NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavin protease highly expressed in various cancer cells.NQO1 catalyzes a futile redox cycle in substrates,leading to substantial reactive oxygen species(ROS)production.This ...NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavin protease highly expressed in various cancer cells.NQO1 catalyzes a futile redox cycle in substrates,leading to substantial reactive oxygen species(ROS)production.This ROS generation results in extensive DNA damage and elevated poly(ADP-ribose)polymerase 1(PARP1)-mediated consumption of nicotinamide adenine dinucleotide(NAD^(+)),ultimately causing cell death.Nicotinamide phosphoribosyltransferase(NAMPT),the rate-limiting enzyme in the NAD^(+)salvage synthesis pathway,emerges as a critical target in cancer therapy.The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+depletion.In this study,we designed,synthesized,and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT.Among these,compound T8 demonstrated potent antitumor properties.Specifically,T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT.This discovery offers a promising new molecular entity for advancing anticancer research.展开更多
基金This work was supported by the National Key Research and Development Programme of China(No.YFA1303800)the Fundamental Research Funds for the Central Universities(No.2632023TD10)the National Natural Science Foundation of China(No.81930109).
文摘NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavin protease highly expressed in various cancer cells.NQO1 catalyzes a futile redox cycle in substrates,leading to substantial reactive oxygen species(ROS)production.This ROS generation results in extensive DNA damage and elevated poly(ADP-ribose)polymerase 1(PARP1)-mediated consumption of nicotinamide adenine dinucleotide(NAD^(+)),ultimately causing cell death.Nicotinamide phosphoribosyltransferase(NAMPT),the rate-limiting enzyme in the NAD^(+)salvage synthesis pathway,emerges as a critical target in cancer therapy.The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+depletion.In this study,we designed,synthesized,and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT.Among these,compound T8 demonstrated potent antitumor properties.Specifically,T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT.This discovery offers a promising new molecular entity for advancing anticancer research.
