RT Journal Article
SR Electronic
T1 Investigation into Enhancing Capecitabine Efficacy in Colorectal Cancer by Inhibiting Focal Adhesion Kinase Signaling
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 4667
OP 4676
DO 10.21873/anticanres.12772
VO 38
IS 8
A1 JAE JUN SIM
A1 MIN HEE PARK
A1 JEONG-HEUM BAEK
A1 HAEJUN LEE
A1 KEUN-YEONG JEONG
A1 HWAN MOOK KIM
YR 2018
UL http://ar.iiarjournals.org/content/38/8/4667.abstract
AB Background/Aim: Capecitabine is a pro-drug of 5-fluorouracil (5-FU), and is an orally available chemotherapeutic used to treat colorectal cancer (CRC). Recently, research has focused on improving its efficacy at lower doses in order to minimize its well-known toxicities. In this study, we investigated the possibility of improving the antitumor effect of capecitabine against CRC by destabilizing focal adhesion kinase (FAK) signaling. Materials and Methods: Optimal dosages for capecitabine and lactate calcium salt (LCS) were determined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide MTT assay. The viability of CRC cells was investigated by MTT and clonogenic assays after single or combination treatment with capecitabine and LCS. Western blot analyses were used to determine changes in the expression of components of the FAK and AKT signaling cascade, and this information was used to elucidate the underlying mechanism. A xenograft model was established to evaluate the antitumor efficacy of the combination treatment, as well as its necrotic effect and organ toxicity. Results: The addition of LCS to capecitabine treatment led to an increase in the proteolysis of the FAK signaling cascade components, including SRC proto-oncogene, non-receptor tyrosine kinase; AKT serine/threonine kinase 1; and nuclear factor-kappa B, resulting in a decrease in the viability and clonogenic ability of CRC cells. In vivo antitumor efficacy, including tumor necrosis, was significantly increased with the combination treatment relative to both single treatments, and no organ toxicity was found in any experimental group. Conclusion: The addition of LCS increased the anticancer efficacy of capecitabine at a lower dose than is currently used in human patients.