CD44/CD133-Positive Colorectal Cancer Stem Cells are Sensitive to Trifluridine Exposure

• Published in: Scientific reports Vol. 9; no. 1; pp. 14861 - 8
• Main Authors: Tsunekuni, Kenta, Konno, Masamitsu, Haraguchi, Naotsugu, Koseki, Jun, Asai, Ayumu, Matsuoka, Kazuaki, Kobunai, Takashi, Takechi, Teiji, Doki, Yuichiro, Mori, Masaki, Ishii, Hideshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.10.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/31; 38; 38/77; 5-Fluorouracil; 631/67/1059/99; 631/67/71; AC133 Antigen - genetics; AC133 Antigen - metabolism; Antimetabolites, Antineoplastic - pharmacology; Antiviral drugs; Cancer therapies; CD44 antigen; Cell Line, Tumor; Chemotherapy; Colon - metabolism; Colon - pathology; Colon cancer; Colorectal cancer; Colorectal carcinoma; Drug Combinations; Drug Synergism; Flow cytometry; Fluorouracil - pharmacology; Frontotemporal dementia; Gene Expression; Humanities and Social Sciences; Humans; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Inhibitory Concentration 50; Metastases; multidisciplinary; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Phosphorylation; Pyrrolidines - pharmacology; Science; Science (multidisciplinary); Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Stem cells; Thymidine; Thymidine kinase; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Thymine - pharmacology; Trifluridine - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-50968-6

Cancer stem cells (CSCs) are involved in metastatic colorectal cancer recurrence, but no effective therapy targeting these cells is currently available. Because trifluridine (FTD)/tipiracil therapy is used for refractory colorectal cancer, we sought to determine whether FTD is effective against CSC-like cells. CD44 + CD133 + high-expressing and other populations of human DLD-1 colon cancer cells were separately isolated through fluorescence-activated cell sorting. The sphere-forming activity of each population and the anti-sphere-forming effects of FTD and fluorouracil (5-FU) on CD44 + CD133 + cells were then measured. CD44 + CD133 + DLD-1 cells formed substantially more spheres than other cells. Moreover, treating CD44 + CD133 + DLD-1 cells with subtoxic concentrations of FTD (1 µM) inhibited sphere formation, and this was superior to the effect of subtoxic concentrations (1 µM) of 5-FU. The associated inhibition rates for FTD and 5-FU were 58.2% and 26.1%, respectively. Further, CD44 + CD133 + DLD-1 cells expressed higher levels of thymidine kinase 1, which is responsible for FTD phosphorylation, than DLD-1 cells, and FTD was incorporated into the DNA of CD44 + CD133 + DLD-1 cells. Thus, our data show that FTD treatment is effective against CSC-like cells and might be applied as CSC-targeting chemotherapy for tumor subtypes with high CD44 and CD133 expression.