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Title

Curcumin stimulates reactive oxygen species production and potentiates apoptosis induction by the antitumor drugs arsenic trioxide and lonidamine in human myeloid leukemia cell lines.

AuthorsSánchez, Yolanda ; Simón, Gloria P. ; Calviño, Eva ; Blas, Elena de ; Aller, Patricio
KeywordsApoptosis
Arsenic trioxide
Curcumin
Lonidamine
Myeloid leukaemia cells
Reactive oxygen species
Human acute myeloid leukemia
Issue DateOct-2010
PublisherAmerican Society for Pharmacology and Experimental Therapeutics
CitationJournal of Pharmacology and Experimental Therapeutics 335(1):114-123(2010)
AbstractArsenic trioxide (ATO, Trisenox) is an important antileukemic drug, but its efficacy is frequently low when used as a single agent. Here, we demonstrate that the apoptotic action of ATO is greatly increased when combined with subcytotoxic curcumin concentrations in U937 and HL60 human acute myeloid leukemia cells, and with lower efficacy in K562 chronic myelogenous leukemia cells. Curcumin exerts similar cooperative effect with the mitochondria-targeting drug lonidamine, whereas 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, X-linked inhibitor of apoptosis down-regulation, and 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 proapoptotic action in combination with ATO and lonidamine is mimicked by pro-oxidant agents (2-methoxyestradiol and H(2)O(2)) and prevented by antioxidant agents [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride and N-acetyl-l-cysteine]. Within the assayed time period (16-24 h), curcumin does not significantly modify p38-mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase phosphorylation/activation or nuclear factor-κB activity, but it greatly stimulates extracellular signal-regulated kinase (ERK) phosphorylation, and decreases Akt phosphorylation. Experiments using mitogen-activated protein kinase kinase/ERK inhibitors [2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126)] and phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) indicate that ERK activation does not mediate and even restrains apoptosis potentiation, whereas Akt down-regulation facilitates apoptosis generation. In summary, cotreatment with curcumin may represent a useful manner of increasing the efficacy of ATO and lonidamine as antitumor drugs in myeloid leukemia cells.
DescriptionArticle, publication date, citation information and the supplementary material can be found at online version of this article, available at: http://jpet.aspetjournals.org doi:10.1124/jpet.110.168344
Publisher version (URL)http://dx.doi.org/10.1124/jpet.110.168344
http://jpet.aspetjournals.org/content/335/1/114.full
URIhttp://hdl.handle.net/10261/42228
DOI10.1124/jpet.110.168344
ISSN0022-3565
E-ISSN1521-0103
Appears in Collections:(CIB) Artículos
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