RESUMEN
BACKGROUND: Cholangiocarcinoma is a highly malignant, usually fatal cancer with limited therapeutic options. Receptor tyrosine kinases contribute to the development and progression of this cancer. The relatively selective tyrosine kinase inhibitor imatinib mesylate (STI-571 or Gleevec(R)) has recently been licensed. However, the ability of this drug to inhibit signal transduction and induce apoptosis in human cholangiocarcinoma cells is incompletely studied. Thus, our goal was to examine the ability of STI-571 to induce apoptosis in KMCH-1 cells, a human cholangiocarcinoma cell line. METHODS: Apoptosis was assessed morphologically and also biochemically by measuring caspase activity and the mitochondrial membrane potential. STI-571 induced apoptosis and inhibited growth of KMCH-1 cells in a time- and concentration-dependent manner. The induction of apoptosis was accompanied by mitochondrial depolarization followed by a 4.5-fold increase in caspase activation and was abrogated by the pancaspase inhibitor z-VAD(OMe)-fmk. Interestingly, cholangiocarcinoma cells do not express detectable PDGFR, c-Abl or c-Kit, which are protein kinases known to be directly inhibited by STI-571. However, a significant decrease in epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) phosphorylation was observed following treatment with STI-571. This decrease in EGFR and FAK phosphorylation was associated with a reduction in Akt activity resulting in loss of Mcl-1, a potent anti-apoptotic Bcl-2 family protein. CONCLUSIONS: These results indicate that STI-571 induces caspase-dependent apoptosis in a human cholangiocarcinoma cell line and suggest that STI-571 might warrant further investigation as a possible agent for treatment of human cholangiocarcinoma.
Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos , Caspasas/efectos de los fármacos , Colangiocarcinoma/patología , Piperazinas/farmacología , Pirimidinas/farmacología , Análisis de Varianza , Benzamidas , Caspasas/metabolismo , Factor de Crecimiento Epidérmico/efectos de los fármacos , Factor de Crecimiento Epidérmico/metabolismo , Femenino , Humanos , Mesilato de Imatinib , Immunoblotting , Masculino , Mitocondrias/metabolismo , Probabilidad , Sensibilidad y Especificidad , Células Tumorales CultivadasRESUMEN
OBJECTIVES: The aim of this study was to identify temporal trends in the rate of Helicobacter pylori (H. pylori) testing, prevalence, and treatment among patients with peptic ulcer disease in Olmsted County, MN, from 1984 through 1997. METHODS: All 3317 Olmsted County residents with a clinical diagnosis of peptic ulcer disease at the Mayo Clinic from 1984 through 1997 were identified. The complete medical records of an age-, sex-, and calendar year-stratified random sample were reviewed (n = 720); 298 patients (41%) had confirmed peptic ulcer disease. Changes in proportions of H. pylori testing, infection, and treatment over time were analyzed by logistic regression. RESULTS: Of the 298 patients with confirmed peptic ulcer disease, 32% were tested for H. pylori; 36% were positive for infection, of whom 66% received antibiotic therapy. The rate of testing for H. pylori increased from 0% in 1984 to 96% in 1997, but the prevalence of infection did not change (36.4% vs 36.5%). The rate of treatment of those infected increased from 0% to 95%. By logistic regression, calendar year was associated with H. pylori testing and treatment but not infection. Recent use of nonsteroidal anti-inflammatory drugs was reported by 58% of patients, and 44% presented with GI bleeding. CONCLUSIONS: Physicians' practice of testing and treating for H. pylori in patients with confirmed peptic ulcer disease has steadily increased over the past 14 yr. However, in our study, only 36% of these patients were infected with H. pylori, whereas the majority used nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore, testing seems to be more appropriate than empiric treatment in patients with peptic ulcer disease.
Asunto(s)
Gastroenterología/tendencias , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Úlcera Péptica/microbiología , Práctica Profesional/tendencias , Antibacterianos/uso terapéutico , Antiinflamatorios no Esteroideos/efectos adversos , Infecciones por Helicobacter/complicaciones , Humanos , Minnesota , Úlcera Péptica/inducido químicamenteRESUMEN
Inhibitor of apoptosis proteins (IAPs) interact with and inhibit caspases-3, -7, and -9. This interaction can be inhibited by Smac/DIABLO, a polypeptide released from mitochondria upon initiation of the apoptotic signaling process. Here we demonstrate that the first 4-8 N-terminal amino acids of Smac/DIABLO fused to the Drosophila antennapaedia penetratin sequence, a carrier peptide, enhance the induction of apoptosis and long term antiproliferative effects of diverse antineoplastic agents including paclitaxel, etoposide, 7-ethyl-10-hydroxycamptothecin (SN-38), and doxorubicin in MCF-7 breast cancer cells. Similar effects were observed in additional breast cancer and immortalized cholangiocyte cell lines. Further analysis demonstrated that the Smac-penetratin fusion peptide crossed the cellular membrane, bound XIAP and cIAP1, displaced caspase-3 from cytoplasmic aggregates, and enhanced drug-induced caspase action in situ. These studies demonstrate that inhibition of IAP proteins can modulate the efficacy of antineoplastic agents.