Investigation of the toxic effects and mechanism of in vitro cancer cells of nano-drug-modified ceramidase inhibitors.

Cancer is an area where the most drug researches are conducted in the field of health and new drugs are rapidly introduced into clinical use. In recent years, with the development of nanoparticle based drugs, it is aimed to provide targeted toxic effects on cancer cells and lower side effects in healthy cells. For this purpose, nanoparticles targeting various mechanisms and molecules in signaling cell proliferation and differentiation are being developed. Ceramidase is an enzyme that converts ceramide into sphingosine 1-phosphate and fatty acids. Acid ceramidase activity has been shown to be increased in tumor cells compared to normal cells. In addition, overexpression of ceramidases renders tumor cells resistant to tumor necrosis factor and radiation. For these reasons, ceramidase inhibitors are important targets in the development of anticancer drugs. In addition to its effects on thymidilate synthetase, fluorouracil and carmofur, which are also inhibitors of ceramidase were loaded into nanotransport systems and their effects on breast cancer cell lines MCF-7, MDA-MB-231 and HUVECs were investigated. For this purpose, Rosin ester, which is a biocompatible nanocarrier, and Poly-Ethylene-Glycol were used. Cytotoxic effects of nanoparticles were investigated by SEM and DLS. The cytotoxic effects of our nanoparticles in the range of 10-100 concentration μM on breast cancer cells were determined. The cytotoxic activity of nano 5-FU and nano carmofur was found to be higher in the MCF-7 cell line than in the MDA-MB-231 cell line. In our study S1P, ASAH1 enzyme levels and Bcl-2 protein expression decreased compared to control cells, especially for S1P and ASAH1. This result was lower for nano carmofur applied cells. Therefore, we think that 5-FU and carmofur effect cell death by acting on ASAH1 and S1P. ASAH1 and S1P enzymes activity may increase when loading of these drugs into the nano carriers. There were no significant changes in ASAH1 and S1P enzyme levels in healthy HUVEC cells, these results suggest that our nano compounds can be used on cancer cells.