Malignant mesothelioma (MM) is a tumor arising from mesothelium. MM patients’ survival is poor. The polyphenol 4′,5,7,-trihydroxyflavone Apigenin (API) is a “multifunctional drug”. Several studies have demonstrated API anti-tumoral effects. However, little is known on the in vitro and in vivo anti-tumoral effects of API in MM. Thus, we analyzed the in vitro effects of API on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, and autophagy of human and mouse MM cells. We evaluated the in vivo anti-tumor activities of API in mice transplanted with MM #40a cells forming ascites. API inhibited in vitro MM cells survival, increased reactive oxygen species intracellular production and induced DNA damage. API activated apoptosis but not autophagy. API-induced apoptosis was sustained by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of both caspase 9 and caspase 8, cleavage of PARP-1, and increase of the percentage of cells in subG1 phase. API treatment affected the phosphorylation of ERK1/2, JNK and p38 MAPKs in a cell-type specific manner, inhibited AKT phosphorylation, decreased c-Jun expression and phosphorylation, and inhibited NF-κB nuclear translocation. Intraperitoneal administration of API increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of tumor growth. Our findings may have important implications for the design of MM treatment using API.
In this paper, multitasking core-shell Fe 3 O 4 @Cu@Au superparamagnetic nanoparticles (MNPs) functionalised either with folic acid (FA) or methotrexate (MTX) have been used for engulfment of human granulocytes. MNPs internalisation into phagocytes allows to use the cells as carriers thus avoiding the rapid clearance and decreasing of concentration commonly experienced in case of in vivo nanoparticles administration. MNPs have been coated with poly-L-lysine (PLL), which contributes to improve their dispersion into polar solvents. Moreover, this coating improves the cellular uptake and allows the further functionalisation with MTX and FA. Experimental evidences of granulocytes engulfment have been obtained by both SEM and fluorescence microscopy, upon prior labelling of the lysines residues with suitable fluorescent probes. The superparamagnetic nature of the MNPs makes the system easily drivable into a specific tissue upon exposure to a defined magnetic field. The success of the internalisation experiments indicates that the system is a promising tool as theranostic agent for treatment of a variety of diseases, including tumours.
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