Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 23, Pages 7162-7174Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-0302
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Funding
- NIH Cancer Center Support Grant [5P30CA045508]
- Lustgarten Foundation
- Cold Spring Harbor Laboratory Association
- David Rubinstein Center for Pancreatic Cancer Research at MSKCC
- V Foundation [PG009685 -VFNDV2018-017]
- Thompson Foundation
- Simons Foundation [552716]
- NIH [P30CA045508, P50CA101955, P20CA192996, U10CA180944, U01CA168409, U01CA210240, R33CA206949, R01CA188134, R01CA190092, R50CA211506]
- Donaldson Charitable Trust
- Pancreatic Cancer Action Network [PG009667 -PANCAN 18-35-CHIO]
- Columbia University Medical Center (Paul Marks Scholar Award)
- Northwell Health Affiliation
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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 anticancer 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 knockout or pharmacologic 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.
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