Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autophagy is known as an important regulatory mediator for cell survival or death and its important role in cancer. Pemetrexed (PTX) has been used in chemotherapy for lung cancer. However, the underlying molecular mechanisms have not been fully clarified. To investigate the role of autophagy induced by PTX in A549 cells, we performed MTT assay, acridine orange staining, western blotting, Annexin V/PI by using the 3-MA autophagy inhibitor. PTX induced autophagy after 48 h treatment in A549 cells. Furthermore, PTX showed acidic vesicular organelles (AVOs) and expressed LC3-II in A549 cells. The induction of autophagy by PTX was inhibited by 3-MA which was confirmed by reduced AVOs. When the autophagy was inhibited, Annexin V was increased. In addition, PARP cleavage was increased as shown by western blotting. Taken together, PTX induced autophagy in A549 cells and these cellular events possibly cause the apoptotic and/or necrotic cell death of A549 cells.
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PMID:The role of autophagy induced by pemetrexed in lung adenocarcinoma cells. 2462 22

GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway-related genes, deoxyuridine triphosphatase and dihydrofolate reductase, the silencing of which sensitized non-small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of dihydrofolate reductase currently used to treat patients with nonsquamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate PARPs, thereby accelerating NAD consumption. Genetic or pharmacologic blockade of PARP activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat nonsquamous NSCLC.
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PMID:Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption. 2514 69