Novel therapeutic strategy combining β-carotene with 5-FU to overcome uL3-mediated chemoresistance in colorectal cancer cells

One of the major obstacles for the clinical use of 5-FU is the acquired multidrug resistance (MDR) that frequently occurs during colorectal cancer (CRC) chemotherapy. Our previous data demonstrated that ribosomal protein uL3 status is strictly associated to 5-FU chemoresistance. Carotenoids have shown the ability to improve cancer cell response to cytotoxic drugs providing a safer choice to defeat MDR. The analysis of a cohort of 594 CRC patients revealed a correlation between uL3 expression and both progression-free survival and response to treatment. uL3 low transcriptional state was found to be associated with increased expression of specific ATP-binding cassette (ABC) genes. By using 2D and 3D models of 5-FU resistant CRC cells deleted and stably silenced for uL3, we investigated the effect of a novel therapeutic strategy by combining β-carotene and 5-FU. Our results demonstrated that the combined treatment induced cell cycle arrest and apoptosis and significantly reduced the expression levels of analyzed ABC genes. In conclusion, this study may provide a more effective therapeutic approach to treat CRCs lacking functional p53 and expressing low levels of uL3.