Discovery of Nonquinone Substrates for NAD(P)H: Quinone Oxidoreductase 1 (NQO1) as Effective Intracellular ROS Generators for the Treatment of Drug-Resistant Non-Small-Cell Lung Cancer

The
elevation of oxidative stress preferentially in cancer cells
by efficient NQO1 substrates, which promote ROS generation through
redox cycling, has emerged as an effective strategy for cancer therapy,
even for treating drug-resistant cancers. Here, we described the identification
and structural optimization studies of the hit compound 1, a new chemotype of nonquinone substrate for NQO1 as an efficient
ROS generator. Further structure–activity relationship studies
resulted in the most active compound 20k, a tricyclic
2,3-dicyano indenopyrazinone, which selectively inhibited the proliferation
of NQO1-overexpressing A549 and A549/Taxol cancer cells. Furthermore, 20k dramatically elevated the intracellular ROS levels through
NQO1-catalyzed redox cycling and induced PARP-1-mediated cell apoptosis
in A549/Taxol cells. In addition, 20k significantly suppressed
the growth of A549/Taxol xenograft tumors in mice with no apparent
toxicity observed in vivo. Together, 20k acts as an efficient
NQO1 substrate and may be a new option for the treatment of NQO1-overexpresssing
drug-resistant NSCLC.