1st International and 10th National Iranian Conference on Bioinformatics

Home Accepted Papers

Bioinformatic Selection and Evaluation of Novel Drug Candidates to Inhibit Notch Signaling Pathway Based on Drug Repositioning Approach

Paper ID : 1428-ICB10

Authors:

Mina Mirian *¹, عباس جعفریان دهکردی², فاطمه سفاری³, امیرعلی حریری⁴

¹هیات علمی دانشگاه علوم پزشکی اصفهان، دانشکده داروسازی، گروه بیوتکنولوژی دارویی

²هیات علمی دانشگاه علوم پزشکی اصفهان، دانشکده داروسازی، گروه فارماکولوژی

³داروساز عمومی

⁴دانشجوی داروسازی دانشگاه علوم پزشکی اصفهان، دانشکده داروسازی، گروه بیوتکنولوژی دارویی

Abstract:

The notch signaling pathway has a vital role in cell division, proliferation and cell survival among other pathways (1). There are some evidences that show inhibition of this pathway could overcome drug resistance in chemotherapy (2). Several attempts have been performed to block this pathway independently and concurrently with chemotherapy in cancer therapies. Drug repositioning -using approved drugs for new purposes- has been interested as a new strategy for drug development (3). Here, some approved drugs were selected with respect to Notch 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 accuracy of docking results, A549 cells were treated with selected drugs, and cell survival was determined using MTT assay and flowcytometry analysis. Moreover, A549 cells were simultaneously treated with doxycycline and ibuprofen to evaluate synergism effects.
ADAM17 protein was selected as a critical protein for blocking the Notch pathway, based on intracellular network findings. Doxycycline, tetracycline, ibuprofen, diclofenac and meloxicam were selected by docking. For each drug, IC50 was determined against the A549 cell line. Doxycycline and ibuprofen showed a synergistic cytotoxic effect on A549 cells when they were simultaneously used. The flowcytometry results showed doxycycline and ibuprofen can induce cell death using apoptosis mechanisms, especially in the co-treatment conditions.
Taken together, the determination of ADAM17 relation with other proteins and transformation in cancers has illustrated the importance of this protein (4). These findings showed the cytotoxic effects of doxycycline and ibuprofen on A549 cell lines, especially when they were simultaneously applied. These findings suggest that selected drugs could be utilized for lung cancer chemotherapy, after more investigation.

Keywords:

Drug Repositioning, Lung Cancer, Notch Signaling Pathway

Status : Paper Accepted (Poster Presentation)