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01-09-2019 | Acute Myeloid Leukemia | Original Paper

A novel alkylating deacetylase inhibitor molecule EDO-S101 in combination with cytarabine synergistically enhances apoptosis of acute myeloid leukemia cells

Authors: Jingrui Jin, Shihui Mao, Fenglin Li, Xia Li, Xin Huang, Mengxia Yu, Wenjian Guo, Jie Jin

Published in: Medical Oncology | Issue 9/2019

Abstract

Acute myeloid leukemia (AML) is a devastating disease. Hybrid agents with dual activity, which have been shown to possess anti-cancer effect, are expected to potentially improve the prognosis of AML patients. EDO-S101 is a novel alkylating deacetylase inhibitor molecule synthesized by the addition of the hydroxamic acid of histone deacetylases inhibitor vorinostat into bendamustine, a DNA-damaging agent. However, the effect of EDO-S101 in combination with traditional chemotherapy drugs has not been studied in AML. In this study, we investigated the effect of EDO-S101 in combination with cytarabine in treating AML cells. The synergic activity against AML was identified by remarkable reduction of cell viability, significant apoptosis enhancement and the upregulation of the cleaved PARP, Casepase-3 and -7 proteins compared with monotherapy. To explain the drivers, we detected the DNA damage pathway including DNA double-strand breaks marker γ-H2AX and DNA damage checkpoint proteins, which was supposed to be responsible for the enhanced apoptosis activity. In summary, our data demonstrated that EDO-S101 in combination with cytarabine could synergistically induce the apoptosis of AML cells and it might be a potential regimen for treating leukemia.

Assi SA, Imperato MR, Coleman DJL, Pickin A, Potluri S, Ptasinska A, et al. Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nat Genet. 2018;51(1):151–62. https://doi.org/10.1038/s41588-018-0270-1.CrossRefPubMedPubMedCentral

Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA: a cancer journal for clinicians. 2016;66(4):271–89. https://doi.org/10.3322/caac.21349.CrossRef

Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361(13):1249–59. https://doi.org/10.1056/NEJMoa0904544.CrossRefPubMedPubMedCentral

Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet. 2013;381(9865):484–95. https://doi.org/10.1016/S0140-6736(12)61727-9.CrossRefPubMed

Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–74. https://doi.org/10.1182/blood-2009-07-235358.CrossRefPubMed

Wei AH, Tiong IS. Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML. Blood. 2017;130(23):2469–74. https://doi.org/10.1182/blood-2017-08-784066.CrossRefPubMed

Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487–94. https://doi.org/10.1200/JCO.2010.30.1820.CrossRefPubMed

Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89. https://doi.org/10.1056/NEJMoa1112304.CrossRefPubMedPubMedCentral

Jurcic JG. Highlights in hematologic malignancy treatments: leukemia, myelodysplastic syndromes, and allotransplant-new drugs on the horizon for acute myeloid leukemia. JAMA Oncol. 2017;3(3):299–300. https://doi.org/10.1001/jamaoncol.2016.3928.CrossRefPubMed

10.

Stiborova M, Eckschlager T, Poljakova J, Hrabeta J, Adam V, Kizek R, et al. The synergistic effects of DNA-targeted chemotherapeutics and histone deacetylase inhibitors as therapeutic strategies for cancer treatment. Curr Med Chem. 2012;19(25):4218–38.CrossRef

11.

Balfour JA, Goa KL. Bendamustine. Drugs. 2001;61(5):631–8. https://doi.org/10.2165/00003495-200161050-00009 (Discussion 9–40).CrossRefPubMed

12.

Blumel S, Goodrich A, Martin C, Dang NH. Bendamustine: a novel cytotoxic agent for hematologic malignancies. Clin J Oncol Nurs. 2008;12(5):799–806. https://doi.org/10.1188/08.CJON.799-806.CrossRefPubMed

13.

Hoy SM. Bendamustine: a review of its use in the management of chronic lymphocytic leukaemia, rituximab-refractory indolent non-Hodgkin’s lymphoma and multiple myeloma. Drugs. 2012;72(14):1929–50. https://doi.org/10.2165/11209510-000000000-00000.CrossRefPubMed

14.

