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

Abstract

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.

• Authors: Kenta Tsunekuni, Masamitsu Konno, Naotsugu Haraguchi, Jun Koseki, Ayumu Asai, Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi, Yuichiro Doki, Masaki Mori, Hideshi Ishii
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 14861 (10 16 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31619711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AC133 Antigen
• Antimetabolites, Antineoplastic
• CD44 protein, human
• Drug Combinations
• Hyaluronan Receptors
• PROM1 protein, human
• Pyrrolidines
• Thymidine Kinase
• thymidine kinase 1
• tipiracil
• Thymine
• Trifluridine
• Fluorouracil

Topics

• AC133 Antigen (genetics, metabolism)
• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Colon (metabolism, pathology)
• Drug Combinations
• Drug Synergism
• Fluorouracil (pharmacology)
• Gene Expression
• Humans
• Hyaluronan Receptors (genetics, metabolism)
• Inhibitory Concentration 50
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Pyrrolidines (pharmacology)
• Spheroids, Cellular (drug effects, metabolism, pathology)
• Thymidine Kinase (genetics, metabolism)
• Thymine (pharmacology)
• Trifluridine (pharmacology)