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New drug delivery systems are highly needed in research and clinical area to effectively treat gliomas by reaching a high antineoplastic drug concentration at the target site without damaging healthy tissues. Intranasal (IN) administration, an alternative route for non-invasive drug delivery to the brain, bypasses the blood-brain-barrier (BBB) and eliminates systemic side effects. This study evaluated the antitumor efficacy of farnesylthiosalicylic acid (FTA) loaded (lipid-cationic) lipid-PEG-PLGA hybrid nanoparticles (HNPs) after IN application in rats. FTA loaded HNPs were prepared, characterized and evaluated for cytotoxicity. Rat glioma 2 (RG2) cells were implanted unilaterally into the right striatum of female Wistar rats. 10 days later, glioma bearing rats received either no treatment, or 5 repeated doses of 500 μM freshly prepared FTA loaded HNPs via IN or intravenous (IV) application. Pre-treatment and post-treatment tumor sizes were determined with MRI. After a treatment period of 5 days, IN applied FTA loaded HNPs achieved a significant decrease of 55.7% in tumor area, equal to IV applied FTA loaded HNPs. Herewith, we showed the potential utility of IN application of FTA loaded HNPs as a non-invasive approach in glioblastoma treatment. [ABSTRACT FROM AUTHOR]

Objectives We aimed to develop lipid-polyethylene glycol ( PEG)-polymer hybrid nanoparticles, which have high affinity to tumour tissue with active ingredient, a new generation antineoplastic drug, farnesylthiosalicylic acid ( FTA) for treatment of glioblastoma. Method Farnesylthiosalicylic acid-loaded poly(lactic-co-glycolic acid)-1,2 distearoyl-glycerol-3-phospho-ethanolamine-N [methoxy ( PEG)-2000] ammonium salt ( PLGA- DSPE- PEG) with or without 1,2-dioleoyl-3-trimethylammonium-propane ( DOTAP) hybrid nanoparticles has been prepared and evaluated for in-vitro characterization. Cytotoxicity of FTA-loaded nanoparticles along with its efficacy on rat glioma-2 ( RG2) cells was also evaluated both in vitro (in comparison with non-malignant cell line, L929) and in vivo. Key findings Scanning electron microscopy studies showed that all formulations prepared had smooth surface and spherical in shape. FTA and FTA-loaded nanoparticles have cytotoxic activity against RG2 glioma cell lines in cell culture studies, which further increases with addition of DOTAP. Magnetic resonance imaging and histopathologic evaluation on RG2 tumour cells in rat glioma model (49 female Wistar rats, 250-300 g) comparing intravenous and intratumoral injections of the drug have been performed and FTA-loaded nanoparticles reduced tumour size significantly in in-vivo studies, with higher efficiency of intratumoral administration than intravenous route. Conclusion Farnesylthiosalicylic acid-loaded PLGA- DSPE- PEG- DOTAP hybrid nanoparticles are proven to be effective against glioblastoma in both in-vitro and in-vivo experiments. [ABSTRACT FROM AUTHOR]

Novel series of Farnesylthiosalicylic acid-diamine/phenylpropenoic acid hybrids were designed and synthesized. Their in vitro growth inhibitory assays showed that most compounds displayed strong antiproliferation activity against seven cancer cells. Especially, the new hybrid 12f, by the conjugation of 10a with ferulic acid, could selectively suppress the proliferation of tumor cells and display significantly lower toxicities to normal cells than its intermediate 10a. Furthermore, 12f dose-dependently induced SMMC-7721 cell apoptosis. Additionally, our observations demonstrated that 12f inhibited both Ras-related signaling and phosphorylated NF- κB synergistically, which may be advantageous to the strong antitumor activities of 12f. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers. [ABSTRACT FROM AUTHOR]

