naphthoquinones and Carcinoma--Adenoid-Cystic

Adenoid cystic carcinoma (ACC) is one of the most common malignancies of the major and minor salivary glands. However, the molecular mechanism underlying the aggressive growth of human salivary ACC remains unclear. In the present study, we showed that survivin, which belongs to the family of inhibitors of apoptosis, is closely related to the high expression of CDK4 and cyclin D1 in human ACC specimens. By employing the small-molecule drug YM155, we found that the inhibition of survivin in ACC cells caused significant cell death and induced autophagy. Chloroquine, an autophagy inhibitor, prevented cell death induced by YM155, suggesting YM155-induced autophagy contributed to the cell death effects in ACC cells. More importantly, evidence obtained from a xenograft model using ACC-2 cells proved the occurrence of YM155-induced autophagy and cell death in vivo was correlated with the suppression of Erk1/2 and S6 activation as well as increased TFEB nuclear translocation. Taken together, our results indicate YM155 is a novel inducer of autophagy-dependent cell death and possesses therapeutic potential in ACC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Adenoid Cystic; Cell Line, Tumor; Female; Heterografts; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Naphthoquinones; Neoplasm Transplantation; Phosphorylation; Salivary Glands; Signal Transduction; Survivin

In the present study, we explored the expression and correlation of survivin with HIF-1α, TGF-β1 and TFE3 in adenoid cystic carcinoma (AdCC). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was assessed by immunohistochemical staining of a tissue microarray containing tissue samples of normal salivary gland (NSG), pleomorphic adenoma (PA) and AdCC. Correlation analysis of these proteins revealed that increased survivin expression was associated with the overexpression of HIF-1α (P<0.001, r = 0.5599), TGF-β1 (P<0.001, r = 0.6616) and TFE3 (P<0.001, r = 0.7747). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was not correlated with the pathological type of human AdCC (P>0.05). Selective inhibition of survivin by YM155 and siRNA significantly reduced human SACC-83 cell proliferation, with the corresponding decrease in expression of HIF-1α, TGF-β1 and TFE3. The data indicate that the overexpression of survivin in AdCC is related to HIF-1α, TGF-β1 and TFE3. We hypothesize from these findings that the inhibition of survivin may be a novel strategy for neoadjuvant chemotherapeutic and radiosensitive treatment of AdCC.

Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Carcinoma, Adenoid Cystic; Case-Control Studies; Cell Line, Tumor; Cluster Analysis; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Imidazoles; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Naphthoquinones; Neoplasm Grading; Salivary Gland Neoplasms; Survivin; Transforming Growth Factor beta1

The aim of this study was to examine the anti-invasion effect of Shikonin on human high-metastatic adenoid cystic carcinoma (ACC-M) cells and to explain the possible molecular mechanism involved.. The ACC-M cells were treated with Shikonin (0, 2.5, 5, 10 μM) for 24 h. The protein levels and gelatinolytic activities of MMP-2 and MMP-9 were analyzed using Western blot and Gelatin zymography test, respectively. Matrigel invasion assays were used to investigate tumor invasive potential and electromobility shift assays were used to determine the activity of NF-κB.. The invasiveness of ACC-M cells was reduced in a dose dependent manner following 24-h treatment of up to 10 μM of the Shikonin at which concentration no cytotoxicity occurred. The protein levels and gelatinolytic activities of MMP-9 were significantly suppressed by increasing Shikonin concentrations. The down-regulation of MMP-9 appeared to be via the inactivation of NF-κB as the treatment with Shikonin suppressed the protein level of phosphate-IkBa, which was accompanied by a decrease in DNA-binding level of the factor.. Shikonin inhibits tumor invasion via downregulation of MMP-9 expression in ACC-M cells. Pharmacologic inhibition of the NF-κB-mediated MMP-9 expression by Shikonin might be a powerful treatment option for ACC patients in future.

Topics: Antineoplastic Agents; Blotting, Western; Carcinoma, Adenoid Cystic; Cell Culture Techniques; Cell Line, Tumor; Cell Survival; Coloring Agents; Dose-Response Relationship, Drug; Down-Regulation; Drugs, Chinese Herbal; Electrophoresis, Polyacrylamide Gel; Humans; I-kappa B Proteins; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Naphthoquinones; Neoplasm Invasiveness; NF-kappa B; Tetrazolium Salts; Thiazoles; Time Factors; Tumor Necrosis Factor-alpha