title: Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer.
abstract: The antitumor activities of type III interferon (IFN) (interleukin [IL]-28 and IL-29) and the combination of type III IFN and type I IFN (IFN-α) were evaluated using human non-small cell lung cancer (NSCLC). The expression of type III and type I receptor complexes was detected in NSCLC lines. IL-29 significantly inhibited the in vitro growth of a wide range of NSCLC lines in a dose-dependent fashion. To a lesser degree, IL-28A also displayed growth inhibitory activity. Antitumor activity of type III IFN is associated with cell cycle arrest at the G1 phase and apoptosis. IL-29 upregulated cyclin-dependent kinase inhibitor p21Waf1/Cip1 in cells sensitive, but not insensitive, to antiproliferative activity, and knockdown of p21 with small interfering RNA largely attenuated the antiproliferative effect. Intratumoral and systemic administration of IL-29 inhibited OBA-LK1 and LK-1, but not A549, tumor growth in severe combined immunodeficiency mice. Immunohistochemical analyses demonstrated marked upregulated p21 and downregulated Ki-67 expression in tumors treated with IL-29. The interferon combination of IL-29 and IFN-α displayed a more effective antiproliferative effect and a more intense p21 expression than each reagent alone in vitro. Furthermore, interferon combination therapy suppressed in vivo NSCLC growth more effectively than interferon monotherapy. These findings demonstrate that type III IFN can mediate direct antitumor activities via increased p21 expression and induction of apoptosis and cooperate with type I IFN to elicit more efficient direct antitumor activities, and suggest the possibility that type III IFN might improve the efficacy and reduce the side-effects of type I IFN cancer therapy.
authors: Department of Nutrition Physiology, Faculty of Pharmaceutical Sciences, Josai University, Sakado, Japan.
authors: Hitomi
authors: H
authors: Fujie
authors: Toshiaki
authors: T
authors: Tanaka
authors: Masatoshi
authors: M
authors: Tagawa
authors: Niu
authors: N
authors: Kaijun
authors: Mika
authors: M
authors: Watanabe
authors: Takashi
authors: T
authors: Suzuki
authors: Katsutoshi
authors: K
authors: Nakayama
authors: Muneo
authors: M
authors: Numasaki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000032:analysis / Q000187:drug effects; D018121:Receptors, Cytokine / Q000032:analysis / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000095022:Interferon Lambda
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D009363:Neoplasm Proteins; D053633:Receptor, Interferon alpha-beta; D018121:Receptors, Cytokine; C493956:CDKN1A protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C471046:interleukin 28alpha receptor