Novel FTS-diamine/cinnamic acid hybrids 7a- f were prepared, and their in vitro biological activities were evaluated. It was found that 7c showed the strongest anti-proliferation activities against cancer cells in vitro and significant growth inhibition of tumor in vivo, and more potential for inhibitory selectivity to tumor cells than intermediate 6 and FTS. Furthermore, the anti-proliferative effect of 7c in Lovo cell lines followed a similar pattern, which included a dose-dependent induction of cell apoptosis via the up-regulation of Bax as well as activated caspase-3 and down-regulation of Bcl-2, and the inhibition of cancer cells migration and invasion in a concentration-dependent way. More importantly, 7c could significantly block Ras-related signaling pathways, which may contribute to its pro-apoptotic induction of the cancer cell lines and its inhibition of carcinoma cell proliferation, migration, and invasion. Therefore, our novel findings may provide a new framework for the discovery of new FTS hybrids for the intervention of human carcinoma cells. [ABSTRACT FROM AUTHOR]

3-(phenylsulfonyl)- 4-(4-((S)-1-(2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio) benzoyl) pyrrolidine-2-carbonyloxy)but-2-ynyloxy)-1,2,5-oxadiazole-2-oxide is a novel furoxan-based nitric oxide-releasing derivative of arnesylthiosalicylic acid. Previous experimental results showed that it was a good prospective anticancer agent both in vitro and in vivo. To study its route of administration, mechanism of action, and metabolic processes, the metabolites of this derivative were studied in an in vitro fermentation model with rat intestinal microflora. A high performance liquid chromatography–electrospray ionization tandem mass spectrometry method in positive ion mode was used to elucidate the structures of these metabolites. By comparing changes in the pseudomolecular ions, fragmental ions, and retention times with those of parent drug, four metabolites were observed, which were associated with the following metabolic events: reduction of the aliphatic triple bond, hydroxylation of the benzene ring, loss of NO free radical, and hydrolysis of the ester bond. [ABSTRACT FROM AUTHOR]

Abstract: Fourteen hybrids of farnesylthiosalicylic acid (FTS) with various diamines were synthesized and biologically evaluated. It was found that FTS-monoamide molecules (10a–g) displayed strong anti-proliferative activity against seven human cancer cell lines, superior to FTS and FTS-bisamide compounds (11a–g). The mono-amide 10f was the most active, with IC50s of 3.78–7.63μM against all tested cancer cells, even more potent than sorafenib (9.12–22.9μM). In addition, 10f induced SMMC-7721 cell apoptosis, down-regulated the expression of Bcl-2 and up-regulated Bax and caspase-3. Furthermore, 10f had the improved aqueous solubility relative to FTS. Finally, treatment with 10f dose-dependently inhibited the Ras-related signaling pathways in SMMC-7721 cells. Collectively, 10f could be a promising candidate for the intervention of human cancers. [Copyright &y& Elsevier]

There is substantial evidence suggesting that the Ras inhibitor farnesylthiosalicylic acid (FTS) may modulate various aspects of immune function and inflammation in addition to its well known anti-cancer activity. In this regard, we have recently shown that FTS suppresses T lymphocyte-mediated immune responses. Mast cells (MC), the main effector cells in the elicitation of the allergic response, are known to secrete granule-associated mediators and to release prostaglandins and cytokines on FCεRI-cross-linking, thereby contributing to the pathogenesis of allergic diseases. We hypothesized that MC act as an additional target for FTS. In the present work we analyze the effects of FTS on MC degranulation, prostaglandin release, and cytokine release in vitro, and on the elicitation of IgE-mediated MC dependent cutaneous allergic inflammation in vivo. First we have established that FTS inhibited Ras activation in MC. Next, we have shown that FTS preferentially inhibited prostaglandin (PG) D and tumor necrosis factor (TNF)-α release without having any significant effect on MC β-hexosaminidase secretion. In vivo administration of FTS inhibited the late phase of passive cutaneous anaphylaxis reaction. The time course of FTS-induced inhibition in vivo correlated with mediators release and not with degranulation. This data suggests that FTS may have an inhibitory effect on MC mediated allergic inflammation, and thus may be considered as a possible therapeutic modality. [ABSTRACT FROM AUTHOR]

