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Abstract: 13F-1 is a 5-fluorouracil prodrug containing an Asn–Gly–Arg (NO2) COOCH3 tripeptide. 13F-1 might possess the activity against cancer growth by targeting Aminopeptidase N (APN/CD13). Our goal in this study was to evaluate the inhibitory effect of 13F-1 on the growth of human colonic carcinoma by both in vitro and in vivo studies. Experiments were performed in colonic carcinoma Colo205 cells, which highly express APN/CD13 on cell surface. The inhibition of 13F-1 on cancer cell growth was estimated by the colorimetric and clonogenic assays. The assays of Annexin V-FITC/PI and JC-1 fluorescence probe were employed to determine the apoptotic cells. Further experiment was performed in mice bearing Colo205 xenografts. 13F-1 was injected for three consecutive weeks. The specimens of Colo205 xenografts were removed for TUNEL staining and western blotting analysis. The expressions of APN/CD13 were analyzed by immunofluorescent flow cytometry and western blotting assays. 13F-1 significantly inhibited Colo205 cell proliferation. 13F-1 by injection delayed the expansion of Colo205 xenografts without significant toxicity to mice. The inhibitory effect of 13F-1 might arise from its role in apoptotic induction. Further analysis indicated that 13F-1 strongly inhibited APN/CD13 expression on cancer cell surface. In contrast, 5-FU did not affect APN/CD13 expression. These results indicated the mechanism of 13F-1 action that 13F-1׳s effect was associated with its role in suppression of APN/CD13 expression. Conclusion, 13F-1 could be developed as a promising agent for treatment of cancers with high expression of APN/CD13. [Copyright &y& Elsevier]

Abstract: Background: Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid. We have previously reported that AKBA can reduce the number and size of colonic adenomatous polyps in the APCMin/+ mouse model. In this study, we evaluated the effect of AKBA on human colonic adenocarcinoma growth. Its efficacy and toxicity were compared with those of the non-steroidal anti-inflammatory drug aspirin. Methods: The inhibition of cancer cell growth was estimated by colorimetric and clonogenic assay. Cell cycle distribution was analyzed by the flow cytometry assay. Annexin V-FITC/PI staining and JC-1 fluorescence probe assays were performed to determine the apoptotic cells. Further experiment was carried out in mice with HT-29 xenografts. AKBA was orally administered for 24days. The HT-29 xenografts were removed for TUNEL staining and western blotting analysis. Blood was obtained for clinical chemical analysis, and samples of organs were sectioned for microscopic assessment. Results: AKBA significantly inhibited human colon adenocarcinoma growth, showing arrest of the cell cycle in G1-phase and induction of apoptosis. AKBA administration in mice effectively delayed the growth of HT-29 xenografts without signs of toxicity. The activity of AKBA was more potent than that of aspirin. Western blotting suggested that this activity may arise from its multiple effects on the activation of apoptotic proteins, suppression of inflammatory cytokines and modulation of EGFR and ATM/P53 signaling pathways in the HT-29 xenografts. Conclusions: AKBA prevents the growth of colonic adenocarcinoma through modulation of multiple signaling pathways. General significance: AKBA could be a promising agent in the prevention of colonic adenocarcinomas. [Copyright &y& Elsevier]

Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid, which is an active component of the gum resin of Boswellia serrata. AKBA has been used as an adjuvant medication for treatment of inflammatory diseases. In this study, we aimed to evaluate the efficacy of AKBA as a chemopreventive agent against intestinal adenomatous polyposis in the adenomatous polyposis coli multiple intestinal neoplasia ( APCMin/+) mouse model. APCMin/+ mice were administered AKBA by p.o. gavage for 8 consecutive weeks. The mice were sacrificed and the number, size and histopathology of intestinal polyps were examined by light microscopy. AKBA decreased polyp numbers by 48.9% in the small intestine and 60.4% in the colon. An even greater AKBA effect was observed in preventing the malignant progression of these polyps. The number of large (>3 cm) colonic polyposis was reduced by 77.8%. Histopathologic analysis demonstrated a significant reduction in the number of dysplastic cells and in the degree of dysplasia in each polyp after AKBA treatment. There was no evidence of high grade dysplasia or intramucosal carcinoma in any of the polyps examined within the treated group. More interestingly, interdigitated normal appearing intestinal villi were observed in the polyps of the treated group. During the course of the study, AKBA was well tolerated by the mice with no obvious signs of toxicity. Results from immunohistochemical staining, Western blotting and enzyme-linked immunosorbent assay indicated that the chemopreventive effect of AKBA was attributed to a collection of activities including antiproliferation, apoptosis induction, antiangiogenesis and anti-inflammation. AKBA was found to exert its chemopreventive action through the inhibition of the Wnt/β-catenin and NF-κB/cyclooxygenase-2 signaling pathways. Our findings suggest that AKBA could be a promising regimen in chemoprevention against intestinal tumorigenesis. [ABSTRACT FROM AUTHOR]

