Show simple item record

dc.contributor.authorLeitch, Calumen_US
dc.contributor.authorOsdal, Terezaen_US
dc.contributor.authorAndresen, Vibekeen_US
dc.contributor.authorMolland, Maren Kristine Butleren_US
dc.contributor.authorKristiansen, Silje Elisabethen_US
dc.contributor.authorNguyen, Nhi Xuanen_US
dc.contributor.authorBruserud, Øysteinen_US
dc.contributor.authorGjertsen, Bjørn Toreen_US
dc.contributor.authorMcCormack, Emmeten_US
dc.PublishedLeitch C, Osdal T, Andresen V, Molland, Kristiansen SE, Nguyen, Bruserud Ø, Gjertsen BT, McCormack E. Hydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemia. OncoTarget. 2016;7(7):8105-8118eng
dc.description.abstractPalliative 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.en_US
dc.publisherImpact Journalseng
dc.rightsAttribution CC BYeng
dc.titleHydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemiaen_US
dc.typePeer reviewed
dc.typeJournal article

Files in this item


This item appears in the following Collection(s)

Show simple item record

Attribution CC BY
Except where otherwise noted, this item's license is described as Attribution CC BY