The anti-leukaemic activity of novel synthetic naphthoquinones against acute myeloid leukaemia: Induction of cell death via the triggering of multiple signalling pathways

Maher Hallak, Thida Win, Ofer Shpilberg, Shmuel Bittner, Yosef Granot, Ittai Levy, Ilana Nathan

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 2O 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.

Original languageEnglish
Pages (from-to)459-470
Number of pages12
JournalBritish Journal of Haematology
Volume147
Issue number4
DOIs
StatePublished - 1 Nov 2009

Keywords

  • Apoptosis
  • Mitochondria
  • Mitogen-activated protein kinases
  • Reactive oxygen species
  • TW-92

ASJC Scopus subject areas

  • Hematology

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