title: Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl.
abstract: Pharmacologically safe compounds that can inhibit the proliferation of tumor cells have potential as anticancer agents. Curcumin, a diferuloylmethane, is a major active component of the food flavor turmeric (Curcuma longa) that has been shown to inhibit the proliferation of a wide variety of tumor cells. The apoptotic intermediates through which curcumin exhibits its cytotoxic effects against tumor cells are not known, and the participation of antiapoptotic proteins Bcl-2 or Bcl-xl in the curcumin-induced apoptosis pathway is not established. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human acute myelogenous leukemia HL-60 cells and in established stable cell lines expressing Bcl-2 and Bcl-xl. Curcumin inhibited the growth of HL-60 cells (neo) in a dose- and time-dependent manner, whereas Bcl-2 and Bcl-xl-transfected cells were relatively resistant. Curcumin activated caspase-8 and caspase-3 in HL-60 neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Similarly, time-dependent poly(ADP)ribose polymerase (PARP) cleavage by curcumin was observed in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Curcumin treatment also induced BID cleavage and mitochondrial cytochrome c release in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. In neo HL-60 cells, curcumin also downregulated the expression of cyclooxygenase-2. Because DN-FLICE blocked curcumin-induced apoptosis, caspase-8 must play a critical role. Overall, our results indicate that curcumin induces apoptosis through mitochondrial pathway involving caspase-8, BID cleavage, cytochrome c release, and caspase-3 activation. Our results also suggest that Bcl-2 and Bcl-xl are critical negative regulators of curcumin-induced apoptosis.
authors.affiliation: Cytokine Research Section, Department of Bioimmunotherapy, Box 143, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Ruby John
authors.initials: RJ
authors.lastname: Anto
authors.forename: Asok
authors.initials: A
authors.lastname: Mukhopadhyay
authors.forename: Kate
authors.initials: K
authors.lastname: Denning
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D003474:Curcumin / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D003574:Cytochrome c Group / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D053200:Fas-Associated Death Domain Protein; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D019169:Jurkat Cells; D008565:Membrane Proteins; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D003574:Cytochrome c Group; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D007527:Isoenzymes; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003474:Curcumin