Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (Nrf2) activation through ERK and PI3K/Akt pathway in colon cancer

Insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) signaling plays an important role in tumor progression in patients with certain gastrointestinal tract cancers. In addition to lowering cholesterol in serum, statins have pleiotropic effects, including anti-oxidative, anti-inflammatory or anti-neoplastic effects. Therefore, the present study investigated whether statins could induce the apoptosis of colon cancer cells and regulate the expression of IGF-1R and its associated signaling pathways in the present study. It was demonstrated that simvastatin and pravastatin suppressed cell proliferation and induced cell death in human HT-29 cells, but simvastatin was more potent than pravastatin. Simvastatin induced apoptosis in a concentration-dependent manner. In addition, simvastatin suppressed the expression of IGF-1R and inhibited the activity of phosphorylated-extracellular signal-regulated kinase (ERK)1/2 and phosphorylated-Akt activated by IGF-1. Simvastatin and IGF-1 each stimulated the activity of phosphorylated ERK1/2. However, simvastatin inhibited cell proliferation and IGF-1 stimulated cell proliferation. Mevalonic acid and PD98059 reversed the ERK activation and apoptosis induced by treatment with simvastatin. It was concluded that simvastatin induces the apoptosis of human colon cancer cells and inhibits IGF-1-induced ERK and Akt expression via the downregulation of IGF-1R expression and proapoptotic ERK activation. Simvastatin may be beneficial for the treatment of colon cancer. The present study suggested that statin may possess therapeutic potential for the treatment of colon cancer.

Background/Aims: Metformin has been found to have antineoplastic activity in some cancer cells. This study was performed to determine whether metformin inhibits the proliferation of bile duct cancer cells by inducing apoptosis and its effects on the expression of gene-related proteins involved in cancer growth.

Statins act as antineoplastic agents through the inhibition of cell proliferation. This study sought to demonstrate the effects of statins on extrahepatic bile duct cancer cell apoptosis and to document the changes in protein expression involved in tumor growth and suppression. Human extrahepatic bile duct cancer cells were cultured. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed to determine the effect of statins on cell proliferation. Apoptosis was measured by a cell death detection enzyme-linked immunosorbent assay and caspase-3 activity assay, and flow cytometry was used to determine the percentage of cells in each phase of the cell cycle. The protein expression of Bax, Bcl-2, insulin-like growth factor 1 (IGF-1) receptor, extracellular signal-regulated kinase 1/2 (ERK1/2), and Akt was measured by Western blot analysis. Simvastatin suppressed cell proliferation by inducing G1 phase cell cycle arrest in bile duct cancer cells. Furthermore, it induced apoptosis via caspase-3 activation, downregulated the expression of the Bcl-2 protein, and enhanced the expression of the Bax protein. Moreover, simvastatin suppressed the expression of the IGF-1 receptor and IGF-1-induced ERK/Akt activation. Simvastatin induces apoptosis in bile duct cancer cells, which suggests that it could be an antineoplastic agent for bile duct cancer.

Preclinical studies have demonstrated that statins have anticancer properties and act in an additive or synergistic way when combined with anticancer therapy. We conducted this meta-analysis of randomized, controlled phase II or III trials to evaluate the effect of statins added to systemic anticancer therapy in patients with solid cancer. A systematic literature search was performed to identify all randomized trials that were designed to investigate the effect of statins in patients with cancer using PubMed, EMBASE, Google Scholar, and Web of Science (up to August 2018). From eight randomized controlled trials, 1760 patients were included in the pooled analyses of odds ratios (ORs) with 95% confidence intervals (CIs) for grade 3–5 adverse events (AEs) and overall response rate (ORR) and hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). The addition of statin to anticancer agents did not significantly increase the incidence of grade 3–5 AEs (OR = 1.03, 95% CI: 0.81–1.29, p = 0.78). However, the combination of statin and anticancer agents did not improve ORR (OR = 0.96, 95% CI: 0.77–1.20, p = 0.72) compared with that of anticancer therapy alone. In addition, statins added to systemic anticancer therapy failed to prolong PFS (HR = 0.99, 95% CI: 0.90–1.10, p = 0.92) and OS (HR = 0.91, 95% CI: 0.76–1.11, p = 0.52). In conclusion, this meta-analysis of randomized controlled trials does not support clinical benefits of statins added to systemic anticancer therapy in patients with solid cancer.

The present study was undertaken to investigate the mechanism of action of brazilin on gluconeogenesis and ketogenesis in isolated rat hepatocytes and to elucidate the hypoglycemic mechanism of brazilin. Brazilin decreased gluconeogenesis at 100 μM in hepatocytes isolated from diabetic rats. Brazilin also decreased basal and glucagon-induced gluconeogenesis in hepatocytes from normal rats. Fatty acids (octanoate or oleate)-induced gluconeogenesis was significantly reduced by brazilin, but ketogenesis was not influenced. The depletion of extracellular or intracellular calcium decreased gluconeogenesis in hepatocytes and brazilin inhibited gluconeogenesis in calcium-depleted media. Brazilin lowered dibutyryl cAMP (Bt2cAMP)-induced gluconeogenesis and the intracellular adenosine 3′,5′-cyclic monophosphate (cAMP) level in glucagon-treated hepatocytes. It was also found that brazilin does not require calcium for inhibition of gluconeogenesis, but may inhibit the down-stream of cAMP signaling pathways. These data suggest that a decreased gluconeogenic flux in hepatocytes might at least partly contribute to the hypoglycemic effects of brazilin. STZ:streptozotocin BSA:bovine serum albumin SD rat:Sprague-Dawley rat i. p.:intraperitoneal EDTA:ethylenediaminetetraacetic acid cAMP:adenosine 3′,5′-cyclic monophosphate Bt2cAMP:dibutyryl cAMP PBS:phosphate buffered saline