Page 82 - 2018_09-Mondo

D. Wu et al.
cell line PC3.40 Isobavachalcone has been reported to inhibit AKT1 kinase in a dose-dependent manner in vitro with an IC50 value of 32.90 μM.39 However, the anti-can- cer properties and mechanisms of isobavachalcone are not fully understood. As described in this paper, we iden- tified isobavachalcone as a potent, direct human DHODH inhibitor, and systematically validated it by, for example, enzymatic and isothermal titration calorimetry assays, thermal shift, and NMR. To the best of our knowl- edge, this is the first report of isobavachalcone’s potent differentiation-inducing activity in AML and anti- leukemic effect in mouse xenograft models. However, other potential off-target effects caused by isobavachal- cone in AML cells remain to be determined in the future. Taken together, these results provide compelling evidence of isobavachalcone’s potent anti-leukemia activity by interfering with the biosynthetic pathway of pyrimidine nucleotides through suppression of DHODH catalytic activity.
Several major breakthroughs have been made recently in the diagnosis and therapy of AML; however resistance is still a daunting barrier.9,23 It was reported that known DHODH inhibitors, leflunomide and A771726 can increase the sensitivity of cells to adriamycin in triple- negative breast cancer.41 However, the biological conse- quences and clinical benefits of these agents in AML remain unclear. In this study, we demonstrated that the combination of the DHODH inhibitor isobavachalcone and adriamycin effectively suppressed the growth of AML cells and prolonged survival in xenograft models of AML without obvious toxicity, offering a promising ther- apeutic strategy for AML. The detailed molecular mecha- nism of the synergistic effect of this combination of drugs remains to be studied further. For example, PTEN is a well-known tumor suppressor gene and loss of PTEN is associated with chemoresistance in multiple types of can- cers.42 Recently, Deepti et al. revealed that PTEN-deficient
cancers are heavily dependent on an intact pathway for de novo pyrimidine synthesis, which makes such tumors vul- nerable to DHODH inhibition.43 Thus, dual targeting of DHODH and mTOR/AKT may offer a strategy for fur- ther overcoming chemoresistance in AML patients with PTENalterations.
In summary, we demonstrated that isobavachalcone triggers apoptosis and differentiation of AML cells via pharmacological inhibition of human DHODH, laying the groundwork for future AML treatment strategies. Importantly, administration of isobavachalcone enhanced the anti-cancer efficiency of adriamycin in a xenograft model of human AML. The comprehensive preclinical findings presented here suggest that isobavachalcone is a potential therapeutic agent for AML with a novel molec- ular mechanism, and that further development of the drug for use in the clinic is warranted.
Acknowledgments
Funds: this work was supported by the National Natural Science Foundation of China (81773775), Shanghai Committee of Science and Technology (15431902000), and State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University, CMEMR2017-B01). This work was also supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K99HL138272 to FC. The project was funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was also supported [in part] by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.
References
1. Khwaja A, Bjorkholm M, Gale RE, et al. Acute myeloid leukaemia. Nat Rev Dis Primers. 2016;2:16010.
2. Siegel RL, Miller KD, Jemal A. Cancer statis- tics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
3. Roboz GJ. Current treatment of acute myeloid leukemia. Curr Opin Oncol.
2012;24(6):711-719.
4. Tallman MS, Gilliland DG, Rowe JM. Drug
therapy for acute myeloid leukemia. Blood.
2005;106(4):1154-1163.
5. Pollyea DA, Gutman JA, Gore L, Smith CA,
Jordan CT. Targeting acute myeloid leukemia stem cells: a review and principles for the development of clinical trials. Haematologica. 2014;99(8):1277-1284.
6. Wei AH, Tiong IS. Midostaurin, enasidenib, CPX-351, gemtuzumab ozogomycin and venetoclax bring new hope to AML. Blood. 2017;130(23):2469-2474.
7. Buckley SA, Kirtane K, Walter RB, Lee SJ, Lyman GH. Patient-reported outcomes in acute myeloid leukemia: where are we now? Blood Rev. 2018;32(1):81-87.
8. Kadia TM, Ravandi F, Cortes J, Kantarjian H.
Toward individualized therapy in acute myeloid leukemia: a contemporary review. JAMA Oncol. 2015;1(6):820-828.
9. Kavanagh S, Murphy T, Law A, et al. Emerging therapies for acute myeloid leukemia: translating biology into the clinic. JCI Insight. 2017;2(18). pii: 95679.
10. Diao Y, Lu W, Jin H, et al. Discovery of diverse human dihydroorotate dehydroge- nase inhibitors as immunosuppressive agents by structure-based virtual screening. J Med Chem. 2012;55(19):8341-8349.
11. Liu S, Neidhardt EA, Grossman TH, Ocain T, Clardy J. Structures of human dihydroorotate dehydrogenase in complex with antiprolifer- ative agents. Structure. 2000;8 (1):25-33.
12. Löffler M, Fairbanks LD, Zameitat E, Marinaki AM, Simmonds HA. Pyrimidine pathways in health and disease. Trends Mol Med. 2005;11(9):430-437.
13. Janzer A, Sykes D, Gradl S, et al. Abstract 3086: Inhibitors of the enzyme dihydrooro- tate dehydrogenase, overcome the differen- tiation blockade in acute myeloid leukemia. Cancer Res. 2017;77(13):3086-3086.
14. Sykes D, Kfoury Y, Mercier F, et al. Inhibition of dihydroorotate dehydrogenase overcomes
differentiation blockade in acute myeloid
leukemia. Cell. 2016;167(1):171-186.
15. Rd BH, Raymond E, Awada A, et al. Pharmacokinetic and phase I studies of bre- quinar (DUP 785; NSC 368390) in combina- tion with cisplatin in patients with advanced malignancies. Invest New Drug. 1998;16(1):
19-27.
16. Pally C, Smith D, Jaffee B, et al. Side effects
of brequinar and brequinar analogues, in combination with cyclosporine, in the rat. Toxicology. 1998;127(1-3):207-222.
17. Wang J, Hu K, Guo J, et al. Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK. Nat Commun. 2016;7:11363.
18. Lu W, Cheng F, Yan W, et al. Selective target- ing p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA. Oncogene. 2017;31(10):4719-4731.
19. Fiskus W, Sharma S, Shah B, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2014;28(11):2155-2164.
20. Metzeler KH, Hummel M, Bloomfield CD, et al. An 86-probe-set gene-expression signa-
1482
haematologica | 2018; 103(9)