Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic efficacy of low dose administration of 5-fluorouracil (5-FU) and cisplatin (CDDP) (low dose FP) has been reported in patients with advanced and recurrent gastric carcinoma. Mechanism(s) by which low dose FP exerts antitumor effect is not entirely clear. We investigated mechanism(s) of the therapeutic efficacy in combination with 5-FU and CDDP in terms of signal transduction pathways leading to apoptosis. Using two human gastric carcinoma cell lines, MKN28 and MKN45, antitumor effect in combination treatment with 5-FU and CDDP was assessed by MTT 5-day assay. The significant antitumor effect was determined with more than 50% growth inhibition compared to control cells. Enhancement of antitumor effect in the combination treatment was analyzed using isobologram. Apoptotic cell death was assessed by DNA ladder formation assay, and expression of apoptosis-related genes was detected by Western blotting. Concentration of free platinum and 5-FU was measured by high-pressure liquid chromatography (HPLC), and dihydropyrimidine dehydrogenase (DPD) activity and total folate levels were assessed by enzyme immunoassays. Antitumor effect in single treatment with 5-FU was not observed significantly with the concentration from 1 to 5 microM in vitro. In contrast, antitumor effect in combination treatment with 5-FU and CDDP showed a synergism with the concentration of CDDP from 1.5 to 3 microM. Single treatment with CDDP also did not show significant antitumor effect with the concentration from 1.5 to 3 microM. The enhancement in the synergistic effect by CDDP was dose-dependent. Any free platinum treated with low dose CDDP was not detected into gastric carcinoma cells, however, treatment with CDDP induced a receptor signaling pathway, that is mediated by Fas but not DR4. It may directly activate caspase 3 leading to apoptosis. Although the receptor signaling pathway in apoptosis was not observed by 5-FU, Bax-induced cytochrome c and caspase 3 was also observed in a receptor-independent pathway by 5-FU and CDDP. Total folate levels by cotreatment with CDDP was increased to 1.5-fold compared to 5-FU alone, whereas DPD activity and 5-FU concentration were not changed by cotreatment of CDDP in vivo. The enhancement of antitumor effect by low dose FP can be explained as follows: i) low dose treatment with CDDP induces apoptotic cell death through a receptor signaling pathway even in absence of free platinum into cells; ii) increased folate level by CDDP and a non-receptor signaling pathways by 5-FU contribute to apoptotic cell death in gastric carcinoma.
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PMID:Mechanism(s) of antitumor action in protracted infusion of low dose 5-fluorouracil and cisplatin in gastric carcinoma. 1183 67

The aim of this study is to clarify the benefit of combination chemotherapy in gastric cancer based on a cell-signal inhibitor and an anticancer drug. Two scirrhous gastric cancer cell lines and two non-scirrhous gastric cancer cell lines were used. Five anticancer drugs (5-fluorouracil [5FU], paclitaxel, oxaliplatin, irinotecan, and gemcitabine) and four cell-signal inhibitors, mammalian target of rapamycin (mTOR) inhibitor, glycogen synthase kinase 3beta, p38alphabetaMAPK, and cyclin-dependent kinase, were used. The proliferation of cancer cells was examined by MTT assay and in vivo study. The apoptosis of cancer cells and the expression of apoptosis-related molecules were examined by flow cytometry, real-time PCR, and immunostaining. mTOR inhibitors with 5FU showed a synergistic antiproliferative effect in scirrhous gastric cancer, whereas the other signal inhibitors showed no synergistic effect with any anticancer drugs. mTOR inhibitor decreased the IC(50) of 5FU and increased the apoptosis rate in scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. The pan-caspase inhibitor, zVAD-fmk, inhibits apoptosis induced in combination with 5FU and mTOR inhibitor. mTOR inhibitor decreased dihydropyrimidine dehydrogenase, thymidylatesynthase, and bcl-2 expression, and increased caspase-3 and p21 expression of scirrhous gastric cancer cells, but did not affect those of non-scirrhous gastric cancer cells. In an in vivo study, mTOR inhibitor significantly enhanced the therapeutic efficacy of S1, an analog of 5FU. These findings suggest that mTOR inhibitor interacts with 5FU in a synergistic manner in scirrhous gastric cancer cells by the activation of the apoptosis signal. Therefore, mTOR inhibitor is a promising therapeutic agent in combination with 5FU in scirrhous gastric cancer.
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PMID:Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer. 1976 96

The aim of the present study was to investigate the role of NK4, an antagonist for hepatocyte growth factor (HGF) and the Met receptor, in regulating the response of cholangiocarcinoma (CCA) cells to 5-fluorouracil (5-FU). We established the CCA cell line, HuCC-T1, to produce abundant NK4 (Hu-NK4). Cell proliferation, cell cycle distribution, apoptosis, 5-FU metabolism and intracellular signaling were examined. There were no significant differences in the mRNA levels of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase between the mock-transfected control Hu-Em cells and Hu-NK4 cells, suggesting that NK4 expression does not alter 5-FU metabolism. Moreover, cell cycle analysis showed that 5-FU treatment caused a decrease in the proportion of cells in the G2/M phase while NK4 gene expression had little effect on the cell cycle distribution. However, 5-FU-induced apoptosis was significantly increased in the Hu-NK4 cells when compared to that in the Hu-Em cells. Further investigation revealed that NK4 gene expression enhanced 5-FU-induced caspase-3 and caspase-9 activation, and that the apoptosis of cells was associated with modulation of expression of the Bcl-2 family members. Furthermore, western blot analysis revealed that both NK4 and 5-FU were inhibitors for HGF-induced phosphorylation of Met, but they may be independent factors. Collectively, these results suggest that following 5-FU treatment in CCA cell lines, NK4 was involved in apoptosis induction through the intrinsic mitochondrial pathway. This indicates that NK4 may be an important mediator of 5-FU-induced cell death. Moreover, downregulation of NK4 in response to 5-FU may represent an intrinsic mechanism of resistance to this anticancer drug.
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PMID:NK4 regulates 5-fluorouracil sensitivity in cholangiocarcinoma cells by modulating the intrinsic apoptosis pathway. 2361 66

Traditional Chinese medicines have been recognized as a new source of anticancer drugs or chemotherapy adjuvant to enhance the efficacy of chemotherapy and to ameliorate the side effects. This study aimed to investigate the antitumor effects of combined Scutellaria barbata D. Don extract (SBE) and 5-FU treatment in vitro and in vivo and the potential mechanisms. SBE was prepared and analyzed by HPLC. Tumor growth inhibition both in vitro and in vivo, cell apoptosis, apoptosis related protein expressions (P53, bid, bax, bcl-2), caspase-3 activities and 5-FU related enzymes were assessed. SBE could significantly synergize the antitumor effects of low dose 5-FU both in vivo and in vitro. SBE could increase the apoptosis inducing effect of low dose 5-FU in both Bel-7402 and HCT-8 cells. Also, caspase-3 activities, P53 and bax expressions were significantly increased, while bid and bcl-2 expressions were significantly decreased in drug combination groups, compared with individual drug treatment groups. Furthermore, SBE could significantly decrease the mRNA levels of dihydropyrimidine dehydrogenase. These results showed that combined treatment with SBE and low dose 5-FU can significantly inhibit the tumor growth both in vitro and in vivo, which might be related with apoptosis and regulations of 5-FU metabolism.
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PMID:Scutellaria barbata D. Don extract synergizes the antitumor effects of low dose 5-fluorouracil through induction of apoptosis and metabolism. 2369 49