tenovin-6 and Lung-Neoplasms

Lung cancer is one of the most commonly diagnosed cancers and it is associated with high rates of morbidity and mortality. Metastasis and relapse of the tumor depend on the survival and proliferation of lung cancer stem cells (LCSCs). The ability to identify CSCs may prevent recurrence and lead to more effective treatments. Sirtuins are a group of deacetylases that include seven variants (SIRT1‑7), with sirtuin 1 (SIRT1) being the most intensively investigated. Evidence suggests that SIRT1 is both a tumor‑suppressor gene and an oncogene. SIRT1 can deacetylate the tumor‑suppressor protein p53 to decrease its activity. SIRT1 activators increase the deacetylation of p53, whereas SIRT1 inhibitors can stimulate p53 by inhibiting deacetylation. In the present study, CD44+ and CD133+‑enriched A549 (non‑small cell lung cancer) cells collected using the CD44 and CD133 CSC surface markers by fluorescence‑activated cell sorting method were treated with SIRT1 inhibitors (tenovin‑6 and sirtinol) and SIRT1 activators (resveratrol and SRT1720), and their effects on apoptosis, as well as the mRNA and protein expression of SIRT1 and p53 were investigated. Of these agents, it was found that resveratrol increased p53 expression by 4.1‑fold, decreased SIRT1 expression by 0.2‑fold, and it was the most potent inducer of apoptosis.

Topics: A549 Cells; AC133 Antigen; Antineoplastic Agents; Apoptosis; Benzamides; Carcinoma, Non-Small-Cell Lung; Heterocyclic Compounds, 4 or More Rings; Humans; Hyaluronan Receptors; Lung Neoplasms; Naphthols; Neoplastic Stem Cells; Resveratrol; Sirtuin 1

Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non-histone proteins; however, antitumour effects by suppressing SIRT1 activity in non-small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathological significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin-6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin-fixed paraffin-embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence-free survival after adjusted for histology and pathologic stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin-6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin-6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin-6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1-deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up-regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase-3-dependent apoptosis. The study concluded that metformin with tenovin-6 may enhance antitumour effects through LKB1-independent SIRT1 down-regulation in NSCLC cells.

Topics: Acetylation; Adenocarcinoma of Lung; AMP-Activated Protein Kinase Kinases; Antineoplastic Agents; Apoptosis; Benzamides; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Drug Therapy, Combination; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Hypoglycemic Agents; Lung Neoplasms; Male; Metformin; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Protein Serine-Threonine Kinases; Sirtuin 1; Survival Rate; Tumor Cells, Cultured