ABSTRACT
Breast cancer is a group of diseases in which cells divide out of controlled, typically resulting in a mass. Erlotinib is targeted cancer drug which functions as an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It is used mainly to treat of non-small cell lung cancer patients and has an action against pancreatic cancer. Vorinostat (aka suberanilohydroxamic acid) is an inhibitor of histone deacetylases (HDAC), which has an epigenetic modulation activity. It is used to treat cutaneous T cell lymphoma. In the present study, the erlotinib (ERL) and vorinostat (SAHA) loaded TiO2 nanoparticles (NPs) were used for the treatment of the breast cancer cells (MDA-MB-231 and MCF-7) and human cancerous amniotic cells (WISH). Cell count and viability were negatively affected in all treatments compared to normal cells and bare TiO2 NPs. Apoptosis results indicated a significant increase in the total apoptosis in all treatments compared with control cells. ERL- and SAHA-loaded TiO2 NPs treatments arrested breast cancer cells at G2/M phase, which indicate the cytotoxic effect of these treatment. Partner and localizer of BRCA2 (PALB2) gene expression was assessed using qPCR. The results indicate that PLAB2 was upregulated in ERL- and SAHA-loaded TiO2 NPs compared with control cells and can be used as nanocarrier for chemotherapy drugs. However, this conclusion necessitates further confirmative investigation.
ABSTRACT
Gelatinolytic matrix metalloproteinases (MMP-2, -9) play a critical role not only in mammals physiology but also during inflammation and healing processes. The natural stilbenoid, resveratrol (RES), exhibits potent antioxidant effects, in a hormetic mode of action, and is known to inhibit MMP-9. However, RES administration exhibits major issues, including poor bioavailability and water solubility, hampering its potential therapeutic effect in vivo In the present study, we synthesized and evaluated five novel RES-lipid conjugates to increase their cell membrane penetration and improve their bioavailability. The best in vitro MMP-9 inhibitory activity of RES-lipids conjugates was observed with RES-linoleic acid (LA) (5 µM), when dissolved in a natural deep eutectic solvent (NADES), composed of an equimolar content of 1,2-propanediol:choline chloride (ChCl):water. The inhibition of MMP-9 expression by RES-LA in activated THP-1 monocytes, was, at least due to the deactivation of ERK1/2 and JNK1/2 MAP kinase signaling pathways. Moreover, RES-LA exhibited a strong effect protecting the TNF-α-induced exacerbated permeability in an HUVEC in vitro monolayer (by 81%) via the integrity protection of intercellular junction proteins from the MMP-9 activity. This effect was confirmed by using several complementary approaches including, the real-time monitoring of trans-endothelial electric resistance (TEER), the Transwell HUVEC permeability level, the microscopic examination of the platelet endothelial cell adhesion molecule-1 (CD31/PECAM-1) integrity as well as the fluorescence in intercellular spaces. Consequently, following this strong in vitro proof-of-concept, there is a need to test this promising RES-lipid derivative compound to control the pathological endothelial permeability in vivo.
