Abstract
BackgroundGastric cancer (GC) is a multifactorial disease with high mortality. Anti-HER2 therapy is a promising strategy in GC treatment and trastuzumab was approved by FDA (Food and Drug Administration) as the first and the second line of treatment of the disease.PurposeThe aim of the study was to examine the effectiveness of a combination of etoposide with trastuzumab or pertuzumab in AGS gastric cancer cells and breast cancer cells such as MCF-7, MDA-MB-231 and HCC1954.Methods and findingsThe cytotoxic effects of the tested compounds against gastric and breast cancer cells were checked by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assay. The anti-proliferative potential was analyzed by the incorporation of [3H]-thymidine into DNA. Fluorescent microscopy and flow cytometry was used to demonstrate the effect of the compounds on apoptosis. The mitochondrial membrane potential, and the activity of caspase-8 and caspase-9 were assessed. Autophagosomes and autolysosomes formation was checked by flow cytometry. The concentrations of Beclin-1, LC3A and LC3B were performed using ELISA. The expression of LC3A/B was also determined. The results from our study proved that the combination of etoposide with anti-HER2 antibodies was not cytotoxic against breast cancer cells, whereas the combination of etoposide with anti-HER2 antibodies decreased viability and DNA biosynthesis in gastric cancer cells. The interaction of etoposide with pertuzumab or trastuzumab induced programmed cell death via extrinsic and intrinsic apoptotic pathways in AGS gastric cancer cells, but did not affect autophagy, where a decrease of Beclin-1, LC3A and LC3B was observed in comparison with the untreated control.ConclusionsThe study demonstrated that etoposide (12.5 μM) with pertuzumab represent a promising strategy in gastric cancer treatment, but further in vivo examinations are also required.
Highlights
Human epidermal growth factor receptor 2 (HER2) molecular pathway plays a significant role in the etiopathogenesis of many types of cancer and anti-HER2 therapy represents an important approach in targeted anticancer treatment [1]
The study demonstrated that etoposide (12.5 μM) with pertuzumab represent a promising strategy in gastric cancer treatment, but further in vivo examinations are required
The preliminary studies were performed to check the effect of etoposide and its combination with trastuzumab and pertuzumab on the viability of breast cancer cells
Summary
Human epidermal growth factor receptor 2 (HER2) molecular pathway plays a significant role in the etiopathogenesis of many types of cancer and anti-HER2 therapy represents an important approach in targeted anticancer treatment [1]. Monoclonal antibodies (trastuzumab and pertuzumab) and tyrosine kinase inhibitors are commonly used in treatment of cancer with overexpressed HER2 [2,4]. The first indication for the use of this antibody was HER2+ metastatic breast cancer, but FDA approved it in HER2 positive metastatic gastric cancer, where represents the first line of treatment [5]. Clinical trials, where the efficacy of antibody drug conjugates or tyrosine kinase inhibitors are still ongoing in HER2+ advanced gastric cancer [6]. The antibody drug conjugate (trastuzumab emtansine) showed promising tumor inhibitory effect in preclinical studies, but in one randomized trial, T-DM1 was not superior to chemotherapy in patients with HER2-positive advanced gastric cancer [7]. The aim of the study was to examine the effectiveness of a combination of etoposide with trastuzumab or pertuzumab in AGS gastric cancer cells and breast cancer cells such as MCF-7, MDA-MB-231 and HCC1954
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