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

Author:

Wang, Feng

Li, Shan

Rosencrans, William M

Cheng, Kai-Wen

Stott,Gordon

Mroczkowski, Barbara

Chou, Tsui-Fen [ORCID]
Author Address

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., NExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA., Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.,

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-?B 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. © 2022 Wiley-VCH GmbH.

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