Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins.
Whether garcinol, the active component of Garcinia indica, can modulate the sensitivity of cancer cells to TRAIL, a cytokine currently in phase II clinical trial, was investigated. We found that garcinol potentiated TRAIL-induced apoptosis of cancer cells as indicated by intracellular esterase activity, DNA strand breaks, accumulation of the membrane phospholipid phosphatidylserine, mitochondrial activity, and activation of caspase-8, -9, and -3. We found that garcinol, independent of the cell type, induced both of the TRAIL receptors, death receptor 4 (DR4) and DR5. Garcinol neither induced the receptors on normal cells nor sensitized them to TRAIL. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and garcinol. In addition, garcinol downregulated various cell survival proteins including survivin, bcl-2, XIAP, and cFLIP, and induced bid cleavage, bax, and cytochrome c release. Induction of death receptors by garcinol was found to be independent of modulation of CCAAT/enhancer-binding protein-homologous protein, p53, bax, extracellular signal-regulated kinase, or c-Jun-NH(2)-kinase. The effect of garcinol was mediated through the generation of reactive oxygen species, in as much as induction of both death receptors, modulation of antiapoptotic and proapoptotic proteins, and potentiation of TRAIL-induced apoptosis were abolished by N-acetyl cysteine and glutathione. Interestingly, garcinol also converted TRAIL-resistant cells into TRAIL-sensitive cells. Overall, our results indicate that garcinol can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of antiapoptotic proteins. Mol Cancer Ther; 9(4); 856-68. (c)2010 AACR.
Prasad
Sahdeo
S
Houston, TX, 77030, USA.
Ravindran
Jayaraj
J
Sung
Bokyung
B
Pandey
Manoj K
MK
Aggarwal
Bharat B
BB
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D013729:Terpenes; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D020928:Mitogen-Activated Protein Kinases; C054597:garcinol; D000111:Acetylcysteine