title: Parthenolide enhances sensitivity of colorectal cancer cells to TRAIL by inducing death receptor 5 and promotes TRAIL-induced apoptosis.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human TRAIL has been evaluated in clinical trials, however, various malignant tumors are resistant to TRAIL. Parthenolide (PT) has recently been demonstrated as a highly effective anticancer agent and has been suggested to be used for combination therapy with other anticancer agents. In this study, we investigate the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. HT-29 (TRAIL-resistant) and HCT116 (TRAIL-sensitive) cells were treated with PT and/or TRAIL. The results demonstrated that combined treatment induced apoptosis which was determined using MTT, cell cycle analysis, Annexin V assay and Hoechst 33258 staining. Interestingly, we confirmed that HCT116 cells have much higher death receptor (DR) 5 than HT-29 cells and PT upregulates DR5 protein level and surface expression in both cell lines. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, p53 cytochrome C release, and caspase cascades. These results suggest that PT sensitizes TRAIL-induced apoptosis via upregulation of DR5 and mitochondria-dependent pathway. Combination treatment using PT and TRAIL may offer an effective strategy to overcome TRAIL resistance of certain CRC cells.
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Se-Lim
authors.initials: SL
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Yu-Chuan
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Young Ran
authors.initials: YR
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Seung Young
authors.initials: SY
authors.lastname: Seo
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Seong Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: In Hee
authors.initials: IH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Seung Ok
authors.initials: SO
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Soo Teik
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Dae-Ghon
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D012717:Sesquiterpenes; D053221:TNF-Related Apoptosis-Inducing Ligand; C002669:parthenolide