γ-Tocotrienol suppresses growth and sensitises human colorectal tumours to capecitabine in a nude mouse xenograft model by down-regulating multiple molecules

Abstract

Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide and even develops resistance to chemotherapeutic agents over time. As a result survival for patients with CRC remains poor.Method:We investigated both in vitro and in vivo effects of γ-tocotrienol (γ-T3) alone and in combination with capecitabine. Apoptosis and cytotoxicity assays were performed by MTT and FACS analysis, whereas expression of proteins was investigated using western blotting and immunohistochemistry. Results: The γ-T3 inhibited the proliferation of CRC cells with wild-type or mutated KRAS. It also induced apoptosis, inhibited colony formation, and suppressed key regulators of cell survival, cell proliferation, invasion, angiogenesis, and metastasis. Furthermore, γ-T3 enhanced the anticancer effects of capecitabine in CRC cells. In a nude mouse xenograft model of human CRC, oral administration of γ-T3 inhibited tumour growth and enhanced the antitumour efficacy of capecitabine. Western blot and immunohistochemical analysis results indicated that expression of Ki-67, cyclin D1, MMP-9, CXCR4, NF-κB/p65, and VEGF was lower in tumour tissue from the combination treatment group. Combination treatment also downregulated NF-κB and NF-κB-regulated gene products. Conclusions: Our findings suggest that γ-T3 inhibited the growth of human CRC and sensitised CRC to capecitabine by regulating proteins linked to tumourigenesis.