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Sulforaphane is Synergistic with CB‐5083 and Inhibits Colony Formation of CB‐5083‐Resistant HCT116 Cells

Wang, Feng and Li, Shan and Rosencrans, William M. and Cheng, Kai-Wen and Stott, Gordon M. and Mroczkowski, Barbara and Chou, Tsui-Fen (2022) Sulforaphane is Synergistic with CB‐5083 and Inhibits Colony Formation of CB‐5083‐Resistant HCT116 Cells. ChemMedChem, 17 (11). Art. No. e202200030. ISSN 1860-7179. doi:10.1002/cmdc.202200030. https://resolver.caltech.edu/CaltechAUTHORS:20220708-104460300

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Abstract

Human p97 is a potential drug target in oncology. Mutation-driven drug resistance is an obstacle to the long-term efficacy of targeted therapy. We found that the ATPase activity for one of the CB-5083-resistant p97 mutants was reduced, which also attenuated the degradation of K48 ubiquitinated proteins in cells. To understand how p97 mutant cells with significantly reduced ATPase activity can still grow, we discovered reduced levels of CHOP and NF-κB activation in the p97 mutant cells and these cellular changes can potentially protect HCT116 cells from death due to lowered p97 activity. In addition, the NF-kB inhibitor Sulforaphane reduces proliferation of CB-5083 resistant cells and acts synergistically with CB-5083 to block proliferation of the parental HCT116 cells. The combination of Sulforaphane and CB-5083 may be a useful treatment strategy to combat CB-5083 resistance.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/cmdc.202200030DOIArticle
https://chemistry-europe.onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fcmdc.202200030&file=cmdc202200030-sup-0001-misc_information.pdfPublisherSupporting Information
ORCID:
AuthorORCID
Li, Shan0000-0002-0829-1821
Rosencrans, William M.0000-0003-1461-8891
Cheng, Kai-Wen0000-0001-9888-9773
Stott, Gordon M.0000-0002-9148-6100
Chou, Tsui-Fen0000-0003-2410-2186
Additional Information:© 2022 Wiley-VCH GmbH. Issue Online: 07 June 2022; Version of Record online: 22 April 2022; Manuscript revised: 04 April 2022; Manuscript received: 17 January 2022. Research Funding: National Institute of Neurological Disorders and Stroke. Grant Number: R01NS102279; National Cancer Institute, National Institutes of Health. Grant Numbers: 75N91019D00024, 75N091019F00129. Data Availability Statement: The data that support the findings of this study are available in the supplementary material of this article.
Funders:
Funding AgencyGrant Number
NIHR01NS102279
NIH75N91019D00024
NIH75N091019F00129
Subject Keywords:p97; VCP; CB-5083; Sulforaphane; CHOP
Issue or Number:11
DOI:10.1002/cmdc.202200030
Record Number:CaltechAUTHORS:20220708-104460300
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220708-104460300
Official Citation:Sulforaphane is Synergistic with CB‐5083 and Inhibits Colony Formation of CB‐5083‐Resistant HCT116 Cells. F. Wang, S. Li, W. M. Rosencrans, K.-W. Cheng, G. M. Stott, B. Mroczkowski, T.-F. Chou, ChemMedChem 2022, 17, e202200030; DOI: 10.1002/cmdc.202200030
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115440
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Jul 2022 18:10
Last Modified:11 Jul 2022 18:10

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