Genistein selectively potentiates arsenic trioxide-induced apoptosis in human leukemia cells via reactive oxygen species generation and activation of reactive oxygen species-inducible protein kinases (p38-MAPK, AMPK)

✍ Scribed by Yolanda Sánchez; Donna Amrán; Carlos Fernández; Elena de Blas; Patricio Aller

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: French
• Weight: 626 KB
• Volume: 123
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.23639

✦ Synopsis

Abstract

The observation that genistein may behave as a pro‐oxidant agent lead us to examine the capacity of this isoflavone to modulate the toxicity of the oxidation‐sensitive anti‐leukemic agent arsenic trioxide (ATO), and for comparison other anti‐tumor drugs. Co‐treatment with genistein increased ATO‐provoked apoptosis and activated apoptosis regulatory events (Bcl‐X~L~ down‐regulation, cytochrome c and Omi/HtrA2 release from mitochondria, XIAP decrease and caspase‐8/Bid and caspase‐3 activation) in U937 promonocytes and other human leukemia cell lines (HL60, THP‐1, Jurkat, RPMI‐8866), but not in phytohemagglutinin‐stimulated non‐tumor peripheral blood lymphocytes (PBLs). Genistein, alone and with ATO, stimulated reactive oxygen species generation, and apoptosis was attenuated by N‐acetyl‐L‐cysteine and butylated hydroxyanisole. Addition of low H~2~O~2~ concentrations mimicked the capacity of genistein to increase ATO‐provoked apoptosis in leukemia cells, but not in PBLs. By contrast, co‐treatment with genistein or H~2~O~2~ failed to potentiate the toxicity of DNA‐targeting agent cisplatin, the proteasome inhibitor MG‐132 and the histone deacetylase inhibitor MS‐275. Within the here used time‐period (14 hr) genistein, alone or with ATO, did not significantly affect Akt phosphorylation and NF‐κB binding activity, nor decreased intracellular GSH content. However, it elicited N‐acetyl‐L‐cysteine‐inhibitable phosphorylation of p38‐MAPK and AMPK, and apoptosis was attenuated by pharmacologic inhibitors against these kinases. The pro‐oxidant capacity of genistein might be exploited to improve the efficacy of ATO as anti‐leukemic agent, and perhaps the efficacy of other oxidation‐based therapeutic approaches. © 2008 Wiley‐Liss, Inc.