A bis-Benzylidine Piperidone Targeting Proteasome Ubiquitin Receptor RPN13/ADRM1 as a Therapy for Cancer

Ravi K. Anchoori, Balasubramanyam Karanam, Shiwen Peng, Joshua W. Wang, Rosie Jiang, Toshihiko Tanno, Robert Z. Orlowski, William Matsui, Ming Zhao, Michelle A. Rudek, Chien fu Hung, Xiang Chen, Kylie J. Walters, Richard B.S. Roden

Research output: Contribution to journalArticle

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+ Tcell responses, suggesting its therapeutic potential.

Original languageEnglish (US)
Pages (from-to)791-805
Number of pages15
JournalCancer cell
Volume24
Issue number6
DOIs
StatePublished - Dec 9 2013

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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