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The anti‐leukaemic activity of novel synthetic naphthoquinones against acute myeloid leukaemia: induction of cell death via the triggering of multiple signalling pathways
Author(s) -
Hallak Maher,
Win Thida,
Shpilberg Ofer,
Bittner Shmuel,
Granot Yosef,
Levy Itai,
Nathan Ilana
Publication year - 2009
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2009.07867.x
Subject(s) - apoptosis , mitochondrion , p38 mitogen activated protein kinases , cytochrome c , programmed cell death , kinase , biology , protein kinase a , intracellular , mapk/erk pathway , microbiology and biotechnology , biochemistry , chemistry
Summary 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.