TY - JOUR
T1 - Resveratrol blocks interleukin-1β-induced activation of the nuclear transcription factor NF-κB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells
AU - Estrov, Zeev
AU - Shishodia, Shishir
AU - Faderl, Stefan H
AU - Harris, David
AU - Van, Quin
AU - Kantarjian, Hagop M.
AU - Talpaz, Moshe
AU - Aggarwal, Bharat B
PY - 2003/8/1
Y1 - 2003/8/1
N2 - Resveratrol, an edible polyphenolic stilbene, has been reported to possess substantial antileukemic activities in different leukemia cell lines. We investigated whether resveratrol is active against fresh acute myeloid leukemia (AML) cells and its mechanism of action. Because interleukin 1β (IL-1β) plays a key role in proliferation of AML cells, we first tested the effect of resveratrol on the AML cell lines OCIM2 and OCI/AML3, both of which produce IL-1β and proliferate in response to it. Resveratrol inhibited proliferation of both cell lines in a dose-dependent fashion (5-75 μM) by arresting the cells at S phase, thus preventing their progression through the cell cycle; IL-1β partially reversed this inhibitory effect. Resveratrol significantly reduced production of IL-1β in OCIM2 cells. It also suppressed the IL-1β-induced activation of transcription factor nuclear factor κB (NF-κB), which modulates an array of signals controlling cellular survival, proliferation, and cytokine production. Indeed, incubation of OCIM2 cells with resveratrol resulted in apoptotic cell death. Because caspase inhibitors Ac-DEVD-CHO or z-DEVD-FMK partially reversed the antiproliferative effect of resveratrol, we tested its effect on the caspase pathway and found that resveratrol induced the activation of the cysteine protease caspase 3 and subsequent cleavage of the DNA repair enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase. Finally, resveratrol suppressed colony-forming cell proliferation of fresh AML marrow cells from 5 patients with newly diagnosed AML in a dose-dependent fashion. Taken together, our data showing that resveratrol is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.
AB - Resveratrol, an edible polyphenolic stilbene, has been reported to possess substantial antileukemic activities in different leukemia cell lines. We investigated whether resveratrol is active against fresh acute myeloid leukemia (AML) cells and its mechanism of action. Because interleukin 1β (IL-1β) plays a key role in proliferation of AML cells, we first tested the effect of resveratrol on the AML cell lines OCIM2 and OCI/AML3, both of which produce IL-1β and proliferate in response to it. Resveratrol inhibited proliferation of both cell lines in a dose-dependent fashion (5-75 μM) by arresting the cells at S phase, thus preventing their progression through the cell cycle; IL-1β partially reversed this inhibitory effect. Resveratrol significantly reduced production of IL-1β in OCIM2 cells. It also suppressed the IL-1β-induced activation of transcription factor nuclear factor κB (NF-κB), which modulates an array of signals controlling cellular survival, proliferation, and cytokine production. Indeed, incubation of OCIM2 cells with resveratrol resulted in apoptotic cell death. Because caspase inhibitors Ac-DEVD-CHO or z-DEVD-FMK partially reversed the antiproliferative effect of resveratrol, we tested its effect on the caspase pathway and found that resveratrol induced the activation of the cysteine protease caspase 3 and subsequent cleavage of the DNA repair enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase. Finally, resveratrol suppressed colony-forming cell proliferation of fresh AML marrow cells from 5 patients with newly diagnosed AML in a dose-dependent fashion. Taken together, our data showing that resveratrol is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.
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U2 - 10.1182/blood-2002-11-3550
DO - 10.1182/blood-2002-11-3550
M3 - Article
C2 - 12689943
AN - SCOPUS:0042744823
SN - 0006-4971
VL - 102
SP - 987
EP - 995
JO - Blood
JF - Blood
IS - 3
ER -