The notch signaling pathway has a vital role in cell division, proliferation and cell survival among otherpathways. There are some evidences that show inhibition of this pathway could overcome drug resistance inchemotherapy. Several attempts have been performed to block this pathway independently and concurrentlywith chemotherapy in cancer therapies. Drug repositioning -using approved drugs for new purposes- has beeninterested as a new strategy for drug development. Here, some approved drugs were selected with respect toNotch pathway and their cytotoxic effects were evaluated with drug repositioning approach.KEGG and Reactome databases were used to identify the critical proteins in Notch signaling pathway. Then,molecular docking has performed on the target protein using Auto dock software. To evaluate the accuracyof docking results, A۵۴۹ cells were treated with selected drugs, and cell survival was determined using MTTassay and flowcytometry analysis. Moreover, A۵۴۹ cells were simultaneously treated with doxycycline andibuprofen to evaluate synergism effects.ADAM۱۷ protein was selected as a critical protein for blocking the Notch pathway, based on intracellularnetwork findings. Doxycycline, tetracycline, ibuprofen, diclofenac and meloxicam were selected by docking.For each drug, IC۵۰ was determined against the A۵۴۹ cell line. Doxycycline and ibuprofen showed asynergistic cytotoxic effect on A۵۴۹ cells when they were simultaneously used. The flowcytometry resultsshowed doxycycline and ibuprofen can induce cell death using apoptosis mechanisms, especially in the cotreatmentconditions.Taken together, the determination of ADAM۱۷ relation with other proteins and transformation in cancershas illustrated the importance of this protein (۴). These findings showed the cytotoxic effects of doxycyclineand ibuprofen on A۵۴۹ cell lines, especially when they were simultaneously applied. These findings suggestthat selected drugs could be utilized for lung cancer chemotherapy, after more investigation.