Naringenin-induced apoptosis via activation of NF-kappaB and necrosis involving the loss of ATP in human promyeloleukemia HL-60 cells.
Naringenin (NGEN), a flavonoid, has shown cytotoxicity in various human cancer cell lines and inhibitory effects on tumor growth. In this study, we investigated the apoptosis induced by NGEN via the activation of NF-kappaB and necrosis involving the loss of ATP in human promyeloleukemia HL-60 cells. Exposure to NGEN induced apoptosis dose-dependently up until 0.5mM, but not at 1mM as demonstrated by a quantitative analysis of nuclear morphological change and flow cytometric analysis. An extensive inhibitor for caspases, abolished the NGEN-induced apoptosis. The apoptosis-triggering concentration of NGEN was shown to markedly promote the activation of caspase-3, and slightly promote that of caspase-9, but had no effect on caspase-8. NGEN-induced apoptosis caused by induction of specific NF-kappaB-binding activity and involving the degradation of IkappaBalpha. Incubation with a high concentration of NGEN (1mM) reduced intracellular ATP levels, but no change was observed at lower concentrations. NGEN increased dose-dependently hyperpolarization of mitochondrial membrane potential. This result indicates a common pathway to apoptosis and necrosis by NGEN. One of the mechanisms by NGEN-induced apoptosis may relate to the activation of NF-kappaB that correlates with degradation of IkappaBalpha. Induction of necrosis by NGEN suggests causing by intracellular ATP depletion and mitochondria dysfunctions.
Kanno
Syu-Ichi
S
Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. syu-kan@tohoku-pharm.ac.jp
Tomizawa
Ayako
A
Ohtake
Takaharu
T
Koiwai
Kimiko
K
Ujibe
Mayuko
M
Ishikawa
Masaaki
M
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D044950:Flavanones / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009336:Necrosis / Q000188:drug therapy*
D000972:Antineoplastic Agents, Phytogenic; D044950:Flavanones; D016328:NF-kappa B; D000255:Adenosine Triphosphate; D020169:Caspases; C005273:naringenin