Parthenolide Sensitizes Human Colorectal Cancer Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand through Mitochondrial and Caspase Dependent Pathway.
- Author:
Kieu Thi Thu TRANG
1
;
Se Lim KIM
;
Sang Bae PARK
;
Seung Young SEO
;
Chung Hwan CHOI
;
Jin Kyoung PARK
;
Jin Chang MOON
;
Soo Teik LEE
;
Sang Wook KIM
Author Information
- Publication Type:Original Article
- Keywords: Parthenolide; TRAIL; Colorectal neoplasm; TRAIL resistance; Apoptosis
- MeSH: Annexin A5; Antineoplastic Agents; Apoptosis; Bisbenzimidazole; Blotting, Western; Caspases; Cell Cycle; Cell Death; Colorectal Neoplasms*; Cytochromes c; Cytosol; HCT116 Cells; HT29 Cells; Humans*; Lymphoma, B-Cell; Necrosis*; Tumor Necrosis Factor-alpha
- From:Intestinal Research 2014;12(1):34-41
- CountryRepublic of Korea
- Language:English
- Abstract: BACKGROUND/AIMS: Combination therapy utilizing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in conjunction with other anticancer agents, is a promising strategy to overcome TRAIL resistance in malignant cells. Recently, parthenolide (PT) has proved to be a promising anticancer agent, and several studies have explored its use in combination therapy. Here, we investigated the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. METHODS: HT-29 cells (TRAIL-resistant) were treated with PT and/or TRAIL for 24 hours. The inhibitory effect on proliferation was detected using the 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Annexin V staining, cell cycle analysis, and Hoechst 33258 staining were used to assess apoptotic cell death. Activation of an apoptotic pathway was confirmed by Western blot. RESULTS: Treatment with TRAIL alone inhibited the proliferation of HCT 116 cells in a dose-dependent manner, whereas proliferation was not affected in HT-29 cells. Combination PT and TRAIL treatment significantly inhibited cell growth and induced apoptosis of HT-29 cells. We observed that the synergistic effect was associated with misregulation of B-cell lymphoma 2 (Bcl-2) family members, release of cytochrome C to the cytosol, activation of caspases, and increased levels of p53. CONCLUSION: Combination therapy using PT and TRAIL might offer an effetive strategy to overcome TRAIL resistance in certain CRC cells.
