Characterization and property investigation of novel human glucose 6-phosphate dehydrogenase inhibitors in lung cancer cell lines

Abstract

G6PD plays fundamental roles in many cellular processes, including redox balance and lipid and nucleotide synthesis. Overexpression of G6PD is required to promote the proliferation and survival of cancer cells, including lung cancer. Targeting G6PD is a prominent strategy to inhibit cancer cell progression. Finding novel natural compounds with anticancer properties to inhibit G6PD activity needs to be investigated. Our study indicated that SJ006, which is 1,2-naphthoquinone, promoted cytotoxic activity against NSCLC cell lines. Interestingly, SJ006 exhibited a direct inhibitory effect on G6PD activity without interfering with mRNA or protein levels, which were strongly observed in both A549 and H292. Additionally, an uncompetitive inhibition was also proposed as a property of SJ006 to inhibit G6PD in this study through the reduction of Km and Vmax. The increasing level of ROS production was observed, resulting in G2/M phase cell cycle arrest and the elevating of Bax/Bcl2 ratio through the inhibition of G6PD-induced apoptosis in NSCLC cell lines in the presence of SJ006. Moreover, D-(−)-ribose, a bypass product of the PPP, was able to rescue NSCLC proliferation in the presence of SJ006, supporting the inhibitory role of SJ006 on NSCLC proliferation through the G6PD-regulated PPP. Therefore, SJ006 was identified as a novel uncompetitive G6PD inhibitor with anticancer activity that inhibits the progression and survival of NSCLC.