Bioactivation of napabucasin triggers reactive oxygen species-mediated cancer cell death

Froeling, F. E. M., Mosur Swamynathan, M., Deschenes, A., Chio, I. I. C., Brosnan, E., Yao, M. A., Alagesan, P., Lucito, M. S., Li, J., Chang, A. Y., Trotman, L. C., Belleau, P., Park, Y., Rogoff, H. A., Watson, J. D., Tuveson, D. A. (September 2019) Bioactivation of napabucasin triggers reactive oxygen species-mediated cancer cell death. Clin Cancer Res, 25 (23). pp. 7162-7174. ISSN 1078-0432 (Print)1078-0432

Abstract

PURPOSE: Napabucasin (2-acetylfuro-1,4-naphthoquinone or BBI-608) is a small molecule currently being clinically evaluated in various cancer types. It has mostly been recognized for its ability to inhibit STAT3 signaling. However, based on its chemical structure, we hypothesized that napabucasin is a substrate for intracellular oxidoreductases and therefore may exert its anti-cancer effect through redox cycling, resulting in reactive oxygen species (ROS) production and cell death. EXPERIMENTAL DESIGN: Binding of napabucasin to NAD(P)H:quinone oxidoreductase-1 (NQO1), and other oxidoreductases, was measured. Pancreatic cancer cell lines were treated with napabucasin, and cell survival, ROS generation, DNA damage, transcriptomic changes and alterations in STAT3 activation were assayed in vitro and in vivo. Genetic knock-out or pharmacological inhibition with dicoumarol was used to evaluate the dependency on NQO1. RESULTS: Napabucasin was found to bind with high affinity to NQO1 and to a lesser degree to cytochrome P450 oxidoreductase (POR). Treatment resulted in marked induction of ROS and DNA damage with an NQO1- and ROS-dependent decrease in STAT3 phosphorylation. Differential cytotoxic effects were observed, where NQO1-expressing cells generating cytotoxic levels of ROS at low napabucasin concentrations were more sensitive. Cells with low or no baseline NQO1 expression also produced ROS in response to napabucasin, albeit to a lesser extent, through the one-electron reductase POR. CONCLUSIONS: Napabucasin is bioactivated by NQO1, and to a lesser degree by POR, resulting in futile redox cycling and ROS generation. The increased ROS levels result in DNA damage and multiple intracellular changes, one of which is a reduction in STAT3 phosphorylation.

Item Type:	Paper
Subjects:	organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line diseases & disorders > pulmonary disease > oxidative stress diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:	Watson, James D. Tuveson, David A. Trotman, Lloyd C. Froeling, Fieke Swamynathan, Manojit Mosur Deschenes, Astrid Brosnan, Erin Alageson, Priya Belleau, Pascal Park, Youngkyu
Communities:	CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Trotman lab CSHL labs > Tuveson lab CSHL Cancer Center Shared Resources > Animal Shared Resource
Depositing User:	Matthew Dunn
Date:	16 September 2019
Date Deposited:	26 Sep 2019 15:43
Last Modified:	29 Jun 2021 19:18
PMCID:	PMC6891204
URI:	https://repository.cshl.edu/id/eprint/38424

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