The anti-leukaemic activity of novel synthetic naphthoquinones against acute myeloid leukaemia: induction of cell death via the triggering of multiple signalling pathways.
ABSTRACT Naphthoquinones, such as menadione, display lower toxicity than anthracyclins used in cancer chemotherapy. Novel anti-leukaemic compounds comprised of chloro-amino-phenyl naphthoquinones with substitutions on the benzoic ring were developed. Structure-activity relationship studies indicated that the analogue with both methyl and amine substitutions (named TW-92) was the most efficient in killing leukaemic cells. Treatment of U-937 promonocytic cells with TW-92 induced apoptotic or necrotic cell death, dependent on incubation and dose conditions. TW-92 induced rapid phosphorylation of p38 mitogen-activated protein kinase (p38(MAPK)) and of extracellular signal-regulated protein kinases (ERK1/2). The generation of apoptosis was preceded by intracellular H(2)O(2) accumulation accompanied by glutathione depletion, the former inhibited by di-phenyl-iodonium (DPI), an inhibitor of NADPH oxidase. TW-92 induced swelling of isolated rat liver mitochondria, indicative of a direct effect on mitochondria. Apoptosis in intact cells was accompanied by a decrease in mitochondrial membrane potential, cytochrome c release and caspase activation. In addition, the level of Mcl-1, an anti-apoptotic regulatory protein, was down-regulated, whereas the expression of the pro-apoptotic BAX was elevated. Finally, TW-92 exerted strong pro-apoptotic and necrotic effects in primary acute myeloid leukaemia samples when given in submicromolar concentrations. Together, these findings demonstrate that TW-92 may provide an effective anti-leukaemic strategy.
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ABSTRACT: In the title compound, C(18)H(21)ClN(2)O(4), the mol-ecular sytructure is stabilized by two intra-molecular N-H⋯O hydrogen bonds. In the crystal, mol-ecules are linked by pairs of C-H⋯O hydrogen bonds, forming inversion dimers with graph-set motif R(2) (2)(10). N-H⋯O hydrogen bonds further link the dimers into C(10) chains along .Acta Crystallographica Section E Structure Reports Online 08/2012; 68(Pt 8):o2361. · 0.35 Impact Factor
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ABSTRACT: ABSTRACT Mantle cell lymphoma (MCL) characterized by the t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression, is one of the most challenging lymphomas to treat. Iron chelators, like deferasirox, have previously been shown to exhibit anti-proliferative properties; however, their effect on MCL cells has never been investigated. We showed that deferasirox exhibited antitumoral activity against the MCL cell lines; HBL-2, Granta-519 and Jeko-1, with IC(50) values of 7.99±2.46μM, 8.93±2.25μM and 31.86±7.26μM, respectively. deferasirox induced apoptosis mediated through caspase-3 activation and decreased cyclin D1 protein levels resulting from increased proteasomal degradation. We also demonstrated downregulation of phosphor-Rb (Ser780) expression which resulted in increasing levels of the E2F/Rb complex and G(1)/S arrest. Finally, we showed that deferasirox activity was dependent on its iron chelating ability. The present data indicate that deferasirox, by downregulating cyclin D1 and inhibiting its related signals, may constitute a promising adjuvant therapeutic molecule in the strategy for MCL treatment.Leukemia & lymphoma 09/2012; · 2.61 Impact Factor
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ABSTRACT: Dimeric naphthoquinones (BiQ) were originally synthesized as a new class of HIV integrase inhibitors but have shown integrase-independent cytotoxicity in acute lymphoblastic leukemia cell lines suggesting their use as potential anti-neoplastic agents. The mechanism of this cytotoxicity is unknown. In order to gain insight into the mode of action of binaphthoquinones we performed a systematic high-throughput screen in a yeast isogenic deletion mutant array for enhanced or suppressed growth in the presence of binaphthoquinones. Exposure of wild type yeast strains to various BiQs demonstrated inhibition of yeast growth with IC(50)s in the microM range. Drug sensitivity and resistance screens were performed by exposing arrays of a haploid yeast deletion mutant library to BiQs at concentrations near their IC(50). Sensitivity screens identified yeast with deletions affecting mitochondrial function and cellular respiration as having increased sensitivity to BiQs. Corresponding to this, wild type yeast grown in the absence of a fermentable carbon source were particularly sensitive to BiQs, and treatment with BiQs was shown to disrupt the mitochondrial membrane potential and lead to the generation of reactive oxygen species (ROS). Furthermore, baseline ROS production in BiQ sensitive mutant strains was increased compared to wild type and could be further augmented by the presence of BiQ. Screens for resistance to BiQ action identified the mitochondrial external NAD(P)H dehydrogenase, NDE1, as critical to BiQ toxicity and over-expression of this gene resulted in increased ROS production and increased sensitivity of wild type yeast to BiQ. In yeast, binaphthoquinone cytotoxicity is likely mediated through NAD(P)H:quonine oxidoreductases leading to ROS production and dysfunctional mitochondria. Further studies are required to validate this mechanism in mammalian cells.PLoS ONE 01/2010; 5(5):e10846. · 3.73 Impact Factor