title: A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor.
abstract: The PI3K-AKT pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment. We previously reported that a novel PI3K inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC.
authors.affiliation: Department of General Surgery, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Ishida
authors.affiliation: Department of General Surgery, Kawasaki Medical School, Okayama 700-8505, Japan. Electronic address: FukazawaT@aol.com.
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukazawa
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229-3039, United States.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of General Surgery, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yamatsuji
authors.affiliation: Department of Diagnostic Radiology 2, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimo
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229-3039, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.affiliation: Department of General Surgery, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003374:Coumarins / Q000494:pharmacology*; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C587597:3-(2-(4-fluorobenzyl)imidazo(2,1-beta)(1),(3)thiazol-6-yl)-2H-chromen-2-one; D000970:Antineoplastic Agents; D001549:Benzamides; D003374:Coumarins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles; C506614:mirdametinib; D004159:Diphenylamine; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: MEK; NSCLC; PI3K
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