A new chromone polymorchromone B was isolated and characterized from the roots of Angelica polymorpha Maxim, a commonly used traditional Chinese medicine. On the basis of spectroscopic analysis, including IR, HR-ESI-MS, 1D and 2D NMR spectral data, and hydrolysis followed by chromatographic analysis, the structure of the new chromone was elucidated as 5-hydroxy-2-[(angeloyloxy)methyl]-2′-(dimethyl)-3′-(2S,3S-epoxy-2-methylbutanoate)-dihydropyran [3′,2′:6,7]chromone. Moreover, it was found that polymorchromone B showed remarkable cytotoxic activity against A-549 cell lines. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Sialic acid, as a terminal saccharide residue on cell surface glycoconjugates, plays an important role in a variety of biological processes. However, the precise nature of the molecules in gastric cancers has not been unveiled nor documented to be of clinical relevance. Herein, we measured the expression of α 2, 3-linked sialic acid residues by using a specific lectin as well as the potential of invasion and metastasis of gastric cancer was analyzed. Methods: The expression of α 2, 3-linked sialic acid residues in 100 cases of gastric cancer samples was evaluated using Maackia amurensis leukoagglutinin (MAL) histochemical staining analysis. The assays of cytochemical staining and flow cytometry were employed to determine the MAL positive cells in the gastric cancer cell lines. The activities of invasion and migration were evaluated using the assays of cell adhesion and transwell chamber. Results: The staining of MAL in gastric cancer tissues showed that high levels of α 2, 3-linked sialic acid residues were closely associated with the invasive depth (P =0.0003) and lymph node metastasis (P =0.0441). In gastric adenocarcinoma cell lines, SGC-7901, the highly metastatic cell line, displayed the most positive reaction with MAL among the selected cell lines. The potential of invasion and migration was confirmed using the assays of adhesion and transwell chamber that SGC-7901 exhibited the high activity of adhesion to extracellular matrix (ECM) and penetration to Matrigel. Conclusion: These results suggested that high level of α 2, 3-linked sialic acid residues was associated with metastatic potential of gastric cancer cells. [Copyright &y& Elsevier]

Abstract: N3-o-toluyl-fluorouracil (TFU), the pro-drug of 5-fluorouracil (5-FU), is the metabolite of N1-acetyl-N3-o-toluyl-fluorouracil (atofluding). We aimed to evaluate the efficacy of TFU as a precursor of 5-FU on the growth inhibition of human gastric carcinoma cell lines SGC-7901 and MKN-45. Growth of SGC-7901 and MKN-45 cells was remarkably suppressed by treatment with TFU in the presence of liver microsomal enzymes in vitro, suggesting that TFU may be converted to 5-FU by the enzymes. Similar treatment of TFU induced apoptosis of the cells, which was deduced from typical apoptotic features such as morphology, the formation of characteristic ladder pattern of DNA migration and the accumulation of sub-G1 phase. Cancer cells xenografts in nude mice were employed to evaluate the efficacy of TFU in vivo. Growth of human gastric carcinoma cells was significantly delayed by oral administration of TFU with low side effects. Apoptosis in xenografts was also observed by means of TUNEL staining method. These results suggest that the treatment of TFU in the presence of liver microsomal enzymes and the oral administration of TFU in mice induced anti-proliferation and apoptosis in gastric carcinoma cells. This suggests that TFU may be a promising pro-drug of 5-FU for cancer treatments. [Copyright &y& Elsevier]

Background/aims: Des-gamma-carboxy prothrombin (DCP), an aberrant prothrombin produced by hepatocellular carcinoma (HCC) cells, is known as a marker for HCC. Recent studies indicated that high levels of DCP are associated with the malignant potential of HCC. In this study, we aimed to investigate the association of DCP with gefitinib treatment failure in HCC and whether DCP counteracts gefitinib-induced growth inhibition and apoptosis of HCC., Methods: The experiments were performed in HCC cell lines HepG2 and PLC/PRF/5. The effects of gefitinib on HCC in the presence or absence of DCP were evaluated by the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Apoptotic cells were identified by Annexin V-FITC/PI staining. Western blotting was performed to analyze the expressions of molecules related to the apoptotic caspase-dependent pathway and epidermal growth factor receptor (EGFR) pathway., Results: Gefitinib inhibited HCC cell proliferation and induced apoptosis in HCC cells. The effects of gefitinib on HCC cells were antagonized by DCP. In the presence of DCP, HCC cells were resistant to the gefitinib-induced inhibition of proliferation and stimulation of apoptosis. DCP prevented the activation of the apoptotic caspase-dependent pathway induced by gefitinib. These antagonistic effects of DCP also arose from its ability to up-regulate EGFR, c-Met and hepatocyte growth factor (HGF) in HCC cells., Conclusion: DCP antagonized gefitinib-induced HCC cell growth inhibition by counteracting apoptosis and up-regulating the EGFR pathway. High levels of DCP might thus lead to low response rates or possibly no response to gefitinib in patients with HCC., (© 2015 S. Karger AG, Basel.)

