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Background: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. Method: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. Result: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. Conclusions: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer. [ABSTRACT FROM AUTHOR]

Background: Activation of Ras oncogene in human tumors is associated with radiation-associated metastatic potential. Although ionizing radiation is one important method of cancer treatments, it has been shown to enhance matrix metalloproteinases (MMPs) activity and facilitates a more aggressive cancer phenotype. Our previous studies showed that andrographolide with lower dose rates of radiation could inhibit RAS-transformed cancer metastasis in vivo; however, the molecular mechanisms are not yet clear. In this study, we aimed to explore the anti-metastatic effect of andrographolide combined with radiation on Ras-transformed cells. Methods: RAS-transformed cells were treated with andrographolide in the presence or absence of irradiation (2–4 Gy) or angiotensin II to examine cell invasion. In vivo tumorigenesis assays were also performed. The MMP-2 activity was detected by using Gelatin zymography. Signal transduction of NF-κB subunit, p65 and phosphor-ERK 1/2, were examined by using Western blotting analysis. Results: Treatment with andrographolide inhibited migration of Ras-transformed cells. Andrographolide treatment with radiation significantly inhibited cancer metastasis in vivo. We found that andrographolide exhibited anti-migration and anti-invasive ability against cancer metastasis via inhibition of MMP2 activity rather than affected MMP-9 and EMT. In addition, combined andrographolide with radiation appeared to be more effective in reducing MMP-2 expression, and this effect was accompanied by suppression of ERK activation that inhibits cancer cell migration and invasion. Conclusions: These findings suggest that andrographolide enhances the anti-metastatic effect of radiation in Ras-transformed cells via suppression of ERK–mediated MMP-2 activity. [ABSTRACT FROM AUTHOR]

Prunella vulgaris (PV) is a traditional Chinese medicine that has been used clinically for centuries in Asian countries to treat herpetic keratitis. In previous studies, PV was shown to suppress TPA-induced activation of MMP-9 and inhibit cell invasion and migration in hepatoma cell lines. However, the detailed molecular mechanism underlying these effects is still unclear. In this study, we investigated the mechanisms underlying PV-mediated inhibition of 12- O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (Huh-7 and HA22T). PV suppressed VEGF and MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-B (NF-B) activity. PV suppressed TPA-induced AP-1 activity by inhibiting phosphorylation of the extracellular signal-related kinase (ERK), downregulating p38 signaling pathways, and suppressing TPA-induced inhibition of NF-B nuclear translocation through IB. PV suppressed TPA-induced activation of ERK/phosphatidylinositol-3-kinase/Akt upstream of NF-B and AP-1. These data suggest that PV modifies the metastatic microenvironment of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways. PV thus may have the therapeutic potential to inhibit the migration and invasion of HCC and act as potential agent for systemic therapies. [ABSTRACT FROM AUTHOR]

We hypothesized that sorafenib plus transarterial chemoembolization (TACE) would confer survival benefits over sorafenib alone for advanced hepatocellular carcinoma (aHCC). We investigated this while using the population-based All-Cancer Dataset to assemble a cohort (n = 3674; median age, 60; 83% men) of patients receiving sorafenib for aHCC (Child-Pugh A) with macro-vascular invasion or nodal/distant metastases. The patients were classified into the sorafenib-TACE group (n = 426) or the propensity score-matched sorafenib-alone group (n = 1686). All of the participants were followed up until death or the end of the study. Time-dependent Cox model and the Mantel–Byar test were used for survival analysis. During the median follow-ups of 221 and 133 days for the sorafenib-TACE and sorafenib-alone groups, 164 (39%) and 916 (54%) deaths occurred, respectively; the corresponding median overall survivals (OS) were 381 and 204 days, respectively (hazard ratio, HR: 0.74; 95% confidence interval, CI, 0.63–0.88; p = 0.021). The one-year and six-month OS were 53.5% and 80.3% in the sorafenib-TACE group and 32.4% and 54.4% in the sorafenib-alone group, respectively. The major complications were comparable between the two groups. The addition of TACE to sorafenib improves survival, with a 26% reduction in mortality. These findings provide strong real-world evidence that supports this combination strategy for eligible Child-Pugh A aHCC patients. [ABSTRACT FROM AUTHOR]