Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma

• Published in: Experimental cell research Vol. 333; no. 2; pp. 316 - 326
• Main Authors: Zuo, Chaohui, Qiu, Xiaoxin, Liu, Nianli, Yang, Darong, Xia, Man, Liu, Jingshi, Wang, Xiaohong, Zhu, Haizhen, Xie, Hailong, Dan, Hanguo, Li, Qinglong, Wu, Qunfeng, Burns, Michael, Liu, Chen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2015
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Antineoplastic Agents - pharmacology; APOPTOSIS; Apoptosis - drug effects; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Caspases - metabolism; Celecoxib; Cell Line, Tumor; CELL PROLIFERATION; Combination therapy; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2; Drug Synergism; ECOLOGICAL CONCENTRATION; FLUORESCENCE; Hepatocellular carcinoma; HEPATOMAS; HLCZ01; Humans; IN VITRO; IN VIVO; INHIBITION; INTERFERON; Interferon-alpha; Interferon-alpha - pharmacology; LIGANDS; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Male; MICE; Mice, Inbred BALB C; Mice, Nude; MORTALITY; Pyrazoles - pharmacology; RADIOPROTECTIVE SUBSTANCES; RECEPTORS; Sulfonamides - pharmacology; THERAPY; TIME DEPENDENCE; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TOXICITY; Tumor necrosis factor-related apoptosis-inducing ligand; Xenograft Model Antitumor Assays; IFN-α; TRAIL; COX-2; Tumor necrosis factor-related apoptosis-inducing ligand; Interferon-alpha; HLCZ01; HCC; Hepatocellular carcinoma; IC; Cyclooxygenase-2; Combination therapy; Apoptosis
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2015.02.013

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4׳,6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors. ●The cytotoxic effect of TRAIL on a developed HCC HLCZ01 cells infected with HBV.●IFN-α and celecoxib induced apoptosis in HLCZ01 cells infected with HBV.●The combined regime reduced the growth of xenotransplanted HCCs in nude mice model.