Distinct combinatorial effects of the plant polyphenols curcumin, carnosic acid, and silibinin on proliferation and apoptosis in acute myeloid leukemia cells

Stella Pesakhov, Marina Khanin, George P. Studzinski, Michael Danilenko

    Research output: Contribution to journalArticlepeer-review

    61 Scopus citations

    Abstract

    Acute myeloid leukemia (AML) is a malignancy without effective treatment for most patients. Here we demonstrate that combinations of the dietary plant polyphenolscurcumin and carnosic acidat noncytotoxic concentrations of each agent, produced a synergistic antiproliferative effect and a massive apoptotic cell death in HL-60 and KG-1a human AML cells. In contrast, combinations of curcumin and another plant polyphenol silibinin had a predominantly additive cytostatic effect, without pronounced cytotoxicity. Neither polyphenol combination affected viability of normal human fibroblasts or proliferating and nonproliferating blood cells. Early stage of curcumin/carnosic acid-induced apoptosis was associated with cleavage (activation) of caspase-8, caspase-9, and caspase-3 and the proapoptotic protein Bid, but not with oxidative stress or altered levels of other Bcl-2 family proteins (Bcl-2, Bcl-xl, Mcl-1, Bax, and Bak). Inhibitors of caspase-8 and caspase-9 markedly attenuated apoptosis, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. Caspase-8 inhibition abrogated Bid cleavage and strongly reduced caspase-9 activation, suggesting that the cross-talk mechanism mediated by caspase-8-dependent Bid cleavage can contribute to the activation of the intrinsic apoptotic pathway by curcumin + carnosic acid. Collectively, these results suggest a mechanistic basis for the potential use of dietary plant polyphenol combinations in the treatment and prevention of AML.

    Original languageEnglish
    Pages (from-to)811-824
    Number of pages14
    JournalNutrition and Cancer
    Volume62
    Issue number6
    DOIs
    StatePublished - 1 Aug 2010

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