Enhancement of the sensitivity of renal cell carcinoma cells to fas-mediated cytotoxicity and apoptosis by the selective cyclooxygenase-2 inhibitor JTE-522.
BACKGROUND
Cyclooxygenase-2 (COX-2) is a key enzyme involved in the production of prostaglandins and its inhibitors have been shown to induce apoptosis in a variety of cancer cells. We reasoned that combination treatment of renal cell carcinoma (RCC) cells with COX-2 inhibitors and anticancer agents may result in synergistic apoptosis. We examined whether the selective COX-2 inhibitor JTE-522 synergizes with anticancer agents in cytotoxicity and apoptosis against RCC cells.


METHODS
The cytotoxicity of the selective COX-2 inhibitor JTE-522 and other anticancer agents against the RCC cell lines and the normal renal cell line was determined by the microculture tetrazolium dye assay.


RESULTS
JTE-522 was cytotoxic against the Caki-1 RCC cell line. JTE-522 and anti-Fas monoclonal antibody (CH-11) exhibited a synergistic cytotoxic effect against Caki-1 cells. In contrast, JTE-522 in combination with 5-fluorouracil, adriamycin, cis-diamminedichloroplatinum, or interferon-alpha, all commonly used clinically, resulted in an additive cytotoxic effect. Synergy achieved in cytotoxicity with JTE-522 and CH-11 was shown to be due to apoptosis.


CONCLUSIONS
The present study demonstrated that the selective COX-2 inhibitor JTE-522 had a cytotoxic effect on RCC and that synergistic cytotoxicity against RCC was obtained with JTE-522 in combination with anti-Fas monoclonal antibody. These results suggest that selective COX-2 inhibitors in combination with immunotherapy may be useful in treating patients with RCC.
Sato
Nodoka
N
Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan. sato.n@ayabe-hsp.or.jp
Mizutani
Yoichi
Y
Li
Yong Nan
YN
Fujiwara
Jun
J
Ishida
Hirokazu
H
Toiyama
Daisuke
D
Abe
Koichi
K
Hayashi
Issei
I
Nakanishi
Hiroyuki
H
Kawauchi
Akihiro
A
Miki
Tsuneharu
T
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D010080:Oxazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D052246:Cyclooxygenase 2 Inhibitors; D010080:Oxazoles; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C411023:anti-Fas monoclonal antibody