Hydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemia
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Calum Leitch1,2, Tereza Osdal1, Vibeke Andresen1,2, Maren Molland1, Silje Kristiansen1, Xuan Nhi Nguyen1, Øystein Bruserud1,3, Bjørn Tore Gjertsen1,2,3, Emmet McCormack1,3
1Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway
2Centre of Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, N-5021 Norway
3Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, N-5021 Norway
Emmet McCormack, e-mail: [email protected]
Keywords: valproic acid, hydroxyurea, AML, DNA damage, p53
Received: August 10, 2015 Accepted: January 01, 2016 Published: January 23, 2016
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.
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