plastochromanol-8 and Colorectal-Neoplasms

Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30-60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Catechols; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chromans; Colorectal Neoplasms; DNA Repair; Fatty Alcohols; Forkhead Box Protein M1; Gene Expression Profiling; Humans; Signal Transduction; Tocotrienols; Vitamin E; Wnt Signaling Pathway

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.. 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.. 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.. Our findings suggest that γ-T3 inhibited the growth of human CRC and sensitised CRC to capecitabine by regulating proteins linked to tumourigenesis.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Apoptosis; Capecitabine; Cell Line, Tumor; Cell Proliferation; Chromans; Colorectal Neoplasms; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Male; Mice; Mice, Nude; Mutation; Neoplasm Proteins; NF-kappa B; Tumor Stem Cell Assay; Vitamin E; Xenograft Model Antitumor Assays