Mechanism-based heparanase inhibitors reduce cancer metastasis in vivo.

Heparan sulfate proteoglycans (HSPGs) mediate essential interactions throughout the extracellular matrix (ECM), providing signals that regulate cellular growth and development. Altered HSPG composition during tumorigenesis strongly aids cancer progression. Heparanase (HPSE) is the principal enzyme responsible for extracellular heparan sulfate catabolism and is markedly up-regulated in aggressive cancers. HPSE overactivity degrades HSPGs within the ECM, facilitating metastatic dissemination and releasing mitogens that drive cellular proliferation. Reducing extracellular HPSE activity reduces cancer growth, but few effective inhibitors are known, and none are clinically approved. Inspired by the natural glycosidase inhibitor cyclophellitol, we developed nanomolar mechanism-based, irreversible HPSE inhibitors that are effective within physiological environments. Application of cyclophellitol-derived HPSE inhibitors reduces cancer aggression in cellulo and significantly ameliorates murine metastasis. Mechanism-based irreversible HPSE inhibition is an unexplored anticancer strategy. We demonstrate the feasibility of such compounds to control pathological HPSE-driven malignancies.

[Medical cannabinoids and their indications in chronic pain]. / Les cannabinoïdes et leurs indications en antalgie chronique.

Democratization of the cannabis consumption and its derivatives incite patients to ask ever more for medical cannabinoid prescriptions, especially in the context of chronic pain. Its use is only validated in certain limited cases, in particular spasticity linked to multiple sclerosis and refractory epilepsies. All other prescriptions require a special request to the OFSP. Moreover, cannabinoid intake may produce several dose-dependent side effects that require a close monitoring with a slow and gradual initiation of its dosage. In the absence of clear medical evidence, many other mechanisms of action need to be investigated with ongoing and future studies to clarify their indication.

La démocratisation de la consommation de cannabis et de ses dérivés pousse les patients à être de plus en plus demandeurs de prescriptions de cannabis à usage médical, d'autant plus dans le cadre de douleurs chroniques. Il convient alors de rappeler que son utilisation n'est validée que dans certains cas restreints, notamment dans la spasticité liée à la sclérose en plaques et les épilepsies réfractaires. Toute autre prescription nécessite une demande spéciale à l'Office fédéral de la santé publique. Par ailleurs, la prise de cannabinoïdes étant liée à nombre d'effets secondaires dose-dépendants, son administration nécessite une surveillance rapprochée et une initiation lente et progressive. En l'absence d'évidence médicale claire, il reste de nombreuses pistes encore à développer pour cibler leur indication.