title: Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1.
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.
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, UK.
authors.forename: Sally-Anne
authors.initials: SA
authors.lastname: Heasman
authors.forename: Lyubov
authors.initials: L
authors.lastname: Zaitseva
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Bowles
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Rushworth
authors.forename: David J
authors.initials: DJ
authors.lastname: Macewan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology*; D003630:Daunorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D003561:Cytarabine; D051547:Heme Oxygenase-1; D003630:Daunorubicin