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Résumé: Les analogues de la thalidomide agissent par un mécanisme d'action original en induisant un rapprochement entre l'E3 ubiquitine ligase CRL4-CRBN et des protéines intracellulaires spécifiques, entraînant l'ubiquitination puis la dégradation protéasomale de ces protéines cibles. La destruction sélective de certaines protéines nécessaires à la survie des cellules tumorales se traduit par un effet cytotoxique direct, auquel s'ajoute un effet immunomodulateur indirect. Depuis les années 2000, les analogues de la thalidomide constituent la pierre angulaire du traitement du myélome multiple et des syndromes myélodysplasiques avec délétion 5q, et sont de plus en plus utilisés dans les lymphomes B. Le profil de toxicité est variable selon la molécule, la pathologie et les traitements associés, avec, au premier plan, la survenue de cytopénies, de thromboses veineuses et d'éruptions cutanées. Le développement de nouveaux analogues de la thalidomide, dont certains sont en essai clinique, devrait permettre d'étendre encore davantage les indications de cette classe thérapeutique. Thalidomide analogues exert their therapeutic effect through a novel and unexpected mechanism of action by inducing proximity between the CRL4-CRBN E3 ubiquitin ligase and specific intracellular proteins, leading to ubiquitination and subsequent proteasomal degradation of these substrate proteins. The selective destruction of target proteins that are essential for tumor cell survival results in a direct cytotoxic effect, which is accompanied by an indirect immunomodulatory effect. Over the last 20 years, thalidomide analogues have become a cornerstone for the treatment of multiple myeloma and myelodysplastic syndromes with 5q deletion. These drugs are also increasingly used for the treatment of B-cell lymphoma. Their toxicity profile mainly consists of cytopenia, venous thrombosis, and skin rashes, but depends on the molecule, the disease context, and concomitant treatments. The development of new thalidomide analogues, of which some are tested in clinical trials, should further extend the indications of this therapeutic drug class. [ABSTRACT FROM AUTHOR]

Abstract The identification of antitumoral substances is the focus of intense biomedical research. Two structural analogues of thalidomide, LNO3 and L3, are two synthetic compounds that might possess such antitumor properties. We evaluated the toxicological effects of these substances, including cytotoxicity, genotoxicity and induction of apoptosis in HTC cells. Additionally, the production of free radicals (nitric oxide and superoxide) was investigated, and the expression of caspases genes 3, 8, and 9 were determined by RT-qPCR. The compounds exhibited cytotoxic effects that resulted in inhibited cell proliferation. LNO3 showed to be more effective and toxic than L3 in all assays. LNO3 stimulated the release of NO and superoxide, which was accompanied by the formation of peroxynitrite. Apoptosis was induced in a dose-dependent manner by both compounds; however, the expression of caspases 3, 8 and 9 was unchanged. These results suggested that L3 and LNO3 possess antiproliferative and pro-apoptotic effects in HTC cells. Additionally, although they exhibited cytotoxicity, L3 and LNO3 might be useful coadjuvants in tumor treatment studies.

Synthetic thalidomide analogues (compounds 1- 35), including phenylphthalimide, pyridylphthalimide, aminobenzylphthalimide, and diphenylazophthalimide, were tested for their cytotoxic effects on human cancer cell lines Hep2 (Human Larynx Carcinoma Cells), HL-60 (Human Myeloid Leukemia Cells), NUGC (Human Gastric Carcinoma Cells), and HONE-1 (Human Nasopharyngeal Carcinoma Cells) because the incidence rate is more prominent in Asian countries than in Western countries. Compounds 17, 27, 28, and 35 were found to have antitumor activity in Hep2 and HL-60 cell lines. Compounds 2, 4, 15, 17, 19, 20, 23, and 27 can inhibit nitric oxide (NO) synthase activity by more than 90%. These thalidomide analogues were found to be potent inducible nitric oxide synthase (iNOS) inhibitors, and the iNOS inhibiting potential of compounds 17 and 27 might be an advantage for anticancer therapy. In conclusion, inhibition of NO synthesis is a new development in cancer therapy for now and in the future. We modified the structures of the thalidomide analogues to have a stronger anticancer effect and a good therapeutic effect. [ABSTRACT FROM AUTHOR]

Abstract: As part of an ongoing effort to develop new thalidomide analogues as antiinflammatory lead-candidates, this paper describes the synthesis and antiinflammatory activity of novel N-phenyl-phthalimide functionalized derivatives (4a–d, 5a,b, 6a,b). The target compounds were assayed in an acute lung inflammatory model and all compounds were able to inhibit TNF-α production and subsequent neutrophil recruitment in the LPS-acute lung inflammatory model. [Copyright &y& Elsevier]

The discovery that multiple myeloma is associated with new vessel formation and is correlated with survival and proliferation led initially to the use of thalidomide for patients with relapsed or refractory disease. The outcome with conventional chemotherapy in this setting has historically been very poor. New insights into the biology of the disease suggests that thalidomide may work via a number of other mechanisms and the advent of the thalidomide analogues with their differential effects on survival and proliferation pathways has opened up a new era in the understanding and treatment of the disease. The encouraging results from phase I/II trials of these agents has meant that for the first time in 50 years there is the opportunity to improve outcome. Further work is in progress to define how best to use these drugs and their role in treatment at different stages of the disease. [ABSTRACT FROM AUTHOR]

Introduction: Thalidomide is an old well-known drug firstly used as morning sickness relief in pregnant women and then withdrawn from the market due to its severe side effects on fetal normal development. However, over the last few decades, the interest in this old drug has been renewed because of its efficacy in several important disorders as, for instance, multiple myeloma, breast cancer, and HIV-related diseases due to its antiangiogenic and immunomodulatory properties. Unfortunately, even in these cases, many after effects as deep vein thrombosis, peripheral neuropathy, constipation, somnolence, pyrexia, pain, and teratogenicity have been reported showing the requirement of careful and monitored use. For this reason, research efforts are geared toward the synthesis and optimization of new thalidomide analogues lacking in toxic effects, able to erase these limits and improve the pharmacological profile., Aims: This review aims to examine the state-of-the-art concerning the current studies on thalidomide and its analogues towards cancer diseases focusing the attention on the possible mechanisms of action involved and the lack of toxicity., Conclusion: In the light of the collected data, thalidomide analogues and their ongoing optimization could lead, in the future, to the realization of a promising therapeutic alternative for fighting cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Thalidomide was synthesised and launched several decades ago as a drug against respiratory infections and was administered to pregnant women for relief of morning sickness. The drug was withdrawn when its teratogenic effects came to light. Thalidomide and its analogues suppressed cell proliferation and angiogenesis and controlled invasion and metastasis of tumours in pre-clinical studies. With the recognition of its immunomodulatory and anti-inflammatory, properties, thalidomide may have found a place in the treatment of many forms of cancer and autoimmune conditions. Herein the signalling pathways modulated by thalidomides via the mediation of vascular endothelial growth factor, phosphoinositide-kinase/protein kinase B and nuclear factor kappa B, and mammalian target of rapamycin, which integrates these signalling systems, are discussed. The mode of action of thalidomides and their strategic utility in therapy are evaluated in the context of potential clinical benefits. Notwithstanding the perceived benefits, the side-effects of thalidomides need to be taken into account; they do exert teratogenic effects in animal models, although being effective at lower doses, the drugs seem to show comparatively manageable and reduced toxicity. Combination therapy of thalidomides and modulators of signaling that they influence may further reduce the severity of the side-effects by delivering inhibitory effects at reduced drug dosages. Pre-clinical evaluations of this kind seem warranted., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)