Grant S, Easley C, Kirkpatrick P. Vorinostat. Nat Rev Drug Discov. 2007;6(1):21–2. https://doi.org/10.1038/nrd2227.CrossRefPubMed

15.

Qiu Y, Li Z, Copland JA, Mehrling T, Tun HW. Combined alkylation and histone deacetylase inhibition with EDO-S101 has significant therapeutic activity against brain tumors in preclinical models. Oncotarget. 2018;9(46):28155–64. https://doi.org/10.18632/oncotarget.25588.CrossRefPubMedPubMedCentral

16.

Festuccia C, Mancini A, Colapietro A, Gravina GL, Vitale F, Marampon F, et al. The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma. J Hematol Oncol. 2018;11(1):32. https://doi.org/10.1186/s13045-018-0576-6.CrossRefPubMedPubMedCentral

17.

Yu J, Qiu S, Ge Q, Wang Y, Wei H, Guo D, et al. A novel SAHA-bendamustine hybrid induces apoptosis of leukemia cells. Oncotarget. 2015;6(24):20121–31. https://doi.org/10.18632/oncotarget.4041.CrossRefPubMedPubMedCentral

18.

Lopez-Iglesias AA, Herrero AB, Chesi M, San-Segundo L, Gonzalez-Mendez L, Hernandez-Garcia S, et al. Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair. J Hematol Oncol. 2017;10(1):127. https://doi.org/10.1186/s13045-017-0495-y.CrossRefPubMedPubMedCentral

19.

Besse L, Kraus M, Besse A, Bader J, Silzle T, Mehrling T, et al. The first-in-class alkylating HDAC inhibitor EDO-S101 is highly synergistic with proteasome inhibition against multiple myeloma through activation of multiple pathways. Blood Cancer J. 2017;7(7):e589. https://doi.org/10.1038/bcj.2017.69.CrossRefPubMedPubMedCentral

20.

Mehrling T, Chen Y. The alkylating-HDAC inhibition fusion principle: taking chemotherapy to the next level with the first in class molecule EDO-S101. Anticancer Agents Med Chem. 2016;16(1):20–8.CrossRef

21.

Grant S. Ara-C: cellular and molecular pharmacology. Adv Cancer Res. 1998;72:197–233.CrossRef

22.

Di Tullio A, Rouault-Pierre K, Abarrategi A, Mian S, Grey W, Gribben J, et al. The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia. Nat Commun. 2017;8(1):1679. https://doi.org/10.1038/s41467-017-01834-4.CrossRefPubMedPubMedCentral

23.

Veuger MJ, Heemskerk MH, Honders MW, Willemze R, Barge RM. Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells. Blood. 2002;99(4):1373–80.CrossRef

24.

M’Kacher R, Frenzel M, Al Jawhari M, Junker S, Cuceu C, Morat L, et al. Establishment and characterization of a reliable xenograft model of hodgkin lymphoma suitable for the study of tumor origin and the design of new therapies. Cancers. 2018;10(11):E414. https://doi.org/10.3390/cancers10110414.CrossRefPubMed

25.

Koczian F, Naglo O, Vomacka J, Vick B, Servatius P, Zisis T, et al. Targeting the ER-mitochondria interface sensitizes leukemia cells towards cytostatics. Haematologica. 2018;104(3):546–55. https://doi.org/10.3324/haematol.2018.197368.CrossRefPubMed

26.

Testa U, Riccioni R. Deregulation of apoptosis in acute myeloid leukemia. Haematologica. 2007;92(1):81–94.CrossRef

27.

Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res. 1993;53(17):3976–85.PubMed

28.

Yang C, Boyson CA, Di Liberto M, Huang X, Hannah J, Dorn DC, et al. CDK4/6 Inhibitor PD 0332991 sensitizes acute myeloid leukemia to cytarabine-mediated cytotoxicity. Cancer Res. 2015;75(9):1838–45. https://doi.org/10.1158/0008-5472.CAN-14-2486.CrossRefPubMedPubMedCentral

29.

