Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment

Therapeutic strategies to limit the chemical injury of xenobiotics : targeting the long non-coding RNA DNM3OS and the adenosine A2A receptor

L'organisme humain est constamment exposé à de nombreuses molécules présentes dans l'environnement nommées xénobiotiques et regroupant des composés naturels et synthétiques, tels que des polluants environnementaux ou des médicaments. L'accumulation cellulaire de ces substances est néfaste et peut conduire à l'apparition d'effets toxiques ou de pathologies graves.Ces travaux proposent des stratégies permettant de limiter l'agression chimique des xénobiotiques dans deux contextes particuliers.D'une part, diverses agressions chroniques, et notamment une exposition régulière à des xénobiotiques, peut induire le développement de lésions de fibrose hépatique. Sur le plan moléculaire, le TGF-β (Transforming Growth factor β) joue un rôle majeur dans l'initiation et la progression de la fibrose en facilitant le recrutement, la prolifération et l'activation des fibroblastes en myofibroblastes. Les options thérapeutiques restent limitées à l'heure actuelle. L'identification de nouvelles options thérapeutiques est donc essentielle, et l'inhibition sélective de la voie du TGF-β dans les myofibroblastes semble être une piste pertinente. En particulier, nous avons montré dans un premier temps que l'expression hépatique du long ARN non codant DNM3OS (Dynamin 3 Opposite Strand) est induite dans deux modèles murins de fibrose hépatique (l'un chirurgical par obstruction des voies biliaires et l'autre chimique par administration de CCl4). De plus, l'administration d'un oligonucléotide anti-sens dirigé contre DNM3OS permet de réduire la sévérité des lésions de fibrose induites par l'administration de CCl4. De manière intéressante, DNM3OS est le précurseur de trois microARN matures, miR-199a-5p, miR-199a-3p et miR-214-3p, dont l'implication dans la voie de signalisation du TGF-β est connue. Des études in vitro par perte et gain de fonction ont ainsi été réalisées afin d'évaluer la contribution de chacun de ces miARN dans le processus de fibrose.D'autre part, le cisplatine est un anti-cancéreux efficace dont l'utilisation est associée chez certains patients à l'apparition d'effets indésirables, en particulier néphrotoxiques. Nous avons montré que l'administration de cisplatine (injection(s) unique ou répétées) induit une augmentation de l'expression rénale du récepteur à l'adénosine A2A chez la souris. De plus, dans un modèle syngénique, la modulation pharmacologique de ce récepteur par un antagoniste sélectif, l'istradefylline, permet de limiter les effets néphrotoxiques du cisplatine tout en préservant ses propriétés antitumorales.Au total, ces travaux nous ont permis d'identifier de nouvelles stratégies thérapeutiques permettant de limiter l'impact des xénobiotiques et en particulier des médicaments sur la santé humaine.The human organism is constantly exposed to a large number of molecules, termed xenobiotics, which include both natural and synthetic compounds, such as environmental pollutants or drugs. The cellular accumulation of these compounds is harmful and can lead to the occurrence of toxic effects or serious pathologies.This work aims at identifying strategies to limit the chemical aggression of xenobiotics in two particular contexts.On the one hand, various chronic aggressions, and in particular chronic exposure to xenobiotics, can induce the development of liver fibrosis lesions. At the molecular level, TGF-β (Transforming Growth factor β) plays a major role in the initiation and progression of fibrosis by promoting the recruitment, proliferation and activation of fibroblasts into myofibroblasts. Currently, therapeutic options remain limited. The identification of new therapeutic options is therefore essential, and the selective inhibition of the TGF-β pathway in myofibroblasts seems to be a relevant approach. In particular, we first showed that hepatic expression of the long non-coding RNA DNM3OS (Dynamin 3 Opposite Strand) is induced in two mouse models of hepatic fibrosis (one surgical by bile duct ligation and the second chemical by CCl4 administration). Moreover, the administration of an antisense oligonucleotide directed against DNM3OS reduces the severity of fibrosis lesions induced by CCl4 administration. Interestingly, DNM3OS is the precursor of three mature microRNAs, miR-199a-5p, miR-199a-3p and miR-214-3p, known to be involved in the TGF-β signaling pathway. In vitro loss- and gain-of-function studies were then performed to evaluate the contribution of each miRNA in the fibrosis process.On the other hand, cisplatin is an effective anti-cancer drug that is associated in some patients with the development of adverse effects, in particular nephrotoxicity. We have shown that cisplatin administration (single or repeated injections) induced an increase in the renal expression of the adenosine A2A receptor in mice. Moreover, in a syngeneic model, pharmacological modulation of this receptor by a selective antagonist, istradefylline, limited the nephrotoxic effects of cisplatin while preserving its antitumor properties.Altogether, this work has allowed us to identify new therapeutic strategies to limit the impact of xenobiotics and in particular drugs on human health

The Versatile Role of miR-21 in Renal Homeostasis and Diseases

MicroRNAs (miRNAs) are small, non-coding RNA species that control gene expression and confer robustness to biological processes. Over the last two decades, their important roles during kidney development, homeostasis and the treatment of diseases have been established, in particular during the onset and progression of various forms of acute and chronic renal disorders. In recent years, miR-21, one of the best-characterized miRNAs to date, has received much attention in renal physiology in particular given its high degree of conservation and expression in kidneys, as well as its potent pathogenic role in various debilitating renal diseases. This review summarizes the current knowledge on miR-21’s involvement in both renal homeostasis and diseases, in particular its double-edged-sword role in acute versus chronic kidney injuries. Finally, we also discuss the potential of miR-21 as a biomarker and therapeutic target in renal diseases

Integrating rare genetic variants into DPYD pharmacogenetic testing may help preventing fluoropyrimidine-induced toxicity

