Combinatorial effect of epigallocatechin-3-gallate and TRAIL on pancreatic cancer cell death.
Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea, can exert growth suppressive effect on human pancreatic cancer cells by evoking apoptotic response. EGCG-induced apoptosis of pancreatic cancer cells is accompanied by growth arrest at an earlier phase of cell cycle along with depolarization of mitochondrial membrane. In this report, using MIA PaCa-2 cells as in vitro model, we demonstrate EGCG-induced cell death involves activation of caspase-8 and disappearance of intact 21 kDa Bid protein. Furthermore, exogenous expression of dominant negative caspase-8 or dominant negative FADD significantly abrogates apoptosis inducing ability of EGCG in MIA PaCa-2 cells. RNase protection assay revealed upregulation of the members of death receptor family, thus indicating the involvement of transmembrane extrinsic signaling in this polyphenol triggered pancreatic carcinoma cell death. Based on this, we examined the effect of EGCG and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) together on pancreatic cancer cells. A synergistic increase in apoptosis and cleavage of procaspase-3 was noted. Furthermore, clonogenic cell survival assay demonstrates the significant diminishment of MIA PaCa-2 cell proliferation in the presence of both EGCG and TRAIL. This combination treatment strategy has potential therapeutic advantage for pancreatic carcinoma.
Basu
Aruna
A
Center for Biomedical Sciences, Department of Pharmacology, Case Comphrehensive Cancer Center, MetroHealth Medical Center, OH 44109, USA. abasu@metrohealth.org
Haldar
Subrata
S
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology; D012260:Ribonucleases / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
D016588:Anticarcinogenic Agents; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D011480:Protease Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D002392:Catechin; C045651:epigallocatechin gallate; D012260:Ribonucleases; D053181:Caspase 8; D053453:Caspase 9