thiourea and Adenocarcinoma-of-Lung

In our previous study, we proved that a novel Heat shock protein 90 (HSP90) inhibitor 4-(3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) benzoic acid (DPB) could inhibit A549 lung cancer cell growth via inducing apoptosis. However, whether DPB affects autophagy is still unknown. Here, we investigated the effects of DPB on autophagy and the improved anti-cancer activity in A549 lung cancer cells. Aggregation of LC3-II was observed using laser scanning confocal microscopy in GFP-LC3 stably transfected U87 cells. Autophagy and apoptosis-related protein levels were examined by Western blot analysis. It is suggested that treatment with DPB (5-20 μmol/L) induced mTOR-independent autophagy in dose- and time-dependent manners. Pre-treatment A549 cells with autophagy inhibitor 3-methyladenine (3-MA, 5 mmol/L) enhanced DPB-induced apoptosis. And, DPB inhibited A549 cell growth more effectively in combination with autophagy inhibitors 3-MA (5 mmol/L) or 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO, 30 μmol/L). These results illustrated that as a potential and promising HSP90 inhibitor, DPB could be utilized in the treatment of cancer combined with the autophagy inhibitor.

Topics: A549 Cells; Adenocarcinoma of Lung; Apoptosis; Autophagy; Cell Proliferation; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Signal Transduction; Thiourea

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a wide variety of cancer cells. Recently, cancer cell resistance to TRAIL-mediated apoptosis has become a challenging issue in the development of TRAIL-based anti-cancer therapies. In this study, we found that 1-(5-chloro-2-methyl-phenyl)-3-[4-(5-trifluoromethyl-pyrazol-1-yl)-phenyl]-thiourea (AW00178) was able to sensitize TRAIL-resistant human lung cancer H1299 cells to TRAIL-mediated apoptosis. Treatment with AW00178, either alone or in combination with TRAIL, induced the expression of CHOP, a protein related to TRAIL sensitivity, and reduced the expression of survivin, an anti-apoptotic protein involved in TRAIL resistance. Additionally, AW00178, alone or in combination with TRAIL, induced the activation of c-Jun and inactivation of Akt. A pharmacologic inhibition study revealed that c-Jun activation and Akt inactivation were strongly related to CHOP induction and survivin down-regulation, respectively. In summary, these results suggested that AW00178 mediated sensitization to TRAIL-mediated apoptosis in H1299 cells by increasing sensitivity and decreasing resistance to TRAIL via the induction of c-Jun-dependent CHOP expression and the reduction of Akt-dependent survivin expression, respectively.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Proto-Oncogene Proteins c-akt; Pyrazoles; Signal Transduction; Survivin; Thiourea; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor CHOP