International audienceVariability in genes involved in drug pharmacokinetics or drug response can be responsible for suboptimal treatment efficacy or predispose to adverse drug reactions. In addition to common genetic variations, large-scale sequencing studies have uncovered multiple rare genetic variants predicted to cause functional alterations in genes encoding proteins implicated in drug metabolism, transport and response. To understand the functional importance of rare genetic variants in DPYD , a pharmacogene whose alterations can cause severe toxicity in patients exposed to fluoropyrimidine-based regimens, massively parallel sequencing of the exonic regions and flanking splice junctions of the DPYD gene was performed in a series of nearly 3000 patients categorized according to pre-emptive DPD enzyme activity using the dihydrouracil/uracil ([UH 2 ]/[U]) plasma ratio as a surrogate marker of DPD activity. Our results underscore the importance of integrating next-generation sequencing-based pharmacogenomic interpretation into clinical decision making to minimize fluoropyrimidine-based chemotherapy toxicity without altering treatment efficacy

MUC1 Drives the Progression and Chemoresistance of Clear Cell Renal Carcinomas

International audienceWhile the transmembrane glycoprotein mucin 1 (MUC1) is clustered at the apical borders of normal epithelial cells, with transformation and loss of polarity, MUC1 is found at high levels in the cytosol and is uniformly distributed over the entire surface of carcinoma cells, where it can promote tumor progression and adversely affects the response to therapy. Clear cell renal cell carcinoma (ccRCC), the main histotype of kidney cancer, is typically highly resistant to conventional and targeted therapies for reasons that remain largely unknown. In this context, we investigated whether MUC1 also plays a pivotal role in the cellular and molecular events driving ccRCC progression and chemoresistance. We showed, using loss- and gain-of-function approaches in ccRCC-derived cell lines, that MUC1 not only influences tumor progression but also induces a multi-drug-resistant profile reminiscent of the activation of ABC drug efflux transporters. Overall, our results suggest that targeting MUC1 may represent a novel therapeutic approach to limit ccRCC progression and improve drug sensitivity

miR-92a-3p regulates cisplatin-induced cancer cell death

Abstract Non-small cell lung cancer is characterized by a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Therefore, the identification of new molecular determinants underlying sensitivity of cancer cells to existing therapy is of particular importance to develop new effective combinatorial treatment strategy. MicroRNAs (miRNAs), a class of small non-coding RNAs, have been established as master regulators of a variety of cellular processes that play a key role in tumor initiation, progression and metastasis. This, along with their widespread deregulation in many distinct cancers, has triggered enthusiasm for miRNAs as novel therapeutic targets for cancer management, in particular in patients with refractory cancers such as those harboring KRAS mutations. In this study, we performed a loss-of-function screening approach to identify miRNAs whose silencing promotes sensitivity of lung adenocarcinoma (LUAD) cells to cisplatin. Our results showed in particular that antisense oligonucleotides directed against miR-92a-3p, a member of the oncogenic miR-17 ~ 92 cluster, caused the greatest increase in the sensitivity of KRAS-mutated LUAD cells to cisplatin. In addition, we demonstrated that this miRNA finely regulates the apoptotic threshold and the proliferative capacity of various tumor cell lines with distinct genetic alterations. Collectively, these data suggest that targeting miR-92a-3p may serve as an effective strategy to overcome treatment resistance of solid tumors

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

International audienceClear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional therapies and known for abnormal lipid accumulation. In this context, we focused our attention on miR-21, an oncogenic miRNA overexpressed in ccRCC, and peroxysome proliferator-activated receptor-α (PPAR- α), one master regulator of lipid metabolism targeted by miR-21. First, in a cohort of 52 primary ccRCC samples, using RT-qPCR and immunohistochemistry, we showed that miR-21 overexpression was correlated with PPAR-α downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-α overexpression (i) decreased miR-21 expression, AP-1 and NF-κB transcriptional activity, and the binding of AP-1 and NF-κB to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-α expression and transcriptional activity mediated by PPAR-α, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-α expression, but also the expression of its targets involved in fatty acid oxidation. In this study, we showed a double-negative feedback interaction between miR-21 and PPAR-α. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC

The FibromiR miR-214-3p Is Upregulated in Duchenne Muscular Dystrophy and Promotes Differentiation of Human Fibro-Adipogenic Muscle Progenitors

International audienceFibrosis is a deleterious invasion of tissues associated with many pathological conditions, such as Duchenne muscular dystrophy (DMD) for which no cure is at present available for its prevention or its treatment. Fibro-adipogenic progenitors (FAPs) are resident cells in the human skeletal muscle and can differentiate into myofibroblasts, which represent the key cell population responsible for fibrosis. In this study, we delineated the pool of microRNAs (miRNAs) that are specifically modulated by TGFβ1 in FAPs versus myogenic progenitors (MPs) by a global miRNome analysis. A subset of candidates, including several “FibromiRs”, was found differentially expressed between FAPs and MPs and was also deregulated in DMD versus healthy biopsies. Among them, the expression of the TGFβ1-induced miR-199a~214 cluster was strongly correlated with the fibrotic score in DMD biopsies. Loss-of-function experiments in FAPs indicated that a miR-214-3p inhibitor efficiently blocked expression of fibrogenic markers in both basal conditions and following TGFβ1 stimulation. We found that FGFR1 is a functional target of miR-214-3p, preventing the signaling of the anti-fibrotic FGF2 pathway during FAP fibrogenesis. Overall, our work demonstrates that the « FibromiR » miR-214-3p is a key activator of FAP fibrogenesis by modulating the FGF2/FGFR1/TGFβ axis, opening new avenues for the treatment of DMD