Suppression of multidrug resistance by treatment with TRAIL in human ovarian and breast cancer cells with high level of c-Myc

Abstract

In this study, we investigated the role of c-Myc in overcoming multidrug resistance (MDR) in human ovarian and breast cancer cells by TRAIL. We showed that P-gp expressing MDR variants (Hey A8-MDR and MCF7-MDR cells) with high level of c-Myc were highly susceptible to TRAIL treatment when compared to their drug-sensitive parental human ovarian cancer Hey A8 and breast MCF-7 cells, respectively. Up-regulation of DR5 TRAIL receptor and down-regulation of c-FLIP and the promotion of caspase-dependent cell death, which contribute to TRAIL sensitization of MDR cells, were regulated by the over-expressed c-Myc in the MDR cells. After targeted inhibition of c-Myc with specific siRNA, these responses to TRAIL disappeared and TRAIL-induced apoptosis was also suppressed in MCF7-MDR cells. Treatment with TRAIL significantly reduced P-glycoprotein (P-gp)-mediated efflux of rhodamine123 in both Hey A8-MDR and MCF7-MDR cells. Furthermore, TRAIL significantly potentiated the cytotoxicity of vinblastine, vincristine, doxorubicin and VP-16 that are P-gp substrate anticancer drugs in both MDR cells, which resulted in the reversal effect of TRAIL on the MDR phenotype. The present study shows for the first time that elevated c-Myc expression in the MDR cells plays a critical role in overcoming MDR by TRAIL that can act as a specific sensitizer for P-gp substrate anticancer drug.

Sphingomyelin synthase 2 overexpression promotes cisplatin‑induced apoptosis of HepG2 cells

“…c-Myc not only modulates the expression of growth genes, but also participates in the expression of DR4 and DR5, which are associated with apoptosis (20,21). When c-Myc was overexpressed, the expression of DR4 and DR5 were also increased, which led to an increase in the sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as DR4 and DR5 are TRAIL receptors (20,21).…”

“…When c-Myc was overexpressed, the expression of DR4 and DR5 were also increased, which led to an increase in the sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as DR4 and DR5 are TRAIL receptors (20,21). This may overcome multidrug resistance in human ovarian, breast and gastric carcinoma cells (20,21).…”

Quantitative immunoproteomics analysis reveals novel MHC class I presented peptides in cisplatin-resistant ovarian cancer cells

“…To validate the results of MHC peptide identification, nine experimentally observed peptides, sTRkDYPAAk (Myc protooncogene protein) [27,28] ILDKkVEkV (Heat shock protein HSP 90-beta) [29], rLAADDFRV (Keratin, type I cytoskeletal 18) [30], rVAPRSGLAAk (Deoxyuridine 5′-triphosphate nucleotidohydrolase, mitochondrial) [31], rVIGTLEEV (Ran GTPase-activating protein 1) [32], yLAPHVRTL (COP9 signalosome complex subunit 1) [33,34], aLSDGVHkI (Fas apoptotic inhibitory molecule 1) [35], rTLAEIAkV (Non-POU domain-containing octamer-binding protein) [22], and vLIDYQRNV (Exportin-1) [36] were selected for synthesis ( Table 2) based on the vital role of their precursor proteins in drug-resistant ovarian cancer [22,[27][28][29][30][31][32][33][34][35][36][37]. The tandem mass spectrometry data of the experimentally observed peptides and their corresponding synthetic analogs are given in Fig.…”

Co-delivery of IL17RB siRNA and doxorubicin by chitosan-based nanoparticles for enhanced anticancer efficacy in breast cancer cells

“…For this purpose, positively charged polysaccharide Chitosan nanoparticles due to their unique properties such as biocompatibility, biodegradability [27,28], non-immunogenicity, high absorption [29] and increased membrane permeability [30] are used for the delivery of DOX. Chitosan is a cationic modified polysaccharide, composed of the repeating units of N-acetyl glucosamine and glucosamine, produced from the partial deacytelation of chitin in alkaline solution which was derived from the shell of insects and some crustaceans like lobsters for the first time [31].…”