Abstract
Colorectal cancer (CRC) is a highly lethal malignant cancer. Capecitabine, a 5-fluororacil (5-FU) derivate, is its first-line drug, but the resistance of CRC to capecitabine is still the most challenging factor for curing patients. It has been suggested that thymidylate synthase (TYMS) level might affect the capecitabine efficacy in CRC patients, but the mechanism still needs more elucidation. Obesity is a risk factor for CRC. Recently, a correlation between serum visfatin, an obesity-elicited adipokine, and CRC development has been found. Thus, the aim of present study is to examine the visfatin capacity in TYMS expression and in the development of capecitabine resistance of CRC. Moreover, an attractive natural component, i.e., resveratrol, has been proposed in anticancer therapy and has hence been examined in the present study to see its potential capacity in the alleviation of CRC resistance. Our results found that visfatin significantly reduces the CRC sensitivity to capecitabine by controlling the TYMS expression via p38 signaling and Sp1 transcription factor. Moreover, resveratrol could significantly alleviate the visfatin effect on capecitabine-treated CRC cells. These results provided new insights to understand the capecitabine susceptibility of CRC under a visfatin-containing environment and a possible therapeutic application of resveratrol in CRC patients with obesity.
Highlights
Colorectal cancer (CRC) has already been one of the commonest diagnosed and lethal malignant cancer types [1,2]
Our results present several important respects: (1) Expression of thymidylate synthase (TYMS) in CRC cells could be induced while visfatin treatment and this induction could decrease the cytotoxicity of capecitabine in human DLD-1 CRC cells. (2) p38 signaling and Sp1 transcription factor controlled the visfatin effect on TYMS expression and subsequent capecitabine-induced cell death. (3)
We showed that visfatin-induced TYMS expression, which results in decreased sensitivity to capecitabine-induced cytotoxicity, might be a significant contributor to the occurrence of resistance in CRC cells
Summary
Colorectal cancer (CRC) has already been one of the commonest diagnosed and lethal malignant cancer types [1,2]. In the past several decades, because of the advance of theranostic drugs, tools, and instruments and the promotion of early CRC screening, the therapeutic and preventive efficacy of CRC has been adequately improved. It has been indicated that the incidence of CRC is still high and, even more, the age of patients suffering from CRC seems to be annually lowered [1,2]. The therapeutic strategy for CRC includes the single and combined treatment of chemotherapy, radiotherapy, and/or surgery. The biggest challenge for CRC therapy and further mortality improvement is the occurrence of resistance. Capecitabine is a fluoropyrimidines carbamate derivate, which is a prodrug and could be converted to the 5-fluororacil (5-FU)
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