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Clin Cancer Res. 2019 Sep 16. doi: 10.1158/1078-0432.CCR-19-0302. [Epub ahead of print]

Bioactivation of Napabucasin Triggers Reactive Oxygen Species-Mediated Cancer Cell Death.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
2
Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.
3
Northwell Cancer Institute, Lake Success, New York.
4
Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
5
Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, New York.
6
Institute for Cancer Genetics, Columbia University, New York, New York.
7
Icahn School of Medicine at Mount Sinai, New York, New York.
8
Boston Biomedical Inc., Cambridge, Massachusetts.
9
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. dtuveson@cshl.edu.
#
Contributed equally

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 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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