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A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer.
Anchoori, Ravi K; Karanam, Balasubramanyam; Peng, Shiwen; Wang, Joshua W; Jiang, Rosie; Tanno, Toshihiko; Orlowski, Robert Z; Matsui, William; Zhao, Ming; Rudek, Michelle A; Hung, Chien-fu; Chen, Xiang; Walters, Kylie J; Roden, Richard B S.
Afiliação
  • Anchoori RK; Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Karanam B; Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Peng S; Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Wang JW; Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Jiang R; Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Tanno T; Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Orlowski RZ; Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • Matsui W; Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Zhao M; Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Rudek MA; Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Hung CF; Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
  • Chen X; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
  • Walters KJ; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
  • Roden RB; Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA; Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA; Department of Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address: roden@jhmi.edu.
Cancer Cell ; 24(6): 791-805, 2013 Dec 09.
Article em En | MEDLINE | ID: mdl-24332045
ABSTRACT
The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of ubiquitin receptor RPN13 in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma (MM) lines, even those resistant to bortezomib, were sensitive to RA190 via endoplasmic reticulum stress-related apoptosis. RA190 stabilized targets of human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After oral or intraperitoneal dosing of mice, RA190 distributed to plasma and major organs except the brain and inhibited proteasome function in skin and muscle. RA190 administration profoundly reduced growth of MM and ovarian cancer xenografts, and oral RA190 treatment retarded HPV16(+) syngeneic mouse tumor growth, without affecting spontaneous HPV-specific CD8(+) T cell responses, suggesting its therapeutic potential.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperidonas / Glicoproteínas de Membrana / Inibidores de Proteassoma / Neoplasias Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperidonas / Glicoproteínas de Membrana / Inibidores de Proteassoma / Neoplasias Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article