Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1

Sally-Anne Heasman 1 , Lyubov Zaitseva 1 , Kristian M. Bowles 2 , Stuart A. Rushworth 1 and David J. MacEwan 1 1 School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK 2 Department 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 Correspondence: David MacEwan, email: // // Abstract 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.