cytochrome-c-t and Salivary-Gland-Neoplasms

Quercetin, one of the most common natural flavonoids, has been reported to possess significant anti-tumor activities both in vitro and in vivo. The present study was to investigate the effects of quercetin on growth and apoptosis in human salivary adenoid cystic carcinoma (ACC). The result from MTT assay showed that quercetin decreased cell viability of both low metastatic cell line ACC-2 and high metastatic cell line ACC-M in a concentration- and time-dependent manner. Moreover, treatment with quercetin resulted in significantly increased apoptosis in ACC cells. Our data also revealed that the apoptosis induced by quercetin treatment was through a mitochondria-dependent pathway which showed close correlation with the down-regulation of the PI3K/Akt/IKK-alpha/NF-kappaB pathway. Most importantly, quercetin significantly prevented in vivo growth of ACC xenografts in nude mice, accompanied by induction of tumor cell apoptosis, suppression of NF-kappaB nuclear translocation, as well as down-regulation of Akt and IKK-alpha activation. In addition, we explored the clinical significance of the PI3K/Akt/IKK-alpha/NF-kappaB signaling axis in ACC by immunohistochemical analysis of tissue specimens followed by the clustering analyses. We determined that the PI3K/Akt/IKK-alpha/NF-kappaB pathway is ubiquitously activated in ACC and plays an essential role in the evasion of apoptosis. Taken together, the results from our study implicated that quercetin would be a promising chemotherapeutic agent against ACC through its function of down-regulating the PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Adenoid Cystic; Caspases; Cell Line, Tumor; Cytochromes c; Enzyme Activation; Humans; I-kappa B Kinase; Membrane Potential, Mitochondrial; Mice; Mice, Nude; Mitochondria; NF-kappa B; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Quercetin; Salivary Gland Neoplasms; Signal Transduction; Xenograft Model Antitumor Assays

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, originally developed for lowering cholesterol. Statins also have pleiotropic effects, independent of cholesterol-lowering effects, including induction of apoptosis in various cell lines. However, the mechanism underlying statin-induced apoptosis is still not fully understood. This study aims to explore the proapoptotic effects and underlying mechanisms of statins on human salivary adenoid cystic carcinoma (SACC). Exposure of SACC cells to mevastatin resulted in cell growth inhibition and apoptosis in a dose-dependent manner, accompanied by the release of cytochrome c and cleavage of caspase-3. A remarkable decrease in phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and increase in phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase were observed. Furthermore, the JNK-specific inhibitor SP600125, but not the p38-specific inhibitor SB203580, abolished mevastatin-induced cell growth inhibition and apoptosis in SACC cells. This was supported by results in which the JNK inhibitor efficiently blocked mevastatin-induced JNK phosphorylation, but not p38 phosphorylation, and further decreased mevastatin-induced phosphorylation of ERK1/2. Taken together, the results suggest that the JNK pathway was required for mevastatin-induced cell growth inhibition and apoptosis in SACC cells. Statins could be potential anticancer agents for SACC chemotherapy.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Adenoid Cystic; Caspase 3; Cell Proliferation; Cytochromes c; Enzyme Activation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; JNK Mitogen-Activated Protein Kinases; Lovastatin; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Salivary Gland Neoplasms