Resveratrol blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells.

Abstract

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 1beta(IL-1beta) 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-1beta and proliferate in response to it. Resveratrol inhibited proliferation of both cell lines in a dose-dependent fashion (5-75 microM) by arresting the cells at S phase, thus preventing their progression through the cell cycle; IL-1beta partially reversed this inhibitory effect. Resveratrol significantly reduced production of IL-1beta in OCIM2 cells. It also suppressed the IL-1beta-induced activation of transcription factor nuclear factor kappaB (NF-kappaB), 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.

• Authors: Zeev Estrov, Shishir Shishodia, Stefan Faderl, David Harris, Quin Van, Hagop M Kantarjian, Moshe Talpaz, Bharat B Aggarwal
• Journal: Blood (Blood) Vol. 102 Issue 3 Pg. 987-95 (Aug 01 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12689943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents, Phytogenic
• Interleukin-1
• NF-kappa B
• Stilbenes
• Resveratrol

Topics

• Acute Disease
• Aged
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Bone Marrow (drug effects, pathology)
• Cell Division (drug effects)
• Female
• Humans
• Interleukin-1 (antagonists & inhibitors, biosynthesis)
• Leukemia, Myeloid (pathology)
• Male
• Middle Aged
• NF-kappa B (antagonists & inhibitors, metabolism)
• Resveratrol
• S Phase (drug effects)
• Stilbenes (pharmacology)
• Tumor Cells, Cultured