Triptolide sensitizes resistant cholangiocarcinoma cells to TRAIL-induced apoptosis.
BACKGROUND
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) promotes apoptosis by binding to transmembrane receptors. It is known to induce apoptosis in a wide variety of cancer cells, but TRAIL-resistant cancers have also been documented. In this study, the relative resistance of human cholangiocarcinoma (CCA) cell lines against TRAIL-induced apoptosis is reported and the possible potential synergistic effect with triptolide, a diterpene triepoxide extracted from the Chinese herb Tripterygium wilfordii, in killing TRAIL-resistant CCA cells is investigated.


METHODS
Six human CCA cell lines were treated with various concentrations of TRAIL and the resistant cells were identified and subsequently tested for their sensitivity to a combination of TRAIL and triptolide. The susceptibility and resistance of the cells were based on analysis of cytotoxic and apoptotic induction and expression of anti-apoptotic factors (Mcl-1 and cFLIP).


RESULTS
The treatment of TRAIL induced a dose-dependent decrease in cell viability in 4 out of the 6 cell lines. A combination of TRAIL and triptolide enhanced cytotoxicity and apoptosis in these 2 resistant cell lines. The combined treatment enhanced activation of caspase-8 and its downstream signaling processes compared with the treatment with either one alone.


CONCLUSIONS
The results presented show that human CCA cells were heterogeneous with respect to susceptibility to TRAIL-induced apoptosis. The combination of TRAIL and triptolide could enhance susceptibility to TRAIL-induced apoptotic killing in these TRAIL-resistant CCA cells, thus offering an alternative approach for the treatment of TRAIL-resistant cholangiocarcinoma.
Panichakul
Tasanee
T
Laboratory of Immunology, Chulabhom Research Institute, Bangkok, Thailand. tasanee_p@yahoo.com
Intachote
Pakamas
P
Wongkajorsilp
Adisak
A
Sripa
Banchob
B
Sirisinha
Stitaya
S
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004852:Epoxy Compounds; D006801:Humans; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D010616:Phenanthrenes / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D010616:Phenanthrenes; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C001899:triptolide; D019950:Mitogen-Activated Protein Kinase 1; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases