Augmentation of 1-β-d-Arabinofuranosylcytosine (Ara-C) cytotoxicity in leukaemia cells by co-administration with antisignalling drugs

摘要: Abstract The ribonucleotide reductase inhibitors hydroxyurea (HU), arabinosyl-2-fluoroadenine (F-Ara-A) and 2-chlorodeoxyadenosine (2-CdA) the antisignalling drugs all- trans retinoic acid (ATRA), staurosporine quercetin have been reported to enhance cytotoxicity of 1-β-d-arabinofuranosylcytosine (ara-C). We tested hypothesis that ara-C-sensitising potency agents is equipotent with inhibitors. cytotoxicity, determined by 3-(4,5 dimethylthiazol-2-y1-)5 diphenyltetrazolium bromide (MTT) assay, combinations ara-C named above was compared in leukaemia cell lines HL-60, ara-C-resistant HL-60 (HL-60/ara-C) U937. Furthermore, a range protein tyrosine kinase inhibitors, genistein, CGP 52411, tyrphostin A48 nordihydroguaiaretic (NDGA), for which ara-C-sensitisation has hitherto not described, were included study. All three types acquired increased sensitivity when co-incubated HU or ATRA, but their affected genistein. 2-CdA, A48, NDGA active as sensitisers against cells, 52411 also HL-60/ara-C U937 cells. F-Ara-A toxicity To address mechanism observed sensitisation, influence properties on ara-C-induced apoptosis investigated cells measured shrinkage, DNA loss fragmentation. HU, augmented induced assessed all indicators. decreased effect apoptotic indicators after incubation 4h, 12h. results suggest may be suitable alternatives clinically applied modifiers treatment acute myeloid leukaemia.