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

• Type of Material: Article
• Authors: Shannon Elf, Emory University; Ruiting Lin, Emory University; Siyuan Xia, Emory University; Yaozhu Pan, Emory University; Changliang Shan, Emory University; Shaoxiong Wu, Emory University; Sagar Lonial, Emory University; Manila Gaddh, Emory University; Martha Arellano, Emory University; Hanna Khoury, Emory University; Fadlo Khuri, Emory University; Benjamin H. Lee, Novartis Institutes for BioMedical Research; Titus J. Boggon, Yale University; Jun Fan, Emory University; Jing Chen, Emory University
• Language: English
• Date: 2017-01-12
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Macmillan Publishers Limited, part of Springer Nature
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2016.196
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 36
• Issue: 2
• Start Page: 254
• End Page: 262
• Grant/Funding Information: This work was supported in part by NIH grants CA140515, CA183594, CA174786 (J.C.), the Pharmacological Sciences Training Grant T32 GM008602 (S.E.), DoD grant W81XWH- 12-1-0217 (J.C.).
• Keywords: Genetics & Heredity; DEFICIENCY; PROTEIN-KINASE; Biochemistry & Molecular Biology; AMPK; Oncology; ATTACHMENT; Cell Biology; CANCER CELLS; Life Sciences & Biomedicine; Science & Technology; FAMILY
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology

Abstract

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 anticancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase, exhibit non-immune hemolytic anemia upon exposure to aspirin and various antimalarial drugs. Inspired by these clinical observations, we examined the anticancer potential of combined treatment with 6PGD inhibitors and antimalarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to antimalarial 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 antileukemia treatment without inducing hemolysis.