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To develop new anticancer agents has been considered as a useful and necessary strategy to suppress highly-metastatic lung cancer, the leading cause of cancer-related deaths in the world. In this study, we synthesized a new compound ethyl 6-bromocoumarin-3-carboxylyl L-theanine (TBrC) and studied the anticancer activity of TBrC and its molecular mechanisms of action. Our results show that TBrC remarkably inhibits the proliferation and migration in highly-metastatic lung cancer cells by inducing apoptosis and cell cycle arrest as well as regulating related protein expressions. Further study indicated that TBrC not only enhances the protein levels of Bax, cytosolic cytochrome c, caspase-3 and PARP-1 but also reduces the protein expressions of Bcl-2, cyclin D1, VEGFR1 and NF-κB as well as inhibits the phosphorylation and expressions of VEGFR2 and Akt in the cancer cells. More importantly, TBrC displays strong suppression of highly-metastatic tumor growth and reduces the tumor weight by 61.6 % in tumor-bearing mice without toxicity to the mice. Our results suggest that TBrC suppresses the proliferation and migration of lung cancer cells via VEGFR-Akt-NF-κB signaling pathways; TBrC may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of lung cancer.

The aim of this study is to investigate the effects of theanine, a tea characteristic amino acid, on human lung cancer and leukemia cells. In the present study, we have demonstrated that theanine suppressed the in vitro and ex vivo growth of human non-small cell lung cancer A549 and leukemia K562 cell lines in dose- and time-dependant manners. In addition, theanine displayed the inhibitory effect on the migration of A549 cells. More importantly, theanine enhanced the anticancer activity of anticancer agents such as trichostatin A (the histone deacetylase inhibitor), berbamine and norcantharidin (the anticancer drugs in China) by strongly reducing the viability and/or migration rate in A549 cells. In addition, theanine significantly suppressed A549 cell invasion. Suppression of A549 cell migration may be one of the important mechanisms of action of theanine against the A549 cell invasion. Our present results suggest that theanine may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human lung cancer and leukemia.

Matrine has shown therapeutic and/or adjuvant therapeutic effects on the treatment of some patients with breast cancer. However, its mechanisms of action are largely unknown. To disclose the mechanisms, we investigated in vitro and ex vivo effects of matrine on the cancer cells. Our results confirmed that matrine significantly suppressed the proliferation of highly-metastatic human breast cancer MDA-MB-231 cell line. Matrine displayed synergistic effects with existing anticancer agents celecoxib (the inhibitor of cyclooxygenase-2), trichostatin A (the histone deacetylase inhibitor) and rosiglitazone against the proliferation and VEGF excretions in MDA-MB-231 cells. Matrine induced the apoptosis and cell cycle arrest by reducing the ratios of Bcl-2/Bax protein and mRNA levels in the cancer cells. Matrine significantly reduced the invasion, MMP-9/MMP-2 activation, Akt phosphorylation, nuclear factor kappaB p-65 expression and DNA binding activity, and mRNA levels of MMP-9, MMP-2, EGF and VEGFR1 in MDA-MB-231 cells. Collectively, our results suggest that matrine inhibits the cancer cell proliferation and invasion via EGF/VEGF-VEGFR1-Akt-NF-kappaB signaling pathway.

The bioavailability and action of teas on the invasion of a rat ascites hepatoma cell line, AH109A, were determined and their modes of action were by co-culturing the cancer cells with a rat mesentery-derived mesothelial-cell (M-cell) monolayer in the presence of sera from rats orally given teas and their component, (-)-epigallocatechin gallate (EGCG). The rat sera obtained 2 and 5 hr after oral intubation of a low concentration of green, oolong, or black tea, or EGCG significantly inhibited AH109A invasion underneath the M-cell monolayer. These sera showed a time-dependent and significant inhibitory effect on the AH109A invasion. The 2-hr sera and 2.5 μM EDTA in the medium completely eliminated the enhancement of AH109A invasion induced by a reactive oxygen species (ROS)-generating system. These results show that the inhibition of relevant ROS-potentiated invasion of AH109A cells across the M-cell monolayer may be due to the antioxidative action of EGCG, the in vivo metabolites, and tea-induced changes in the endogenous substances. The results suggest that the drinking of tea in daily life may have certain preventive and therapeutic effects against cancer cell invasion.

To investigate the bioavailability and mode of action of theanine against cancer, we examined in vitro and ex vivo effects of theanine on invasion of a rat ascites hepatoma cell line of AH109A. Theanine dose-dependently inhibited the invasion of AH109A cells across rat mesentery-derived mesothelial-cell (M-cell) monolayers without restraining AH109A cell proliferation in vitro. Rat sera obtained after oral intubation of theanine also inhibited the invasion. A competitive N-methyl-D-aspartate (NMDA) type glutamate receptor antagonist, (±) 2-amino-5-phosphonopentanoic acid (AP-5), dose-dependently counteracted the theanine-mediated in vitro and ex vivo inhibition of AH109A invasion. A competitive non-NMDA type glutamate receptor antagonist, 6,7-dinitroquinoxaline 2,3-dione (DNQX), did not affect this inhibition by theanine in vitro. These results suggest that the inhibition of AH109A invasion by theanine may be mediated by the NMDA receptor of AH109A.

