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 cytotoxicity 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.
Highlights
Over the last 40 years, incidences of testicular carcinoma have steadily increased, becoming the most common cancer in young men [1, 2]
Testicular teratocarcinomas and embryonal carcinoma cells derived from these tumors are extremely sensitive to cisplatin [cis-diamminedichloroplatinum (II)] and its derivatives [4,5,6]; use of high doses of cisplatin is limited by the occurrence of various side effects [7, 8]
Cytotoxic activity of cisplatin and fisetin is enhanced when combined together To determine the cytotoxic effects of cisplatin when given along with fisetin, NT2/D1 cells were exposed to cisplatin and fisetin (Fig. 1A) as monotherapies as well as in combination
Summary
Over the last 40 years, incidences of testicular carcinoma have steadily increased, becoming the most common cancer in young men [1, 2]. A percentage of these carcinomas originating from germ cells either do not respond to treatment or recur post chemotherapy [2, 3]. Testicular teratocarcinomas and embryonal carcinoma cells derived from these tumors are extremely sensitive to cisplatin [cis-diamminedichloroplatinum (II)] and its derivatives [4,5,6]; use of high doses of cisplatin is limited by the occurrence of various side effects [7, 8]. Authors' Affiliations: 1Cell Death and Differentiation Research Laboratory; 2Molecular Sciences Laboratory, National Institute of Immunology, New Delhi 110067, India. Combination regimens with cisplatin have been tried with moderate success; the search continues for improved formulations [9, 10].
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