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Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2018 Apr 06; Vol. 19 (4). Date of Electronic Publication: 2018 Apr 06. - Publication Year :
- 2018
-
Abstract
- Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured owing to the drug resistance. Cancer stem cells are known to regulate resistance to chemotherapy. In the previous study, we established a novel three-dimensional organoid culture model from tumor colorectal tissues of human patients using an air-liquid interface (ALI) method, which contained numerous cancer stem cells and showed resistance to 5-fluorouracil (5-FU) and Irinotecan. Here, we investigate which inhibitor for stem cell-related signal improves the sensitivity for anti-cancer drug treatment in tumor ALI organoids. Treatment with Hedgehog signal inhibitors (AY9944, GANT61) decreases the cell viability of organoids compared with Notch (YO-01027, DAPT) and Wnt (WAV939, Wnt-C59) signal inhibitors. Combination treatment of AY9944 or GANT61 with 5-FU, Irinotecan or Oxaliplatin decreases the cell viability of tumor organoids compared with each anti-cancer drug alone treatment. Treatment with AY9944 or GANT61 inhibits expression of stem cell markers c-Myc, CD44 and Nanog, likely through the decrease of their transcription factor, GLI-1 expression. Combination treatment of AY9944 or GANT61 with 5-FU or Irinotecan also prevents colony formation of colorectal cancer cell lines HCT116 and SW480. These findings suggest that Hedgehog signals mediate anti-cancer drug resistance in colorectal tumor patient-derived ALI organoids and that the inhibitors are useful as a combinational therapeutic strategy against colorectal cancer.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Camptothecin analogs & derivatives
Camptothecin pharmacology
Fluorouracil pharmacology
HCT116 Cells
Humans
Hyaluronan Receptors genetics
Hyaluronan Receptors metabolism
Irinotecan
Neoplastic Stem Cells drug effects
Organoplatinum Compounds pharmacology
Oxaliplatin
Proto-Oncogene Proteins c-myc genetics
Proto-Oncogene Proteins c-myc metabolism
Pyridines pharmacology
Pyrimidines pharmacology
Zinc Finger Protein GLI1 genetics
Zinc Finger Protein GLI1 metabolism
trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride pharmacology
Colorectal Neoplasms metabolism
Drug Resistance, Neoplasm
Hedgehog Proteins antagonists & inhibitors
Organoids drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 19
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 29642386
- Full Text :
- https://doi.org/10.3390/ijms19041098