The effects of teas and related components on the proliferation and invasion of cancer cells were examined by employing both in vitro proliferation and invasion assay systems. Powdered green, oolong and black tea extracts dose-dependently inhibited proliferation and invasion of a rat ascites hepatoma cell line of AH109A but did not affect the proliferation of the normal mesentery-derived mesothelial cells (M-cells) isolated from rats; higher concentrations of powdered oolong and black teas could restrain the proliferation of another tumor cell line of L929. The AH109A cells were found to penetrate underneath the monolayer of M-cells in the presence of 10% calf serum. When each rat serum obtained at 0.5, 1, 2, 3 and 5 h after oral intubation of each tea extract was added to the culture media instead of calf serum at a concentration of 10%, both the invasion and proliferation of AH109A were significantly suppressed. These ex vivo results suggest the potential bioavailability of effective tea components in rats. Furthermore, (–)-epigallocatechin gallate, (–)-epicatechin gallate and (–)-epigallocatechin from green tea as well as the mixture of theaflavin and theaflavin gallates from black tea were shown to be the most effective components against the invasion and proliferation of AH109A. These results show that the inhibitory effects of the teas and related components against AH109A cells are due to the cell-specific and higher sensitivity of the cell line to tea components.

Bufalin, a naturally occurring small-molecule compound from Traditional Chinese Medicine (TCM) Chansu showed inhibitory effects against human prostate, hepatocellular, endometrial and ovarian cancer cells, and leukemia cells. However, whether or not bufalin has inhibitory activity against the proliferation of human non–small cell lung cancer (NSCLC) cells is unclear. The aim of this study is to study the effects of bufalin on the proliferation of NSCLC and its molecular mechanisms of action. The cancer cell proliferation was measured by MTT assay. The apoptosis and cell cycle distribution were analyzed by flow cytometry. The protein expressions and phosphorylation in the cancer cells were detected by Western blot analysis. In the present study, we have demonstrated that bufalin suppressed the proliferation of human NSCLC A549 cell line in time- and dose-dependent manners. Bufalin induced the apoptosis and cell cycle arrest by affecting the protein expressions of Bcl-2/Bax, cytochrome c, caspase-3, PARP, p53, p21WAF1, cyclinD1, and COX-2 in A549 cells. In addition, bufalin reduced the protein levels of receptor expressions and/or phosphorylation of VEGFR1, VEGFR2, EGFR and/or c-Met in A549 cells. Furthermore, bufalin inhibited the protein expressions and phosphorylation of Akt, NF-κB, p44/42 MAPK (ERK1/2) and p38 MAPK in A549 cells. Our results suggest that bufalin inhibits the human lung cancer cell proliferation via VEGFR1/VEGFR2/EGFR/c-Met–Akt/p44/42/p38-NF-κB signaling pathways; bufalin may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of human NSCLC.

The effects of norcantharidin (NCTD) on the growth of highly-metastatic human breast cancer cells were investigated by in vitro and ex vivo assays. Our results indicated that norcantharidin inhibited the in vitro growth of human breast cancer MDA-MB-231 cell line in dose- and time-dependent manners after the cancer cells were treated with norcantharidin at the concentrations of 6, 30 and 60 mumol/L for 24, 48 and 72 h. Moreover, the sera from the NCTD-treated rabbits after intravenous injection of NCTD at 15 and 30 min significantly suppressed the growth of the cancer cells ex vivo. The analyses by Hoechst 33258 staining and flow cytometry showed that the typical apoptotic morphological changes appeared and cell cycles arrested at G2/M phase in MDA-MB-231 cells after the cells were treated for 48 h with NCTD. In addition, NCTD down-regulated the expressions of anti-apoptotic protein Bcl-2 and up-regulated the expressions of pro-apoptotic protein Bax, eventually leading to the reduction of Bcl-2/Bax ratio in MDA-MB-231 cells. Furthermore, NCTD at concentrations of 6, 30 and 60 mumol/L dose-dependently reduced the phosphorylation of Akt and NF-kappaB expression in the breast cancer cell line. Induction of apoptosis and cell cycle arrest as well as reduction of Bcl-2/Bax ratio by NCTD may be the important mechanisms of action of NCTD suppressing the growth of MDA-MB-231 cells, which are associated with inhibition of the Akt and NF-kappaB signaling. Our findings suggest that norcantharidin may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of human breast cancer.

The effects of norcantharidin (NCTD), an anticancer drug in China, on the growth and migration in human lung cancer cells were investigated by in vitro and ex vivo assays. NCTD significantly inhibited the in vitro and ex vivo growth of human non-small cell lung cancer A549 cells in dose- and time-dependent manners. Western blot analysis indicated that NCTD dose-dependently down-regulated the expression of anti-apoptotic protein Bcl-2 and up-regulated the level of pro-apoptotic protein Bax, eventually leading the reduction of ratio of Bcl-2/Bax proteins in A549 cells. Moreover, NCTD significantly suppressed the A549 cell migration in the case of without reducing the cell viability. More importantly, NCTD significantly enhanced the anticancer activity of anticancer agents such as trichostatin A (the histone deacetylase inhibitor), celecoxib (the inhibitor of cyclooxygenase-2) and lovastatin (the inhibitor of HMG-CoA reductase) by strongly reducing the viability and/or the ratio of Bcl-2/Bax protein in A549 cells. Our findings suggest that NCTD may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human lung cancer.