Abstract: ZL11n is a novel furoxan-based nitric oxide (NO)-releasing derivative of farnesylthiosalicylic acid. In this study, we examined the anticancer effects and the potential mechanism of action of ZL11n in vitro and in vivo. It was found that ZL11n exhibited a favorable, selective cytotoxic effect in the HepG2 cell line. The yield of NO in the ZL11n treated HepG2 cells was much higher than in the control group and the normal human liver L-02 cells. Furthermore, the NO concentration was correlated to the degree of cytotoxicity observed. The ZL11n-induced apoptosis was assessed by Annexin V-FITC/propidium iodide flow cytometry assay. ZL11n triggered the mitochondrial/caspase apoptotic pathway by decreasing mitochondrial membrane potential, cytochrome c release from mitochondrial, and reducing the Bcl-2-to-Bax ratio, in addition to activating the caspase cascade. Simultaneously, we found that ZL11n treatment led to an increase in JNK and ERK1/2 phosphorylation. Furthermore, treatment with SP600125 (a JNK inhibitor) and PD98059 (an ERK1/2 inhibitor) prior to ZL11n treatment was found to significantly reverse ZL11n-induced apoptosis. The in vivo findings also revealed that ZL11n significantly reduced tumor volume and weight in the H22 solid tumor mouse model examined. In short, our findings suggest that ZL11n induced apoptosis through the coordination of the mitochondrial apoptotic pathway (activated by NO) and MAPKs signaling pathway (triggered by JNK or ERK). [Copyright &y& Elsevier]

Abstract: Novel furoxan-based nitric oxide (NO)-releasing derivatives (11a–p) of farnesylthiosalicylic acid (FTA) were synthesized. Compounds 11d, 11f, 11k, and 11m–o displayed anti-tumor activities superior to FTA and sorafenib in most cancer cells tested. Analysis of six compounds revealed that 11d, 11f, 11n, 11o, and 11p, but not 11a that had low anti-tumor activity, produced high levels of NO, associated with their strong anti-tumor activity. Furthermore, the anti-tumor activity of 11f was partially mimicked by the furoxan moiety, but reduced by pre-treatment with hemoglobin. Importantly, treatment with 11f inhibited Ras-related signaling in cancer cells. Apparently, the high anti-tumor activity of 11f was attributed to the synergic effect of high levels of NO production and inhibition of Ras-related signaling in cancer cells. Our findings suggest that the furoxan/FTA hybrids may hold greater promise as therapeutic agents for the intervention of human cancers. [Copyright &y& Elsevier]

Primary glioblastomas (GBMs) commonly overexpress the oncogene epidermal growth factor receptor (EGFR), which leads to increased Ras activity. FTA, a novel Ras inhibitor, produced both time- and dose-dependent caspase-mediated apoptosis in GBM cell lines. EGFR-mediated increase in 3H-thymidine uptake was inhibited by FTA. FACS analysis was performed to determine the percent of apoptotic cells. The sub-Go population of GBM cells was increased from 4.5 to 13.8% (control) to over 45–53.6% in FTA-treated cells within 24 h. Furthermore, FTA also increased the activities of both caspase-3 and -9, and PARP cleavage. Treatment of GBMs with FTA before or after EGF addition to the cultures blocked phosphorylation of Akt and mitogen-activated protein kinases (MAPK). FTA also significantly reduced the amount of EGF-induced Ras-GTP as reflected by a decrease in the level of Ras bound to Raf-RBD-GST. This study demonstrates that inhibition of Ras methylation may provide a therapeutic target for the treatment of GBMs overexpressing EGFR.Cell Death and Differentiation (2006) 13, 642–651. doi:10.1038/sj.cdd.4401783; published online 21 October 2005 [ABSTRACT FROM AUTHOR]

