An oral second-generation proteasome inhibitor oprozomib significantly inhibits lung cancer in a p53 independent manner in vitro.

Abstract

The destruction of proteins via the ubiquitin-proteasome system is a multi-step, complex process involving polyubiquitination of substrate proteins, followed by proteolytic degradation by the macromolecular 26S proteasome complex. Inhibitors of the proteasome promote the accumulation of proteins that are deleterious to cell survival and are promising anticancer agents. Oprozomib (OPZ), an oral second-generation proteasome inhibitor, has been shown to inhibit the growth of several cancers in preclinical and clinical trials, including multiple myeloma and head and neck cancers, but its effects on lung cancer has not yet been determined. In this study, we evaluated the inhibitory effects of OPZ on lung cancer cell lines in vitro. The results showed that OPZ significantly suppressed cell proliferation and strongly induced apoptosis in both tested lung cancer cells independent of p53 expression. OPZ was able to cause obvious caspase 3 and PARP cleavages and stabilize p53 and its transcriptional targets p21, PUMA, and Noxa. Moreover, OPZ was capable of sensitizing lung cancer cells to the conventional chemotherapeutic drug cisplatin. Our study provides preclinical data and sheds light on the potential applications of proteasome inhibitor OPZ in lung cancer treatment.

• Authors: Hongge Zhu, Tianhai Wang, Zhou Xin, Yiyi Zhan, Guoming Gu, Xiaoqin Li, Xiuli Wang, Shune Yang, Chunling Liu
• Journal: Acta biochimica et biophysica Sinica (Acta Biochim Biophys Sin (Shanghai)) Vol. 51 Issue 10 Pg. 1034-1040 (Sep 06 2019) ISSN: 1745-7270 [Electronic] China
• PMID: 31518420 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Antineoplastic Agents
• ONX 0912
• Oligopeptides
• Proteasome Inhibitors
• Tumor Suppressor Protein p53

Topics

• Administration, Oral
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Lung Neoplasms (drug therapy, metabolism)
• Oligopeptides (administration & dosage, pharmacology)
• Proteasome Inhibitors (administration & dosage, pharmacology)
• Tumor Suppressor Protein p53 (metabolism)