Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1
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1School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
2Department of Haematology, Norfolk and Norwich University Hospital NHS Trust, Colney Lane, Norwich, NR4 7UY United Kingdom
Received: September 2, 2011; Accepted: September 6, 2011; Published: September 9, 2011;
Keywords: drug-resistance, antioxidant, transcription factor, apoptosis, chemotherapy, MicroRNA
David MacEwan, email:
Haem oxygenase-1 (HO-1) is increasingly regarded as a pro-tumoral target in the treatment of human cancers. Currently, little is known about HO-1 and its role in human acute myeloid leukaemia (AML) to regulate apoptosis in response to chemotherapy. Recently, we showed that HO-1 protects AML samples from tumour necrosis factor-α (TNF)-induced apoptosis - it being regulated by transcription factors Nrf2, NF-ĸB and AP-1. This study aims to analyse the role of HO-1 in regulating apoptosis in AML cells in response to two front-line chemotherapeutic agents used for AML, cytarabine and daunorubicin. Here we show that HO-1 expression in AML samples was increased in response to both cytarabine and daunorubicin treatment, and micro RNA (miRNA) silenced HO-1 expression in combination with either daunorubicin or cytarabine induced a greater apoptotic responses in AML cells. Moreover, we showed that both daunorubicin and cytarabine induced reactive oxygen species (ROS) accumulation to induce apoptosis in AML. However, ROS-dependent induction of HO-1 was limiting the apoptotic response that is seen in AML towards cytarabine and daunorubicin treatment. These findings suggest concurrent inhibition of HO-1 expression in conjunction with chemotherapeutic treatment would improve the number of cases who reach complete remission.
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