Several studies have implicated the Ras/mitogen-activated protein kinase (MAPK) pathway in Pavlovian fear conditioning. RasGRF1 knockout mice show significant deficits in acquisition of long-term fear memories and long-term potentaition (LTP) in the basolateral amygdala (BLA). MAPK kinase inhibition also impairs fear conditioning and amygdaloid LTP. However, there is no direct evidence to date for the involvement of Ras itself in fear conditioning. To address this issue, we examined the effects of intra-amygdala infusions of the selective Ras antagonist farnesylthiosalicylic acid (FTS) on the acquisition and expression of conditional freezing in rats. Micro-infusions of FTS into the BLA prior to contextual fear conditioning significantly impaired acquisition of long-term contextual fear memory in a dose-dependent manner. Post-training FTS infusions had no effect on acquisition of long-term fear memory. The effects of FTS on fear conditioning were specific for the BLA. Finally, intra-amygdala infusions of FTS inhibited MAPK activation in BLA. Collectively, these results provide further evidence for the involvement of amygdaloid Ras in the acquisition of long-term conditional fear memory. [ABSTRACT FROM AUTHOR]

The inhibition of human mesangial cell proliferation by S- trans, trans-farnesylthiosalicylic acid. Background. Many of the proliferative cytokines implicated in human mesangial cell (HMC) proliferation signal through the superfamily of Ras GTPases. The Ras antagonist, S- trans, trans- farnesylthiosalicylic acid (FTS), was used to investigate the effects of the inhibition of Ras signaling on HMC proliferation. Methods. Ras expression and membrane localization, MAPK, and Akt activation were analyzed by Western blotting. Ras activation was determined with a pull-down assay using the Ras-binding domain of Raf. HMC growth curves were assessed using the MTS assay of viable cell number, while DNA synthesis was measured with BrdU incorporation. Hoechst 33342 staining was used to determine apoptosis. Results. FTS reduced the membrane localization of Ras in both serum and platelet-derived growth factor (PDGF). FTS (7.5–20 μmol/L) potently inhibited PDGF-induced HMC proliferation but had no effect on serum-induced proliferation. FTS (10–20 μmol/L) inhibited both Ras and phospho-MAPK activation by serum and PDGF. Furthermore, FTS (10–20 μmol/L) increased HMC apoptosis in the presence of PDGF but not in serum. Moreover, PDGF-stimulated activation of the survival protein Akt was inhibited by FTS. In contrast, serum-stimulated activation of Akt was unaffected by FTS. Conclusion. FTS (5–20 μmol/L) inhibits PDGF-induced but not serum-induced HMC proliferation. FTS (10–20 μmol/L) also promotes HMC apoptosis in the presence of PDGF but not serum. These effects appear to be mediated by inhibitory effects on Ras-dependent signaling that occur as a result of the dislodgment of Ras from its membrane-anchorage sites by FTS. The selectivity of FTS toward PDGF-driven HMC proliferation suggests that FTS may be a valuable therapeutic in mesangioproliferative renal disease. [ABSTRACT FROM AUTHOR]

Exosomes are cell-derived nanovesicles, and lately, cancer-derived exosomes have been reported to carry KRAS protein, which contributes to the malignancy of many cancers. In this study, farnesylthiosalicylic acid (FTS) was used to inhibit the activities of mutated KRAS in colon cancer SW480 cells to discover the potential link between KRAS activities and cancer-derived exosomes. We observed that FTS inhibits KRAS activity in SW480 cells, but promotes their exosome production. When the exosomal proteins of SW480 cells were profiled, a total of 435 proteins were identified with 16 of them showing significant changes (greater than or equal to two-fold) in response to FTS treatment. Protein network analysis suggests KRAS inhibition may trigger stress in the cells. In addition, a high level of acetyl-coA synthetase family member 4 protein which plays an important role in colon cancer survival was identified in the exosomes secreted by FTS-treated SW480 cells. The uptake of these exosomes suppresses the growth of some cell types, but in general exosomes from FTS-treated cells enhance the recipient cell survival when compared to that of untreated cells. Together our findings suggest that FTS may trigger stress in SW480 cells, and induce more exosomes secretion as the survival messenger to mitigate the impact of KRAS inhibition in colon cancer cells. [ABSTRACT FROM AUTHOR]