Curcumin Stimulates Reactive Oxygen Species Production and Potentiates Apoptosis Induction by the Antitumour Drugs Arsenic Trioxide and Lonidamine in Human Myeloid Leukaemia Cell Lines

Arsenic trioxide (ATO, Trisenox) is an important anti-leukaemic drug, but its efficacy is frequently low when used as a single agent. We here demonstrate that the apoptotic action of ATO is greatly increased when combined with subcytotoxic curcumin concentrations in U937 and HL60 human acute myeloid leukaemia cells, and with lower efficacy in K562 chronic myelogenous leukaemia cells. Curcumin exerts similar cooperative effect with the mitochondria-targeting drug lonidamine, while the response is negligible in combination with the DNA-targeting drug cisplatin. Curcumin plus ATO or lonidamine stimulates typical events of the mitochondrial executioner pathway (Bax and Bid activation, cytochrome c release, XIAP down-regulation, caspase-9/-3 activation), and causes mitochondrial transmembrane potential dissipation, which nevertheless represents a late event in the apoptotic response. Curcumin increases anion superoxide production, and its pro-apoptotic action in combination with ATO and lonidamine is mimicked by pro-oxidant agents (2-methoxyestradiol, H2O2) and prevented by anti-oxidant agents (MnTBAP, N-acetyl-L-cysteine). Within the assayed time-period (16-24 h), curcumin does not significantly modify p38-MAPK and JNK phosphorylation/activation or NF-κB activity, but greatly stimulates ERK phosphorylation, and decreases Akt phosphorylation. Experiments using MEK/ERK inhibitors (PD98059, U0126) and PI3K inhibitor (LY294002) indicate that ERK activation does not mediate and even restrains apoptosis potentiation, while Akt downregulation facilitates apoptosis generation. In summary, co-treatment with curcumin may represent a useful manner of increasing the efficacy of ATO and lonidamine as anti-tumour drugs in myeloid leukaemia cells. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on July 6, 2010 as DOI: 10.1124/jpet.110.168344 at A PE T Jornals on Jauary 9, 2018 jpet.asjournals.org D ow nladed from