Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to anti-malarial agent dihydroartemisinin

The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small molecule 6PGD inhibitors Physcion and its derivative S3, shows anti-cancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase (G6PD), exhibit non-immune hemolytic anemia upon exposure to aspirin and various anti-malarial drugs. Inspired by these clinical observations, we examined the anti-cancer potential of combined treatment with 6PGD inhibitors and anti-malarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to anti-malarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel anti-leukemia treatment without inducing hemolysis.