start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=5 article-no= start-page=589 end-page=597 dt-received= dt-revised= dt-accepted= dt-pub-year=2013 dt-pub=201305 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model en-subtitle= kn-subtitle= en-abstract= kn-abstract=An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P = 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation. en-copyright= kn-copyright= en-aut-name=NinomiyaTakashi en-aut-sei=Ninomiya en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TakigawaNagio en-aut-sei=Takigawa en-aut-mei=Nagio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IchiharaEiki en-aut-sei=Ichihara en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OchiNobuaki en-aut-sei=Ochi en-aut-mei=Nobuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MurakamiToshi en-aut-sei=Murakami en-aut-mei=Toshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HondaYoshihiro en-aut-sei=Honda en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KuboToshio en-aut-sei=Kubo en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MinamiDaisuke en-aut-sei=Minami en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KudoKenichiro en-aut-sei=Kudo en-aut-mei=Kenichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TanimotoMitsune en-aut-sei=Tanimoto en-aut-mei=Mitsune kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KiuraKatsuyuki en-aut-sei=Kiura en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med affil-num=2 en-affil= kn-affil=Kawasaki Hosp, Dept Gen Internal Med 4, Kawasaki Med Sch affil-num=3 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med affil-num=4 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med affil-num=5 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med affil-num=6 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med affil-num=7 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med affil-num=8 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med affil-num=9 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med affil-num=10 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med affil-num=11 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=3 article-no= start-page=314 end-page=325 dt-received= dt-revised= dt-accepted= dt-pub-year=2013 dt-pub=201303 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Tumor suppressor p53 is a multifunctional transcription factor that regulates diverse cell fates, including apoptosis and autophagy in tumor biology. p53 overexpression enhances the antitumor activity of oncolytic adenoviruses; however, the molecular mechanism of this occurrence remains unclear. We previously developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301, that kills human osteosarcoma cells, but some human osteosarcoma cells were OBP-301-resistant. In this study, we investigated the antitumor activity of a p53-expressing oncolytic adenovirus, OBP-702, and the molecular mechanism of the p53-mediated cell death pathway in OBP-301-resistant human osteosarcoma cells. The cytopathic activity of OBP-702 was examined in OBP-301-sensitive (U2OS and HOS) and OBP-301-resistant (SaOS-2 and MNNG/HOS) human osteosarcoma cells. The molecular mechanism in the OBP-702-mediated induction of two cell death pathways, apoptosis and autophagy, was investigated in OBP-301-resistant osteosarcoma cells. The antitumor effect of OBP-702 was further assessed using an orthotopic OBP-301-resistant MNNG/HOS osteosarcoma xenograft tumor model. OBP-702 suppressed the viability of OBP-301-sensitive and -resistant osteosarcoma cells more efficiently than OBP-301 or a replication-deficient p53-expressing adenovirus (Ad-p53). OBP-702 induced more profound apoptosis and autophagy when compared with OBP-301 or Ad-p53. E1A-mediated miR-93/106b upregulation induced p21 suppression, leading to p53-mediated apoptosis and autophagy in OBP-702-infected cells. p53 overexpression enhanced adenovirus-mediated autophagy through activation of damage-regulated autophagy modulator (DRAM). Moreover, OBP-702 suppressed tumor growth in an orthotopic OBP-301-resistant MNNG/HOS xenograft tumor model. These results suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy to induce dual apoptotic and autophagic cell death pathways via regulation of miRNA and DRAM in human osteosarcoma cells. Mol Cancer Ther; 12(3); 314-25. en-copyright= kn-copyright= en-aut-name=HaseiJoe en-aut-sei=Hasei en-aut-mei=Joe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SasakiTsuyoshi en-aut-sei=Sasaki en-aut-mei=Tsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OsakiShuhei en-aut-sei=Osaki en-aut-mei=Shuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YamakawaYasuaki en-aut-sei=Yamakawa en-aut-mei=Yasuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KunisadaToshiyuki en-aut-sei=Kunisada en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YoshidaAki en-aut-sei=Yoshida en-aut-mei=Aki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HashimotoYuuri en-aut-sei=Hashimoto en-aut-mei=Yuuri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OnishiTeppei en-aut-sei=Onishi en-aut-mei=Teppei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=UnoFutoshi en-aut-sei=Uno en-aut-mei=Futoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=UrataYasuo en-aut-sei=Urata en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OzakiToshifumi en-aut-sei=Ozaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg affil-num=2 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg affil-num=3 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol affil-num=4 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg affil-num=5 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg affil-num=6 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg affil-num=7 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg affil-num=8 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol affil-num=9 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol affil-num=10 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol affil-num=11 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol affil-num=12 en-affil= kn-affil=Oncolys BioPharma Inc affil-num=13 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg affil-num=14 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol END