title: Distinct combinatorial effects of the plant polyphenols curcumin, carnosic acid, and silibinin on proliferation and apoptosis in acute myeloid leukemia cells.
abstract: Acute myeloid leukemia (AML) is a malignancy without effective treatment for most patients. Here we demonstrate that combinations of the dietary plant polyphenols--curcumin and carnosic acid--at 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.
authors.affiliation: Department of Clinical Biochemistry, Faculty of Health Science, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Stella
authors.initials: S
authors.lastname: Pesakhov
authors.forename: Marina
authors.initials: M
authors.lastname: Khanin
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
authors.forename: Michael
authors.initials: M
authors.lastname: Danilenko
mesh_terms: D045784:Abietanes / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage* / Q000494:pharmacology; D004359:Drug Therapy, Combination; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000008:administration & dosage* / Q000494:pharmacology; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D045784:Abietanes; D009842:Oligopeptides; D010936:Plant Extracts; D012838:Silymarin; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D000077385:Silybin; D020169:Caspases; D003474:Curcumin; C018381:salvin