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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway

Ting-Ting Chao, Cheng-Yi Wang, Chih-Cheng Lai, Yen-Lin Chen, Yi-Ting Tsai, Pao-Tzu Chen, Hen-I Lin, Yuh-Chin T. Huang, Chung-Wai Shiau, Chong-Jen Yu and Kuen-Feng Chen
Journal of Pharmacology and Experimental Therapeutics November 2014, 351 (2) 352-358; DOI: https://doi.org/10.1124/jpet.114.215418
Ting-Ting Chao
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
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Cheng-Yi Wang
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
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Chih-Cheng Lai
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
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Yen-Lin Chen
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
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Yi-Ting Tsai
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
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Pao-Tzu Chen
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
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Hen-I Lin
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
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Yuh-Chin T. Huang
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
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Chung-Wai Shiau
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
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Chong-Jen Yu
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
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Kuen-Feng Chen
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
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This article has a correction. Please see:

  • Correction to “TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway” - January 01, 2018

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.

Footnotes

    • Received April 16, 2014.
    • Accepted August 29, 2014.
  • This study was supported by the Cardinal Tien Hospital [Grants CTH-102-1-2A29, CTH-101-2-2A01, and CTH-102-1-2A20]; and the National Science Council of Taiwan [Grants NSC 102-2314-B-567-001-MY2 and NSC 101-2314-B-567-001-MY3].

  • dx.doi.org/10.1124/jpet.114.215418.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 2
1 Nov 2014
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

TD-19 Induces EGFR Wild-Type NSCLC Apoptosis

Ting-Ting Chao, Cheng-Yi Wang, Chih-Cheng Lai, Yen-Lin Chen, Yi-Ting Tsai, Pao-Tzu Chen, Hen-I Lin, Yuh-Chin T. Huang, Chung-Wai Shiau, Chong-Jen Yu and Kuen-Feng Chen
Journal of Pharmacology and Experimental Therapeutics November 1, 2014, 351 (2) 352-358; DOI: https://doi.org/10.1124/jpet.114.215418

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

TD-19 Induces EGFR Wild-Type NSCLC Apoptosis

Ting-Ting Chao, Cheng-Yi Wang, Chih-Cheng Lai, Yen-Lin Chen, Yi-Ting Tsai, Pao-Tzu Chen, Hen-I Lin, Yuh-Chin T. Huang, Chung-Wai Shiau, Chong-Jen Yu and Kuen-Feng Chen
Journal of Pharmacology and Experimental Therapeutics November 1, 2014, 351 (2) 352-358; DOI: https://doi.org/10.1124/jpet.114.215418
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