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Nanoparticle–Based RNA (siRNA) Combination Therapy Toward Overcoming Drug Resistance in Cancer
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
In response to MDR associated with the alterations of the apoptosis pathways, therapeutic nanoparticles have been co-encapsulated with compounds that repair the dysfunctional apoptotic signaling. One example of such pro-apoptotic compound is ceramide, which is produced by cells under environmental stress and serves as a key messenger in programmed cell death. Some MDR cancer cells hinder apoptosis initiation by over-expressing glucosylceramide synthase that converts ceramide to its inactive, glycosylated form. To address the ceramide metabolism, a polymeric micelle formulation based on poly(ethylene oxide)-poly(epsilon caprolactone) (PEO-PCL) was prepared to co-deliver exogenous ceramide and paclitaxel [96]. Against a paclitaxel-resistant ovarian cancer cell line (SKOV-3TR), the combinatorial formulation was found to raise paclitaxel sensitivity of the MDR cells to the same level as non-MDR cells. Combination with ceramide showed a 100-fold increase in efficacy as compared to paclitaxel-only nanoparticles. Caspase activity study and western blotting results suggest that the co-delivery of ceramide encouraged programmed cell death in the MDR cells. In a more recent study, the combinatorial formulation of ceramide and paclitaxel was found to show improved efficacy against MDR tumors in vivo using a PLGA nanoparticle system [97]. The co-delivery system was shown to increase apoptotic activity and tumor reductions in murine models without significant liver toxicity or reduction in white blood cell count.
Lysosomal Storage Disorders and Enzyme Replacement Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Gaucher disease (GD; named after the French physician Philippe Gaucher, who originally described it in 1882) the most common among the different LSDs is based on mutations of the gene encoding glucosylceramide-β-glucosidase (also named glucocerebrosidase, acid β-glucosidase, and abbr. as GCase or GBA), and occurs in three different forms. In Type I GD the most common GBA mutation is N370S; this GD is also called the “non-neuropathic” type and occurs mainly in Ashkenazi Jews, whereas types II and III have no ethnic predilection, but the largest number of patients with type III GD has been reported from the province of Norrbotten, Sweden (Dahl et al., 1990). In both type II and III GD the characteristic mutation is L483P. Type II GD, also known as acute neuronopathic, occurs in newborns and infants and has a poor prognosis, whereas in case of the chronic neuropathic type III GD, progression of neurologic involvement is usually slower than in type 2 GD, possibly due to protective polymorphisms (e.g., Ortiz-Cabrera et al., 2016 and literature cited therein).
The Role of Nanotechnology in the Treatment of Drug Resistance Cancer
Published in Bhaskar Mazumder, Subhabrata Ray, Paulami Pal, Yashwant Pathak, Nanotechnology, 2019
Sandipan Dasgupta, Anup Kumar Das, Paulami Pal, Subhabrata Ray, Bhaskar Mazumder
Ceramide is a very important molecule in the cell membrane. It also acts as a second messenger in different signaling pathways, including in apoptosis and immune response (Kolesnick and Kronke, 1998; Struckhoff et al., 2004). During radiation and chemotherapeutic treatment, ceramide activates the apoptotic pathway and is also involved in the clustering of the death receptor (CD95) (Gulbins and Grassme, 2002; Kolesnick and Kronke, 1998; Pettus et al., 2002; Schenck et al., 2007). Additionally, ceramide is available in the mitochondrial outer membrane in the permeable channels, which allow the secretion of pro-apoptotic factors such as cytochrome C (Elrick et al., 2006; Siskind, 2005; Siskind et al., 2006). In the mechanism of MDR, the overexpression of glucosylceramide synthase, an enzyme which alters active ceramide into an inactive glucosylceramide, leads to an increase in the threshold of apoptotic cells, a reduction in signaling potential, and a decrease in the amount of intracellular ceramide level (Itoh et al., 2003; Morjani et al., 2001; Senchenkov et al., 2001).
Ceramide pathway: A novel approach to cancer chemotherapy
Published in Egyptian Journal of Basic and Applied Sciences, 2018
Mahdi Mashhadi Akbar Boojar, Masoud Mashhadi Akbar Boojar, Sepide Golmohammad
The entrance of ceramide to the Golgi apparatus is considered as the gateway for the manufacture of glycosphingolipids [29]. In this case, the first step is the addition of glucose from UDP-glucose to ceramide by glucosylceramide synthase enzyme and glucosylated ceramide production [17]. In the next steps, various products of glycosphingolipids, which are mainly structural and cellular markers, are derived from this mediator or additional glucosylated ceramides in the inverse pathway of the reaction are converted by cerebrosidase into its constructive ceramide [3]. Thus, the activity of glucosylceramide synthase is a cell rescuer from ceramide-induced apoptosis and a way to chemotherapy resistance [38].
The effect of portulaca oleracea alkaloids on antidiabetic properties through changes in ceramide metabolism
Published in Egyptian Journal of Basic and Applied Sciences, 2021
Hanie roozi, Masuod Mashhadi Akbar Boojar, Akram Eidi, Ramezanali Khavari-Nejad
Ceramide content elevation is associated with the induction of insulin resistance and may be toxic in a variety of different cell types [7,10]. So, determining the effects of antidiabetic treatment on the ceramide pathway is essential. The biosynthesis and biodegradation of ceramide arise from the function of different enzymatic systems, and they can be affected by several endogenous and exogenous agents. Acid ceramidase (AC) and glucosylceramide synthase (GCS) (as major ceramide degradation factors), and neutral sphingomyelinase (NS) (as a ceramide generator) are the critical enzymes in ceramide metabolism [11].