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

Oncogene volume 36, pages 254–262 (2017)Cite this article

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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.

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Acknowledgements

We thank the Hematology Division Tissue Bank, Winship Cancer Institute of Emory for providing primary tissue samples from leukemia patients. This work was supported in part by NIH grants CA140515, CA183594, CA174786 (to JC), the Pharmacological Sciences Training Grant T32 GM008602 (to SE), DoD grant W81XWH-12-1-0217 (to JC). SE is an NIH pre-doctoral fellow and an ARCS Foundation Scholar. JC is WCI 5K Scholar, Georgia Cancer Coalition Distinguished Scholar, American Cancer Society Basic Research Scholar and Scholar of the Leukemia and Lymphoma Society.

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Author notes

  1. S Elf and R Lin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA, USA

    S Elf, R Lin, S Xia, Y Pan, C Shan, S Lonial, M Gaddh, M L Arellano, H J Khoury, F R Khuri, J Fan & J Chen

  2. Department of Chemistry, Emory University School of Medicine, Atlanta, GA, USA

    S Wu

  3. Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    B H Lee

  4. Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA

    T J Boggon

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  1. S Elf
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Correspondence to J Chen.

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Elf, S., Lin, R., Xia, S. et al. Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin. Oncogene 36, 254–262 (2017). https://doi.org/10.1038/onc.2016.196

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  • DOI: https://doi.org/10.1038/onc.2016.196

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