title: TD-19, an erlotinib derivative, induces epidermal growth factor receptor wild-type nonsmall-cell lung cancer apoptosis through CIP2A-mediated pathway.
abstract: Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutations still respond to gefitinib and erlotinib, suggesting that there may be a mechanism(s) other than the EGFR pathway that mediates the tumoricidal effects. In the current study, we tested the efficacy of TD-19, a novel compound chemically modified from erlotinib, which has more potent apoptotic effects than erlotinib in EGFR wild-type NSCLC cell lines. TD-19 induced significant cell death and apoptosis in H358, H441, H460, and A549 cells, as evidenced by increased caspase-3 activity and cleavage of procaspase-9 and poly (ADP-ribose) polymerase. The apoptotic effect of TD-19 in H460 cells, which were resistant to erlotinib, was associated with downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A), increased protein phosphatase 2A (PP2A) activity, and decreased AKT phosphorylation, but minimal effects on EGFR phosphorylation. Overexpression of CIP2A partially protected the H460 cells from TD-19-induced apoptosis. Okadaic acid, a known PP2A inhibitor, significantly reduced TD-19-induced apoptosis, while forskolin, which increased PP2A activity, increased the apoptotic effect of TD-19. TD-19 inhibited the growth of H460 xenograft tumors by ∼80%. We conclude that TD-19 exerted tumoricidal effects on NSCLC cells. TD-19 provides proof that the CIP2A pathway may be a novel target for the treatment of EGFR wild-type NSCLC.
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Chao
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
authors.forename: Yen-Lin
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Tsai
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
authors.forename: Pao-Tzu
authors.initials: PT
authors.lastname: Chen
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
authors.forename: Hen-I
authors.initials: HI
authors.lastname: Lin
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
authors.forename: Yuh-Chin T
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan cwshiau@ym.edu.tw kfchen1970@ntu.edu.tw.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan cwshiau@ym.edu.tw kfchen1970@ntu.edu.tw.
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: Medical Research Center (T.-T.C., C.-Y.W., Y.-T.T., P.-T.C.), Department of Internal Medicine (C.-Y.W., H.-I.L.), and Department of Pathology (Y.-L.C.), Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (C.-Y.W.); Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan (C.-C.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (Y.-C.T.H.); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan (C.-W.S.); and Department of Internal Medicine (C.-J.Y.) and Department of Medical Research and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan cwshiau@ym.edu.tw kfchen1970@ntu.edu.tw.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001324:Autoantigens / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D011065:Poly(ADP-ribose) Polymerases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D053148:Caspase 3; D053453:Caspase 9