Abstract 1593 PGD as an AMPK-independent target of AICAR for its anti-leukemic effect

AICAr/ acadesine suppresses growth of a broad range of leukemic cells, including drug-resistant ones. However, because of its poor pharmacological properties, AICAr/ acadesine needs further improvements for broadly used in clinical settings. Although AMPK is the best-known target of AICAR, anti-leukemic effects are independent of AMPK. The molecular target of AICAR relevant to its anti-leukemic effects is still unclear. Here we report that 6-phosphogluconate 2-dehydrogenase (PGD), an enzyme in pentose phosphate pathway, is a molecular target of AICAR relevant to the anti-leukemic effect. PGD is inhibited by AICAR/ ZMP in vitro, but AMP did not affect PGD. The level of 6-phosphogluconate is elevated in K562 cells treated with AICAr/ acadesine. A cell-permeable ribulose 5-phosphate or expression of an AICAR-insensitive PGD variant protected K562 cells from AICAr. A PGD inhibitor arrested growth of a broad range of leukemic cells without affecting peripheral mononuclear cells from healthy volunteers. These results indicate that PGD is a molecular target of AICAR relevant to its anti-leukemic effects. Further improvement of PGD inhibitors might generate next-generation of anti-leukemic compounds. This work is supported by an NCI/ NIH grant to Y.S.L. (R01CA168658). J.B.A. was supported in part by College of Medicine, University of Kentucky. This research was also supported by Shared Resource Facilities of the University of Kentucky Lucile P. Markey Comprehensive Cancer Center (P30CA177558).