Wolach O, Itchaki G, Bar-Natan M, Yeshurun M, Ram R, Herscovici C, et al. High-dose cytarabine as salvage therapy for relapsed or refractory acute myeloid leukemia—is more better or more of the same? Hematol Oncol. 2016;34(1):28–35. https://doi.org/10.1002/hon.2191.CrossRefPubMed

30.

Marks PA, Rifkind RA, Richon VM, Breslow R. Inhibitors of histone deacetylase are potentially effective anticancer agents. Clin Cancer Res. 2001;7(4):759–60.PubMed

31.

Feng R, Oton A, Mapara MY, Anderson G, Belani C, Lentzsch S. The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage. Br J Haematol. 2007;139(3):385–97. https://doi.org/10.1111/j.1365-2141.2007.06772.x.CrossRefPubMed

32.

Camphausen K, Burgan W, Cerra M, Oswald KA, Trepel JB, Lee MJ, et al. Enhanced radiation-induced cell killing and prolongation of gammaH2AX foci expression by the histone deacetylase inhibitor MS-275. Cancer Res. 2004;64(1):316–21.CrossRef

33.

Munshi A, Kurland JF, Nishikawa T, Tanaka T, Hobbs ML, Tucker SL, et al. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res. 2005;11(13):4912–22. https://doi.org/10.1158/1078-0432.CCR-04-2088.CrossRefPubMed

34.

Major PP, Egan EM, Beardsley GP, Minden MD, Kufe DW. Lethality of human myeloblasts correlates with the incorporation of arabinofuranosylcytosine into DNA. Proc Natl Acad Sci USA. 1981;78(5):3235–9.CrossRef

35.

Roos WP, Thomas AD, Kaina B. DNA damage and the balance between survival and death in cancer biology. Nat Rev Cancer. 2016;16(1):20–33. https://doi.org/10.1038/nrc.2015.2.CrossRefPubMed

36.

Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol. 2000;10(15):886–95.CrossRef

37.

Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, et al. DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol. 2002;4(12):993–7. https://doi.org/10.1038/ncb884.CrossRefPubMed

38.

Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003;300(5625):1542–8. https://doi.org/10.1126/science.1083430.CrossRefPubMed

39.

Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature. 2000;408(6811):433–9. https://doi.org/10.1038/35044005.CrossRef

40.

Chen Y, Poon RY. The multiple checkpoint functions of CHK1 and CHK2 in maintenance of genome stability. Front Biosci. 2008;13:5016–29.PubMed

41.

Lopez-Girona A, Tanaka K, Chen XB, Baber BA, McGowan CH, Russell P. Serine-345 is required for Rad3-dependent phosphorylation and function of checkpoint kinase Chk1 in fission yeast. Proc Natl Acad Sci USA. 2001;98(20):11289–94. https://doi.org/10.1073/pnas.191557598.CrossRefPubMed

42.

O’Neill T, Giarratani L, Chen P, Iyer L, Lee CH, Bobiak M, et al. Determination of substrate motifs for human Chk1 and hCds1/Chk2 by the oriented peptide library approach. J Biol Chem. 2002;277(18):16102–15. https://doi.org/10.1074/jbc.M111705200.CrossRefPubMed

Title: A novel alkylating deacetylase inhibitor molecule EDO-S101 in combination with cytarabine synergistically enhances apoptosis of acute myeloid leukemia cells
Authors: Jingrui Jin
Shihui Mao
Fenglin Li
Xia Li
Xin Huang
Mengxia Yu
Wenjian Guo
Jie Jin
Publication date: 01-09-2019
Publisher: Springer US
Keyword: Acute Myeloid Leukemia
Published in: Medical Oncology / Issue 9/2019
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-019-1302-0

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A novel alkylating deacetylase inhibitor molecule EDO-S101 in combination with cytarabine synergistically enhances apoptosis of acute myeloid leukemia cells

Abstract

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