Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily. TRAIL is regarded as one of the most promising anticancer agents, because it can destruct cancer cells without showing any toxicity to normal cells. Metformin is an anti-diabetic drug with anticancer activity by inhibiting tumor cell proliferation. In this study, we demonstrated that metformin could induce TRAIL-mediated apoptotic cell death in TRAIL-resistant human lung adenocarcinoma A549 cells. Pretreatment of metformindownregulation of c-FLIP and markedly enhanced TRAIL-induced tumor cell death by dose-dependent manner. Treatment with metformin resulted in slight increase in the accumulation of microtubule-associated protein light chain LC3-II and significantly decreased the p62 protein levels by dose-dependent manner indicated that metformin induced autophagy flux activation in the lung cancer cells. Inhibition of autophagy flux using a specific inhibitor and genetically modified ATG5 siRNA blocked the metformin-mediated enhancing effect of TRAIL. These data demonstrated that downregulation of c-FLIP by metformin enhanced TRAIL-induced tumor cell death via activating autophagy flux in TRAIL-resistant lung cancer cells and also suggest that metformin may be a successful combination therapeutic strategy with TRAIL in TRAIL-resistant cancer cells including lung adenocarcinoma cells.
Highlights
Lung adenocarcinoma, one of the most common malignancies among men and women in the world, is the leading cause of cancer related death
To determine the effect of metformin on TRAILmediated apoptosis, A549, Calu-3 and HCC-15 lung cells were pretreated with different concentrations of metformin for 12 h followed by treatment with Tumor necrosis factor-related apoptosisinducing ligand (TRAIL) protein for an additional 2 h
Combined treatment of TRAIL and metformin decreased cell viability and significantly increased apoptotic cell death of Calu-3, HCC-15 cells (Figure 1E, 1F, 1G and 1H). These results indicated that metformin significantly increased TRAILinduced apoptotic cell death in TRAIL-resistant human lung A549, Calu-3 and HCC-15 cells
Summary
One of the most common malignancies among men and women in the world, is the leading cause of cancer related death. Radiotherapy, surgery, and chemotherapy are recognized as front-line channels for cancer treatment. Advanced tumors are occasionally resistant to single agent therapy. Combination therapy drugs are more effective in curing different types of cancers at advanced stages. Combination chemotherapy can be potent for people with advanced cancers compared to radiation therapy or surgical treatment. The rationale for combination therapy drugs is that these drugs have different mechanisms. Effective and favorable drug combinations have been explored to search for effective combination therapeutics to significantly improve their outcomes in cancer treatment
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