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Targeting DDX3 with a small molecule inhibitor for lung cancer therapy.
Bol, Guus M; Vesuna, Farhad; Xie, Min; Zeng, Jing; Aziz, Khaled; Gandhi, Nishant; Levine, Anne; Irving, Ashley; Korz, Dorian; Tantravedi, Saritha; Heerma van Voss, Marise R; Gabrielson, Kathleen; Bordt, Evan A; Polster, Brian M; Cope, Leslie; van der Groep, Petra; Kondaskar, Atul; Rudek, Michelle A; Hosmane, Ramachandra S; van der Wall, Elsken; van Diest, Paul J; Tran, Phuoc T; Raman, Venu.
Afiliação
  • Bol GM; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Vesuna F; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Xie M; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Zeng J; Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Aziz K; Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Gandhi N; Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Levine A; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Irving A; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Korz D; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Tantravedi S; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Heerma van Voss MR; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Gabrielson K; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Bordt EA; Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.
  • Polster BM; Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.
  • Cope L; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • van der Groep P; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Kondaskar A; Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, MD, USA.
  • Rudek MA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Hosmane RS; Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, MD, USA.
  • van der Wall E; Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
  • van Diest PJ; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Tran PT; Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Raman V; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA vraman2@jhmi.
EMBO Mol Med ; 7(5): 648-69, 2015 May.
Article em En | MEDLINE | ID: mdl-25820276
ABSTRACT
Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3-ß-catenin axis and inhibited non-homologous end joining-the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Radiossensibilizantes / Azepinas / RNA Helicases DEAD-box / Imidazóis / Neoplasias Pulmonares / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: EMBO Mol Med Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Holanda
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Radiossensibilizantes / Azepinas / RNA Helicases DEAD-box / Imidazóis / Neoplasias Pulmonares / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: EMBO Mol Med Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Holanda