Background: Sialic acid, as a terminal saccharide residue on cell surface glycoconjugates, plays an important role in a variety of biological processes. However, the precise nature of the molecules in gastric cancers has not been unveiled nor documented to be of clinical relevance. Herein, we measured the expression of alpha 2, 3-linked sialic acid residues by using a specific lectin as well as the potential of invasion and metastasis of gastric cancer was analyzed., Methods: The expression of alpha 2, 3-linked sialic acid residues in 100 cases of gastric cancer samples was evaluated using Maackia amurensis leukoagglutinin (MAL) histochemical staining analysis. The assays of cytochemical staining and flow cytometry were employed to determine the MAL positive cells in the gastric cancer cell lines. The activities of invasion and migration were evaluated using the assays of cell adhesion and transwell chamber., Results: The staining of MAL in gastric cancer tissues showed that high levels of alpha 2, 3-linked sialic acid residues were closely associated with the invasive depth (P=0.0003) and lymph node metastasis (P=0.0441). In gastric adenocarcinoma cell lines, SGC-7901, the highly metastatic cell line, displayed the most positive reaction with MAL among the selected cell lines. The potential of invasion and migration was confirmed using the assays of adhesion and transwell chamber that SGC-7901 exhibited the high activity of adhesion to extracellular matrix (ECM) and penetration to Matrigel., Conclusion: These results suggested that high level of alpha 2, 3-linked sialic acid residues was associated with metastatic potential of gastric cancer cells.

Antineoplaston A10 (3-phenylacetylamino-2,6-piperidinedion) is a naturally occurring substance and was the first antineoplaston in the human body to be chemically identified. The effect of antineoplaston A10 on human hepatocellular carcinoma cell lines HepG2 and HLE has been examined. Antineoplaston A10 displayed anti-proliferative action inhibiting cell growth in a dose- and time-dependent manner in vitro as measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and clonogenic assays. Incubation with antineoplaston A10 for 48 h induced apoptotic events such as a typical apoptotic morphology, formation of a characteristic ladder pattern of DNA migration and accumulation of sub-G1 phase cells. Next, hepatoma xenografts in nude mice were employed to study the antitumor effects of antineoplaston A10 in vivo. Oral administration of antineoplaston A10 delayed the growth of HepG2 and HLE cells in the mice without a reduction in body weight. A higher proportion of apoptotic cells in xenografts was observed by means of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. In addition, the level of expression of apoptotic marker p53 increased while that of anti-apoptotic protein bcl-2 decreased, as evaluated with immunohistochemical staining in the xenografts. These results suggested that antineoplaston A10 may inhibit the growth of human hepatoma cells through the induction of apoptosis.

Aim: To evaluate the growth inhibition efficacy of atofluding derivative N3-o-toluyl-fluorouracil (TFU) on human gastric carcinoma cell lines SGC-7901 and MKN-45., Methods: Cell growth inhibition by TFU was measured by MTT and clonogenic assays without or with liver microsomal enzymes. Xenografts of cancer cells in nude mice were employed to study the anti-proliferative effects of TFU in vivo., Results: TFU inhibited the growth of SGC-7901 and MKN-45 cells. However, the inhibitory effects of TFU on cell growth were not significant. The inhibition rates were enhanced in the presence of liver microsomal enzymes, ranging 4.73%-48.57% in SGC-7901 cells and 9.0%-62.02% in MKN-45 cells. In vivo, TFU delayed the growth of SGC-7901 and MKN-45 cells in nude mice. The inhibition rates were 40.49%, 63.24%, and 75.98% in SGC-7901 cells and 40.76%, 61.41%, and 82.07% in MKN-45 cells when the oral doses were 25, 50, and 100 mg/kg, respectively. TFU treatment was generally well tolerated by mice with less than 20% reduction in body weight., Conclusion: TFU inhibits the growth of human gastric carcinoma cells. The inhibition rates are increased in the presence of liver microsomal enzymes. The efficacy of TFU may be associated with the sustaining release of 5-fluorouracil (5-FU) mediated by the enzymes.