal carcinoma and cervical carcinoma cells (31)(32)(33). Epithelial ovarian cancer accounts for almost 80% of all ovarian cancer cases and is the leading cause of cancer-associated mortality among women (34).…”

Design and development of dry powder sulfobutylether-β-cyclodextrin complex for pulmonary delivery of fisetin

“…It has shown synergistic activities with other anticancer agents (i.e. cisplatin and cyclophosphamide) in different carcinoma cell lines [2,3] and acts as an adjunct in cancer therapy to alleviate specific adverse effects related to cytotoxic agents or other therapeutics, including protection against ovariectomy-induced bone loss in mice [4] and has a renoprotective effect in cisplatininduced nephrotoxicity in rats [5].…”

Flavones and Flavonols may have Clinical Potential as CK2 Inhibitors in Cancer Therapy

“…Here are citations for the xenograft studies: apigenin, 65-81 luteolin, 111-122 kaempferol, 123 fisetin, [124][125][126] quercetin, 127-145 myrcetin. 146 There are at least 53 published studies in which flavones or flavonols have decreased the growth of human xenografts in nude mice.…”