Despite extensive treatment, glioblastoma inevitably recurs, leading to an overall survival of around 16 months. Understanding why and how tumours resist to radio/chemotherapies is crucial to overcome this unmet oncological challenge. Primary and acquired resistance to Temozolomide (TMZ), the standard-of-care chemotherapeutic drug, have been the subjects of several studies. This work aimed to evaluate molecular and phenotypic changes occurring during and after TMZ treatment in a glioblastoma cell model, the U87MG. These initially TMZ-sensitive cells acquire long-lasting resistance even after removal of the drug. Transcriptomic analysis revealed that profound changes occurred between parental and resistant cells, particularly at the level of the integrin repertoire. Focusing on α5β1 integrin, which we proposed earlier as a glioblastoma therapeutic target, we demonstrated that its expression was decreased in the presence of TMZ but restored after removal of the drug. In this glioblastoma model of recurrence, α5β1 integrin plays an important role in the proliferation and migration of tumoral cells. We also demonstrated that reactivating p53 by MDM2 inhibitors concomitantly with the inhibition of this integrin in recurrent cells may overcome the TMZ resistance. Our results may explain some integrin-based targeted therapy failure as integrin expressions are highly switchable during the time of treatment. We also propose an alternative way to alter the viability of recurrent glioblastoma cells expressing a high level of α5β1 integrin.

The rising global cancer burden, particularly in Sub-Saharan Africa, and the drawbacks of current treatments necessitate the exploration of safer, more effective anticancer agents. Ethnomedicinal plants offer a valuable resource for such discoveries. This review focuses on Khaya senegalensis, a plant traditionally used across Africa to treat a spectrum of ailments, including tumors. We provide a detailed synthesis of its botany, ethnomedicinal applications, phytochemical constituents, and pharmacological properties, with an emphasis on its anticancer potential. Data compiled from PubMed, Web of Science, Science Direct, and other scholarly sources indicate that limonoids are the most abundant and investigated class of phytochemicals in K. senegalensis, though fatty acids, polyphenols, and esters also contribute to its bioactivity. These compounds underpin its diverse pharmacological profile, which encompasses antioxidant, anti-inflammatory, antimicrobial, and anticancer activities. This review consolidates current knowledge to bridge the understanding between its phytochemistry and medicinal uses, identify critical research gaps, and advocate for further investigation into its compounds as prospective leads for anticancer drug development.

Résistance des glioblastomes au témozolomide : implication des voies de signalisation α5β1 integrin et p53: Les glioblastomes sont les tumeurs cérébrales adultes les plus agressives pour lesquelles de nouvelles solutions thérapeutiques sont essentielles. Elles sont très résistantes aux thérapies et des récurrences sont observées dans la majorité des cas. Nous nous intéressons aux intégrines, en particulier l’intégrine α5β1, comme cibles thérapeutiques dans le glioblastome. Les travaux antérieurs ont montré que cette intégrine participait à la résistance à la chimiothérapie utilisée en clinique, le témozolomide (TMZ) en inhibant l’activité du suppresseur de tumeurs p53. Dans cette thèse nous avons évalué une nouvelle option thérapeutique basée sur un traitement combiné d’antagonistes de l’intégrine α5β1 avec des activateurs de p53 dans des cellules de gliome U87MG et leurs congénères rendues résistantes au TMZ. Nous avons montré que la résistance au TMZ s’accompagne d’un grand réarrangement du répertoire des intégrines exprimées par les cellules et que l’intégrine α5β1 reste une cible dans les tumeurs résistantes. Ces cellules restent également sensibles à des inhibiteurs des complexes p53/mdm2 permettant de réactiver la signalisation p53-dépendante. Nos résultats sont en accord avec l’hypothèse d’un intérêt d’une combinaison inhibiteurs d’intégrine et activateurs de p53 pour traiter les glioblastomes récurrents.