title: Hydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemia.
abstract: Palliative care in acute myeloid leukaemia (AML) is inadequate. For elderly patients, unfit for intensive chemotherapy, median survival is 2-3 months. As such, there is urgent demand for low-toxic palliative alternatives. We have repositioned two commonly administered anti-leukaemia drugs, valproic acid (VPA) and hydroxyurea (HU), as a combination therapy in AML. The anti-leukemic effect of VPA and HU was assessed in multiple AML cell lines confirming the superior anti-leukemic effect of combination therapy. Mechanistic studies revealed that VPA amplified the ability of HU to slow S-phase progression and this correlated with significantly increased DNA damage. VPA was also shown to reduce expression of the DNA repair protein, Rad51. Interestingly, the tumour suppressor protein p53 was revealed to mitigate cell cycle recovery following combination induced arrest. The efficacy of combination therapy was validated in vivo. Combination treatment increased survival in OCI-AML3 and patient-derived xenograft mouse models of AML. Therapy response was confirmed by optical imaging with multiplexed near-infrared labelled antibodies. The combination of HU and VPA indicates significant potential in preclinical models of AML. Both compounds are widely available and well tolerated. We believe that repositioning this combination could significantly enhance the palliative care of patients unsuited to intensive chemotherapy.
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.|Centre of Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.
authors.forename: Calum
authors.initials: C
authors.lastname: Leitch
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.
authors.forename: Tereza
authors.initials: T
authors.lastname: Osdal
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.|Centre of Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Andresen
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.
authors.forename: Maren
authors.initials: M
authors.lastname: Molland
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.
authors.forename: Silje
authors.initials: S
authors.lastname: Kristiansen
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.
authors.forename: Xuan Nhi
authors.initials: XN
authors.lastname: Nguyen
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.|Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, N-5021 Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.|Centre of Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.|Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, N-5021 Norway.
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway.|Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, N-5021 Norway.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014635:Valproic Acid / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014635:Valproic Acid; D006918:Hydroxyurea
keywords: AML; DNA damage; hydroxyurea; p53; valproic acid
references.citation: EMBO J. 2001 Dec 17;20(24):6969-78
references.pmid: 11742974
references.citation: J Cancer Res Ther. 2012 Oct-Dec;8(4):510-9
references.pmid: 23361267
references.citation: EMBO J. 2001 Jul 16;20(14):3861-70
references.pmid: 11447127
references.citation: Mol Cell. 2010 Feb 26;37(4):492-502
references.pmid: 20188668
references.citation: Clin Cancer Res. 2010 Apr 15;16(8):2344-51
references.pmid: 20371688
references.citation: Blood. 2012 Nov 22;120(22):4304-10; quiz 4448
references.pmid: 22915643
references.citation: Nature. 2015 Feb 26;518(7540):552-5
references.pmid: 25487151
references.citation: Cleve Clin J Med. 2004 Aug;71(8):633-7
references.pmid: 15449758
references.citation: Curr Opin Oncol. 2012 Nov;24(6):711-9
references.pmid: 23014187
references.citation: Anticancer Res. 2012 Jul;32(7):2791-9
references.pmid: 22753739
references.citation: PLoS One. 2012;7(11):e48992
references.pmid: 23155442
references.citation: Hematology. 2010 Oct;15(5):338-43
references.pmid: 20863429
references.citation: Leukemia. 2006 Jul;20(7):1307-10
references.pmid: 16617320
references.citation: J Clin Oncol. 2012 Jul 20;30(21):2670-7
references.pmid: 22689805
references.citation: BMC Health Serv Res. 2012 Oct 16;12:359
references.pmid: 23066848
references.citation: Blood. 2013 Feb 14;121(7):e34-42
references.pmid: 23243270
references.citation: Nat Rev Drug Discov. 2005 Jan;4(1):71-8
references.pmid: 15688074
references.citation: Br J Haematol. 2011 Mar;152(5):524-42
references.pmid: 21314823
references.citation: Clin Epigenetics. 2013 Jul 30;5(1):12
references.pmid: 23898968
references.citation: Adv Enzyme Regul. 1984;22:27-55
references.pmid: 6382953
references.citation: Oncogene. 2008 Jan 31;27(6):732-40
references.pmid: 17653085
references.citation: Int J Oncol. 2012 Jun;40(6):2140-6
references.pmid: 22469995
references.citation: Semin Oncol. 1992 Jun;19(3 Suppl 9):1-10
references.pmid: 1641648
references.citation: PLoS One. 2010 Dec 14;5(12 ):e14335
references.pmid: 21179472
references.citation: Anticancer Res. 2011 Jun;31(6):2231-9
references.pmid: 21737646
references.citation: Cell Stem Cell. 2014 Oct 2;15(4):431-46
references.pmid: 25280219
references.citation: DNA Repair (Amst). 2008 May 3;7(5):686-93
references.pmid: 18243065
references.citation: Hematology Am Soc Hematol Educ Program. 2012;2012:1-6
references.pmid: 23233553
references.citation: PLoS One. 2010 Jun 18;5(6):e11208
references.pmid: 20585447
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19482-7
references.pmid: 18042714
references.citation: Oncotarget. 2012 Jan;3(1):31-43
references.pmid: 22289787
references.citation: Haematologica. 2005 Jul;90(7):986-8
references.pmid: 15996941
references.citation: Blood. 2014 Jun 26;123(26):4027-36
references.pmid: 24797300
references.citation: Nature. 2011 Mar 3;471(7336):74-9
references.pmid: 21368826
references.citation: Blood. 2004 Sep 1;104(5):1266-9
references.pmid: 15155466
references.citation: Leukemia. 2012 May;26(5):910-7
references.pmid: 22064349
references.citation: Leuk Res. 2009 Jun;33(6):779-87
references.pmid: 19007987
references.citation: J Neurooncol. 2007 Nov;85(2):159-70
references.pmid: 17534580
references.citation: Br J Cancer. 2013 Mar 5;108(4):748-54
references.pmid: 23361058
references.citation: Nat Struct Mol Biol. 2007 Nov;14(11):1096-104
references.pmid: 17934473
references.citation: Cancer. 2006 Jan 1;106(1):112-9
references.pmid: 16323176