Schedule-dependent antitumor effects of 5-fluorouracil combined with sorafenib in hepatocellular carcinoma

Abstract

BackgroundRecently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.MethodsDrug effects on cell proliferation were evaluated by cell viability assays. Combined-effects analyses were conducted according to the median-effect principle. Cell cycle distribution was measured by flow cytometry. Expression levels of proteins related to the RAF/MEK/ERK and STAT3 pathways and to cell cycle progression (cyclin D1) were determined by western blot analysis.ResultsSorafenib and 5-FU alone or in combination showed significant efficacy in inhibiting cell proliferation in both cell lines tested. However, a schedule-dependent combined effect, associated with the order of compound treatments, was observed. Efficacy was synergistic with 5-FU pretreatment followed by sorafenib, but it was antagonistic with the reverse treatment order. Sorafenib pretreatment resulted in a significant increase in the half inhibitory concentration (IC50) of 5-FU in both cell lines. Sorafenib induced G1-phase arrest and significantly decreased the proportion of cells in S phase when administrated alone or followed by 5-FU. The RAF/MEK/ERK and STAT3 pathways were blocked and cyclin D1 expression was down regulated significantly in both cell lines by sorafenib; whereas, the kinase pathways were hardly affected by 5-FU, and cyclin D1 expression was up regulated.ConclusionsAntitumor activity of sorafenib and 5-FU, alone or in combination, is seen in HCC cell lines. The nature of the combined effects, however, depends on the particular cell line and treatment order of the two compounds. Sorafenib appears to reduce sensitivity to 5-FU through down regulation of cyclin D1 expression by inhibiting RAF/MEK/ERK and STAT3 signaling, resulting in G1-phase arrest and reduction of the S-phase cell subpopulation when 5-FU is administrated after sorafenib, in which situation, combination treatment of the two agents results in antagonism; on the other hand, when sorafenib is administrated afterward, it can continue to work since it is not cell cycle specific, as a result, combination treatment of the two agents shows an additive-to-synergistic effect.

A novel red pigment from marineArthrobactersp. G20 with specific anticancer activity

“…All quantitative experiments were repeated at least three times. The data analysis was conducted using GraphPad Prism version 6Á0 and the IC 50 and EC 50 values were obtained from nonlinear regression (Mosaddik et al 2004;Deng et al 2013).…”

Metastatic hepatocellular carcinoma to the pelvis and vertebrae in a patient with chronic hepatitis 'C' with unknown primary

“…According to the latest research, sorafenib has shown promising results in improving the survival of patients with advanced hepatocellular carcinoma; it has also shown remarkable results in combination with 5-fluorouracil in some studies 4. But in our case, we had to resort to the less efficacious option of only using 5-fluorouracil, as the patient could not afford the high cost of Sorafenib 5.…”

Calcitonin Gene-related Peptide Inhibits Tumor Cell Proliferation of Hepatocellular Carcinoma Cells Through the Ras/MEK/ERK Pathway

“…MAPK signaling is critical in HCC tumorigenesis 33) . The anticancer drug 5-fluorouracil combined with the multikinase inhibitor sorafenib inhibits MAPK and STAT3 signaling in HCC cells 34) . Our data showed that CGRP 10 −10 M significantly decreased Ras protein levels.…”