The combination of antitumor drugs, exemestane and erlotinib, induced resistance mechanism in H358 and A549 non-small cell lung cancer (NSCLC) cell lines

Abstract

Context: Estrogens in non-small-cell lung cancer (NSCLC) are important, and their interaction with epidermal growth factor receptor (EGFR) might be crucial. Objective: This study investigates the effect of exemestane, an aromatase inhibitor, and erlotinib, an EGFR inhibitor, on human NSCLC cell lines; H23, H358 and A549. Materials and methods: A cell proliferation assay was used for measuring cell number, apoptosis assay for detecting apoptosis and necrosis and immunoblotting for beclin-1 and Bcl-2 proteins detection. An immunofluorescence assay was used for EGFR localization. A migration assay and zymography were used for cell motility and metalloproteinases (MMPs) expression, respectively. Results: Exemestane, erlotinib or their combination decreased cell proliferation and increased apoptosis. Exemestane's half maximal inhibitory concentration (IC 50 ) was 50 mM for H23 and H358 cells and 20 mM for A549. The IC 50 of erlotinib was 25 mM for all cell lines. Apoptosis increase induced by exemestane was 58.0 (H23), 186.3 (H358) and 34.7% (A549) and by erlotinib was 16.7 (H23), 65.3 (H358) and 66.3% (A549). A synergy effect was observed only in H23 cells. Noteworthy, the combination of exemestane and erlotinib decreased beclin-1 protein levels (32.3 AE 19.2%), an indicator of autophagy, in H23 cells. The combination of exemestane and erlotinib partially reversed the EGFR translocation to mitochondria and decreased MMP levels and migration. Discussion and conclusions: The benefit from a dual targeting of aromatase and EGFR seems to be regulated by NSCLC cell content. The diverse responses of cells to agents might be influenced by the dominance of certain molecular pathways.

In�silico analysis identified miRNA‑based therapeutic agents against glioblastoma multiforme

“…However, to the best of our knowledge, its antitumor effect on GBM has not yet been elucidated. A study by Kritikou et al (68) revealed that the combination of exemestane and erlotinib significantly inhibited EGFR mitochondrial translocation. The EGFR mitochondrial translocation event serves important roles in tumor progression (69) and contributes to drug resistance (70).…”

Curcumin induced apoptosis via PI3K/Akt-signalling pathways in SKOV3 cells

“…The PI3K and the downstream serine/threonine kinase Akt (also known as protein kinase B, PKB) modulate cellular activation, inflammatory response and apoptosis (Fruman & Cantley 2002;Zhang et al 2008). More importantly, the PI3K/Aktsignalling pathway is frequently activated in many types of human cancers including colorectal carcinoma (Luo et al 2003;Kritikou et al 2014;Murugan et al 2015) and has been linked to cancer development. Phosphoinositide 3-kinase (PI3K)-signalling pathway components are crucial to many aspects of cell growth and survival in colorectal carcinoma (CRC) via its regulation in diverse physiologic processes that include cell proliferation, cell-cycle progression, invasion and apoptosis (Kermorgant et al 2001).…”

A Novel Assay for Profiling GBM Cancer Model Heterogeneity and Drug Screening

“…Microtumors (5–6 per group) and spheroids were tested for anti-tumor activity profiles of 6 selected drugs (Table 2) using EC25 or EC50 treatment doses (0–10 μM range) based on literature [28,29,30,31,32]. Cell proliferation activity of microtumors and spheroids were determined with CellTiter-Glo assay kit during the optimized 1 to 14 day culture period.…”