Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Irinotecan is widely used as a chemotherapeutic drug to treat CRC. However, the mechanisms of acquired resistance to irinotecan in CRC remain inconclusive. In the present study, we established a novel irinotecan-resistant human colon cell line to investigate the underlying mechanism(s) of irinotecan resistance, particularly the overexpression of ABC transporters. The irinotecan-resistant S1-IR20 cell line was established by exposing irinotecan to human S1 colon cancer cells. MTT cytotoxicity assay was carried out to determine the drug resistance profile of S1-IR20 cells. The drug-resistant cells showed about 47-fold resistance to irinotecan and cross-resistance to ABCG2 substrates in comparison with S1 cells. By Western blot analysis, S1-IR20 cells showed significant increase of ABCG2, but not ABCB1 or ABCC1 in protein expression level as compared to that of parental S1 cells. The immunofluorescence assay showed that the overexpressed ABCG2 transporter is localized on the cell membrane of S1-IR20 cells, suggesting an active efflux function of the ABCG2 transporter. This finding was further confirmed by reversal studies that inhibiting efflux function of ABCG2 was able to completely abolish drug resistance to irinotecan as well as other ABCG2 substrates in S1-IR20 cells. In conclusion, our work established an in vitro model of irinotecan resistance in CRC and suggested ABCG2 overexpression as one of the underlying mechanisms of acquired resistance to irinotecan. This novel resistant cell line may enable future studies to overcome drug resistance in vitro and improve CRC treatment in vivo.
Highlights
Colorectal cancer (CRC), one of the most common type of malignant tumors, is the third leading cause of cancer-related deaths in the United States and fourth most deadly cancer worldwide [1]
Our results suggested that overexpression of ABCG2 is a key mediator of acquired resistance to irinotecan in CRC; ABCG2 level may be monitored during irinotecan treatment
AIC50 values are represented as mean ± SD of at least three independent experiments performed in triplicate. bResistance fold was calculated by dividing the IC50 values of the resistant S1-IR20 cells by the IC50 of parental S1 cells
Summary
Colorectal cancer (CRC), one of the most common type of malignant tumors, is the third leading cause of cancer-related deaths in the United States and fourth most deadly cancer worldwide [1]. ABCB1, ABCG2, and ABCC1 are able to confer cancer cell MDR to a wide range of anticancer drugs with different chemical structures and mechanisms of action. These ABC transporters, by utilizing energy derived from ATP hydrolysis, extrude substrates from the cytoplasm to the extracellular matrix, resulting in decreased sensitivity of cancer cells to substrate drugs. Our results suggested that overexpression of ABCG2 is a key mediator of acquired resistance to irinotecan in CRC; ABCG2 level may be monitored during irinotecan treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
