Marine actinomycete crude extracts with potent TRAIL-resistance overcoming activity against breast cancer cells

Abstract

Abstract. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, as it can kill tumor cells selectively. In our search of bioactive natural products to overcome TRAIL-resistance, we isolated 47 actinomycete strains from different sediments and seawater samples collected from the Red Sea coast in Egypt and found four crude extracts (EGY1, EGY3, EGY24 and EGY34) displaying TRAIL sensitizing activity in the resistant breast cancer cell line MDA-MB-231. None of these crude extracts exhibited cytotoxic effect on normal mouse embryonic fibroblasts (MEF), with the exception of EGY34. Analysis of the signaling pathways underlying the sensitization of MDA-MB-231 cells to TRAIL-induced apoptosis, by western blotting, revealed that all crude extracts facilitated initiator caspase-8/-10 activation upon TRAIL stimulation, but that in addition, EGY3 and EGY34, alone, induced strong ER-stress activation, with the appearance of BiP in the cytosolic extracts. Our results pave the way to the discovery and the development of marine-derived drugs for cancer therapy.

Marine Actinomycetes-Derived Secondary Metabolites Overcome TRAIL-Resistance via the Intrinsic Pathway through Downregulation of Survivin and XIAP

“…In order to avoid bias due to the fluorescent properties of some of our compounds and with the aim of evaluating whether the latter may nonetheless enhance TRAIL-induced apoptosis, like the actinomycetes EGY1 and EGY34 crude extracts [ 30 ] from which some of the secondary metabolites were extracted, we quantified apoptosis using Hoechst dye. As shown in Figure 4 , all compounds, at 50 µM were able to alone trigger the formation of apoptotic bodies, 6 hours after stimulation as visualized by chromatin condensation under the microscope ( Figure 4 A,B).…”

“…Marine environment covers more than 70% of the earth’s surface and encompasses a great biodiversity of unexplored microorganisms that are likely to provide an interesting source of novel bioactive secondary metabolites [ 58 , 59 ], including compounds displaying ability to increase apoptosis induced by TRAIL [ 60 , 61 , 62 ]. Egypt is surrounded on the east and north by the Red Sea and the Mediterranean Sea with unique microbial communities, particularly actinomycetes [ 30 , 63 , 64 , 65 , 66 ], which are distributed in a variety of marine habitats including sediments and sponges [ 30 , 63 ]. According to the molecular data of 16S rRNA gene sequence analysis, Streptomyces and Micromonospra sp were considered as the main producers of novel secondary metabolites that possess a significant pharmaceutical potential against chemotherapeutic-resistant cancers [ 58 , 65 ].…”

“…The in vitro cytotoxicity of the marine secondary metabolites ( 1 – 8 ) was measured by methylene blue assay as previously described [ 30 ]. In brief, HCT116 and MDA-MB-231 cells were cultured at 4 × 10 4 cells/well in flat-bottomed 96 well plates and then treated with various concentrations of the secondary metabolites (sharkquinone, resistomycin, undecylprodigiosin, butylcycloheptylprodigiosin, elloxazinone A and B, carboxyexfoliazone, and exfoliazone) and incubated at 37 °C for 24 h. Following incubation, the culture media was removed, and the cells were washed three times with 100 µL PBS.…”

“…Because, we and others have demonstrated that crude extracts from marine actinomycetes may represent a novel source of TRAIL sensitizers [ 22 , 30 , 31 ], the present study was conducted to investigate the TRAIL-resistance overcoming or sensitizing ability of eight marine actinomycetes-derived secondary metabolites (sharkquinone, resistomycin, undecylprodigiosin, butylcycloheptylprodigiosin, elloxazinone A and B, carboxyexfoliazone, and exfoliazone).…”

Synthesis of novel bis‐ and poly(benzimidazoles) as well as bis‐ and poly(benzothiazoles) as anticancer agents

“…The anticancer activity of 20 synthesized compounds was estimated against liver cancer cell line (HepG‐2), human breast adenocarcinoma cell line (MCF‐7), and epithelial colorectal adenocarcinoma cells (CaCO‐2) using MTT (3‐[4,5‐dimethylthiazol‐2‐y1]‐2,5‐diphenyltetrazolium bromide) method . The cell lines were obtained from the American Type Culture Collection.…”