Econazole nitrate inhibits PI3K activity and promotes apoptosis in lung cancer cells

Abstract

The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in many cellular processes, including the proliferation, survival and differentiation of lung cancer cells. Thus, PI3K is a promising therapeutic target for lung cancer treatment. In this study, we applied free and open-source protein-ligand docking software, screened 3167 FDA-approved small molecules, and identified putative PI3Kα inhibitors. Among them, econazole nitrate, an antifungal agent, exhibited the highest activity in decreasing cell viability in pathological types of NSCLC cell lines, including H661 (large cell lung cancer) and A549 (adenocarcinoma). Econazole decreased the protein levels of p-AKT and Bcl-2, but had no effect on the phosphorylation level of ERK. It inhibited cell growth and promote apoptosis in a dose-dependent manner. Furthermore, the combination of econazole and cisplatin exhibited additive and synergistic effects in the H661 and A549 lung cancer cell lines, respectively. Finally, we demonstrated that econazole significantly suppressed A549 tumor growth in nude mice. Our findings suggest that econazole is a new PI3K inhibitor and a potential drug that can be used in lung cancer treatment alone or in combination with cisplatin.

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

“…Remarkably, the π-Stacking interaction is constructed with TYR 867. So, we thought that TIC might be a potent inhibitor of PI3K due to the primary pharmacological structure of TIC is an imidazole ring similar to the structure of Econazole, as imidazole antifungal that recently docked PI3K by −7.3 kcal/mol that diminished P-AKT and Bcl2 protein levels [ 34 ]. In our in-silico study, the molecular docking approach was used to study the molecular affinity of TIC with autophagic related proteins ATG4B and PI3Kα, γ isoforms compared to CQ and DOX.…”

Econazole Induces p53-Dependent Apoptosis and Decreases Metastasis Ability in Gastric Cancer Cells

“…In another study, econazole-treated NS1 myeloma cell lines showed reduced proliferation, viability, survival, and dose-dependent changes in DNA synthesis (Denyer et al, 1985). Imidazole antifungal drugs are known to inhibit the proliferation and invasion of breast cancer cells (Bae et al, 2018) and suppress phosphoinositide 3-kinase (PI3K) activity and cause apoptosis of lung cancer cells (Dong et al, 2017). In PC3 human prostate cancer cells, econazole increased the intercellular concentration of Ca 2+ by stimulating Ca 2+ influx into cells and Ca 2+ release from the endoplasmic reticulum via a phospholipase C (PLC)-independent mechanism and inhibited cell proliferation in a dose-dependent manner (Huang et al, 2005).…”

An in vivo Like Micro-Carcinoma Model

“…EGFR, can affect cell proliferation, invasion and angiogenesis (33). BCL-XL promotes cell survival by indirect inhibition of the activity of a pro-apoptotic pathway and is related with proliferation, survival and differentiation of lung cancer cells (34). MYC has been associated to abnormal autonomous proliferation and growth, angiogenesis and suppression of host immune responses (35) and overexpression of EPCAM has been associated epithelial tumors, specifically with an increase in migratory potential (36).…”