The radical scavenger edaravone enhances the anti-tumor effects of CPT-11 in murine colon cancer by increasing apoptosis via inhibition of NF-kappaB.
The transcription factor NF-kappaB is reportedly activated by anti-cancer chemotherapeutic compounds in many cancer cell lines and NF-kappaB activation is one mechanism by which tumors become resistant to apoptosis. Antioxidants have been reported to serve as potent NF-kB inhibitors. In this study, we investigated the ability of edaravone to enhance apoptosis induced by CPT-11 through inhibition of NF-kB. In vitro, SN38, the active metabolite of CPT-11, induced activation of NF-kB, the production of intracellular reactive oxygen species, the activation of caspase-3, and apoptosis in colon26 cells. Pretreatment with edaravone scavenged the SN38-produced reactive oxygen species, and inhibited the SN38-induced activation of NF-kB. Moreover, edaravone enhanced the activation of caspase-3, and the level of apoptosis induced by SN38. In vivo, the combination of edaravone with CPT-11 reduced subcutaneous tumor growth and number of pulmonary metastases more effectively than CPT-11 alone. These results demonstrate that the combination of edaravone with CPT-11 may constitute a new strategy for treating primary and metastatic colon cancer.
Kokura
Satoshi
S
Department of Biomedical Safety Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. s-kokura@mpd.biglobe.ne.jp
Yoshida
Norimasa
N
Sakamoto
Naoyuki
N
Ishikawa
Takeshi
T
Takagi
Tomohisa
T
Higashihara
Hiroshi
H
Nakabe
Nami
N
Handa
Osamu
O
Naito
Yuji
Y
Yoshikawa
Toshikazu
T
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D000077553:Edaravone; D024202:Electrophoretic Mobility Shift Assay; D016166:Free Radical Scavengers / Q000008:administration & dosage; D020287:In Situ Nick-End Labeling; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species
D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000077146:Irinotecan; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000077553:Edaravone; D000983:Antipyrine; D002166:Camptothecin