S-allylmercaptocysteine promotes MAPK inhibitor-induced apoptosis by activating the TGF-ß signaling pathway in cancer cells.

S-allylmercaptocysteine (SAMC), one of the water-soluble organosulfur garlic derivatives, can induce the apoptosis of many types of cancer cells through the MAPK signaling pathway. The TGF-ß signaling pathway also plays a pivotal role in the process of oncogenesis, and has a certain crosstalk with the MAPK pathway. In the present study, hepatocellular carcinoma cell line HepG2 with an intact TGF-ß signal and colon cancer cell line SW620 with an imperfect TGF-ß signal were selected to ascertain whether SAMC induces the apoptosis of cancer cells by TGF-ß signaling. In both cell lines treated with MAPK inhibitors and SAMC, an increased apoptosis rate was observed by electron microscopy, TUNEL and flow cytometric assays. Immunohistochemistry and western blot assays showed that SAMC induced the apoptosis of cancer cells by activating TGF-ß1, TßRII, p-smad2/3, smad4 and smad7 signals, and promoting Bim expression while decreasing Bcl-2 expression and finally activating the mitochondrial apoptosis pathway proteins caspase-3 and caspase-9 in the HepG2 cell line. In contrast, in the SW620 cell line, the apoptosis induced by SAMC only affected TGF-ß1 and smad7 signals, and promoted the expression of Bax and Bad and finally activated the mitochondrial apoptosis pathway protein caspase-9. When we compare the apoptosis rate in both cell lines, a significantly lower apoptosis rate was noted in the SW620 cell line than the rate noted in the HepG2 cell line. In summary, SAMC induces the apoptosis of cancer cells by activating the TGF-ß signaling pathway, after MAPK signaling is inhibited.

Combined use of cyclophosphamide and Chalone 19-peptide in experimental breast cancer.

BACKGROUND: Cyclophosphamide is a potent anticancer drug, but its clinical utility is limited because of its severe side effects, in particular liver damage. Chalone 19-peptide induces apoptosis of tumor cells and inhibits tumor growth. The present study investigated the antitumor effects of a combination of cyclophosphamide and Chalone 19-peptide in experimental breast cancer. METHODS: An animal model of breast cancer was developed, consisting of an MDA-MB-231 cell line implanted in the nude mouse. Eight doses of a combination of cyclophosphamide 50 mg/kg or 100 mg/kg and Chalone 19-peptide 6.6 mg/kg were administered, and the mice were euthanized 28 days after the final drug injection. Histopathologic analysis of tumor size, metastasis, and apoptosis of cancer cells was performed. Control mice were injected intraperitoneally with either cyclophosphamide alone or the same volume of solvent. RESULTS: Tumor sizes in the treatment groups were smaller than in the controls. No metastasis was found in the groups treated with cyclophosphamide and Chalone 19-peptide, but lung metastasis was found in controls. Liver damage in the groups treated with cyclophosphamide was more serious than in the other groups. CONCLUSION: Addition of Chalone 19-peptide can improve the ability of cyclophosphamide to inhibit tumor growth and also reduces side effects.

Fibroblast activation protein-α promotes ovarian cancer cell proliferation and invasion via extracellular and intracellular signaling mechanisms.

Fibroblast activation protein-α (FAPα) is secreted by activated stromal fibroblasts and can promote ovarian cancer cell proliferation, migration and invasion. However, the molecular mechanism by which FAPα promotes tumor cell proliferation and invasion is unknown. The role of the non-enzymatic activities of FAPα in tumor migration and invasion and the intracellular and extracellular signaling mechanisms of FAPα were investigated. In this study, we confirm that FAPα promote ovarian cancer cell proliferation, migration and invasion by extracellular and intracellular signaling mechanisms. These results provide evidence that FAPα, together with integrin α3ß1 and the uPAR signaling complex, mediate cancer cell migration in the HO-8910PM cell line via the small GTPase Rac1. FAPα-mediated upregulation of p-ERK occurred in a time-dependent manner.

The response to interferon is influenced by hepatitis B virus genotype in vitro and in vivo.

PURPOSE: To investigate the effectiveness of an interferon administration on different genotypes of hepatitis B virus (HBV) in vitro and in vivo. METHODS: In vitro, we transfected plasmids carrying different HBV genotypes including recently identified new genotype I into HepG2 and HuH7 cells, then treated with standard interferon alpha (IFN-α); in vivo, we treated mice with pegylated interferon alpha (Peg-IFN-α) after injection with HBV DNA of different genotypes. The culture supernatants from cell culture and sera from mice were collected and used in hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays by ELISA and HBV DNA measurement by PCR. RESULTS: Both in cell culture and in mouse model, it was observed that HBV genotypes A and B exhibited significantly better response to IFN-α2a or Peg-IFN-α2a in terms of reduced expression of HBsAg, HBeAg and the HBV DNA level as compared to HBV genotypes C and D. Moreover, the inhibitory effect of IFN-α2a or Peg-IFN-α2a on HBV genotype I was greater than on genotype C or D, but less than genotype A. However, there was no significant response difference between genotypes A and B, C and D, B and I, respectively. CONCLUSION: The effectiveness of IFN/Peg-IFN to suppress HBV replication is dependent on different HBV genotypes. IFN/Peg-IFN is more effective on HBV genotype A or B than on genotype C, D or I. Treatment regimens are suggested to be adapted to HBV genotype.

Detection of hepatitis B virus DNA in paraffin-embedded intrahepatic and extrahepatic cholangiocarcinoma tissue in the northern Chinese population.

This study explored the importance of hepatitis B virus infection in cholangiocarcinoma pathogenesis in northern China. The clinical data of 66 patients with cholangiocarcinoma were analyzed. The hepatitis B virus gene was amplified using nested polymerase chain reaction, and the hepatitis B virus-related antigen was detected using immunohistochemistry in formalin-fixed, paraffin-embedded tissue from patients with intrahepatic cholangiocarcinoma (n = 23) and extrahepatic cholangiocarcinoma (n = 43). Hepatitis B surface antigen seropositivity was found in 52.2% (12/23) of intrahepatic cholangiocarcinoma cases and 13.9% (6/43) of extrahepatic cholangiocarcinoma cases. Hepatitis B virus DNA (X region) was detectable in 34.8% (8/23) of intrahepatic cholangiocarcinoma cases. Hepatitis B surface antigen and/or hepatitis B core antigen was detectable in 30.4% (7/23) of intrahepatic cholangiocarcinoma cases. All cases with detected viral protein were also positive for hepatitis B virus DNA. In contrast, no hepatitis B virus antigens or hepatitis B virus gene was detected in any of the 43 extrahepatic cholangiocarcinoma cases. Our findings strongly suggest that chronic hepatitis B virus infection is a significant risk factor for intrahepatic cholangiocarcinoma, but not for extrahepatic cholangiocarcinoma, in northern China. Hepatitis B virus infection is potentially independently associated with intrahepatic cholangiocarcinoma.