AGuIX are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.
To clarify the chronology of events leading to anti-Fas-induced apoptosis, and the mechanisms of resistance to this death effector, we compared the response kinetics of three tumour cell lines that display varying sensitivity to anti-Fas (based on levels of apoptosis), in terms of ceramide release, mitochondrial function and the caspase-activation pathway. In the highly sensitive Jurkat cell line, early caspase-8 activation, observed from 2 h after treatment, was chronologically associated with an acute depletion of glutathione and the cleavage of caspase-3 and poly-ADP ribosyl polymerase (PARP), followed by a progressive fall in the mitochondrial transmembrane potential (Delta(psi)m), between 4 and 48 h after treatment. Ceramide levels began to increase 2 h after the addition of anti-Fas (with no increase during the first hour), and increased continuously to 640% of control cells at 48 h. In the moderately sensitive SCC61 adherent cells, comparable results were observed, though with lower levels of ceramide and a delay in the response kinetics, with apoptotic cells becoming flotant. Finally, despite early cleavage of caspase-8 at 2 h, and a sustained level of activation until 48 h, no apoptotic response was observed in anti-Fas-resistant SQ20B cells. This was confirmed by a lack of ceramide generation and mitochondrial changes, and by the absence of any detectable cleavage of caspase-3 or PARP. Inhibition of caspase processing, and amplification of endogenous ceramide signalling by pharmacological agents, allowed us to establish the order of cellular events, locating ceramide release after caspase-8 activation and before caspase-3 activation, and demonstrating a direct involvement for ceramide release in mitochondrial dysfunction. Furthermore, these experiments provide strong arguments for the role of endogenous ceramide as a key executor of apoptosis, rather than as a consequence of membrane alterations.
In a wide range of human cancers, increased levels of heat shock protein 27 (Hsp27) are closely associated with tumorigenesis, metastasis, resistance to anticancer therapeutics, and thus poor prognosis. In this study, we evaluate the radiosensitizing effects of Hsp27 gene silencing using OGX-427, a second-generation antisense oligonucleotide (ASO), on the radioresistant head and neck squamous cell carcinoma (HNSCC) SQ20B cells. In vitro, the downregulation of Hsp27 significantly enhanced radiation-induced apoptotic and clonogenic death, and promoted Akt inactivation. In vivo, combining OGX-427 with local tumor irradiation (5 x 2 Gy) led to a significant regression of SQ20B tumors related to a high rate of apoptosis and decreased levels of glutathione antioxidant defenses. Increasing the total radiation dose (15 x 2 Gy) significantly amplified the radiosensitizing effect of OGX-427. Treatment of tumors with OGX-427 plus radiation resulted in a decrease in angiogenesis associated with a reduced activation of the Akt pathway. Furthermore, the combined treatment enhanced the survival of SQ20B-bearing mice and showed no signs of acute and delayed toxicity. Our findings demonstrate for the first time that Hsp27 knockdown enhances the cytotoxic effects of radiotherapy in vivo and provide preclinical proof of principle for clinical trials using Hsp27 antisense technology in the treatment of patients with HNSCC radioresistant cancers.
Much attention has been devoted to the role of ceramide and derived sphingolipids in the sensitivity of tumors to chemo-and radiotherapy. [1][2][3] In particular, the cytotoxic effects of those treatments decrease when the generation of ceramide is impaired but increase when the degradation of ceramide is blocked.Ceramide homeostasis is controlled by several metabolic events leading to its deacylation, phosphorylation or glycosylation or to sphingomyelin synthesis. Ceramide is now recognized as a major component of the programmed cell death machinery triggered in response to different stimuli, including anti-Fas, chemotherapeutic agents, UV radiation and ␥-radiation. 4,5 Derivative molecules, such as sphingosine, sphingosine-1-phosphate and ceramide-1-phosphate, also appear to be active intracellular mediators. 6 Conversely, glucosylceramide synthesis is an important mechanism by which ceramide-induced apoptosis is averted. 7 It was first demonstrated in this context that high cellular levels of glucosylceramide correlate with multidrug resistance. 8,9 Experiments conducted subsequently with glucosylceramide synthase antisense cDNA restored the sensitivity of breast carcinoma cells to anthracycline. 10 Conversely, the apoptotic response induced by the addition of short-chain ceramide to cell cultures is potentiated by the inhibition of glycosylceramide synthase. 11 Different strategies have been applied to understand ceramidemediated cell signaling by increasing its endogenous levels. The addition of short-chain ceramide to cell cultures first demonstrated 12 the involvement of ceramide in the apoptotic process, but it is not clear whether exogenous ceramide has the same cellular targets as the relevant endogenous species. 13 C 6 -ceramide accumulates in the Golgi apparatus, where it is converted to sphingomyelin and glycosphingolipids. 14,15 It also induces endocytic vesicle formation, resulting in enlarged late endosomes and lysosomes. 16 In situ generation of ceramide by bSMase appeared to be an alternative to the use of nonphysiologic ceramide species. However, bSMase probably generates ceramide in the external leaflet of the plasma membrane, which requires subsequent translocation in the membrane for propagation of the apoptotic signal. 17 The last option involves pharmacologic agents that elicit ceramide production. 1,3 Ceramide elevation should occur by blocking either its glycosylation or its hydrolysis into sphingosine. For example, DL-PDMP (a specific inhibitor of glucosylceramide synthase) either increases cellular ceramide levels 18 or does not 19,20 depending on the cellular model and the concentration used. D-MAPP functions as an inhibitor of alkaline ceramidase, resulting in elevation of ceramide levels in HL60 cells, with consequent growth suppression and cell-cycle arrest. 21 Imipramine can affect ceramide metabolism by inducing the proteolytic degradation of acid sphingomyelinase 22 and disturbing lipid turnover in biologic membranes. [23][24][25] Several studies have reported the killing of ca...
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