The a5b1 integrin represent a new therapeutic target for glioblastoma, which are malignant brain tumors difficult to cure with conventional therapies. Glioblastoma are known to be highly resistant to chemotherapy. We, therefore, investigated whether blocking a5b1 integrin with specific nonpeptidic antagonists concomitantly with chemotherapy (ellipticine and temozolomide) may impact the response to chemotherapy of human glioblastoma. Here we show that inhibiting a5b1 integrin with 2 selective ligands (SJ749 and K34c) decreases chemotherapy-induced premature senescence and facilitates cell apoptosis in a functional p53 background (U87MG cells). When p53 is mutated and inactive (U373 cells), chemotherapy induces p53-independent cell apoptosis instead of senescence that is not improved by integrin antagonists. Silencing p53 in U87MG cells with siRNA as well as evaluating HCT116 p531/1 and p532/2 colon carcinoma cell behavior support the hypothesis of an as yet unknown effect of a5b1 integrin antagonists on the control of chemotherapy-induced premature senescence and apoptosis. a5b1 integrin antagonists modulate the p53 signaling induced by chemotherapy. Our results highlight a new role of the a5b1 integrin in the control of glioblastoma aggressiveness and responsiveness to chemotherapy, which may have a crucial impact in the clinical management of patients suffering from brain tumors.The median survival of patients diagnosed with grade IV astrocytomas (glioblastoma multiforme or GBM) is less than a year whatever the conventional therapies chosen (surgery, radiotherapy and/or chemotherapy). Therefore, new alternatives are highly needed. Integrins were recently identified as potential therapeutic targets as they take part in various cancer stages such as malignant transformation, tumor growth and progression, invasion and metastasis and angiogenesis. Particular emphasis has been given to avb3/b5 integrins that are overexpressed in neovessels nourishing the tumor. A avb3/b5 antagonist, cilengitide, is currently undergoing clinical trials to target neoangiogenesis in malignant glioma. 1,2 The a5b1 integrin emerged more recently as a potential anti cancer target as it is overexpressed in both tumoral neovessels 3,4 and tumoral cells and appears now as an interesting therapeutic target for brain, 5-7 lung 8 and ovarian tumors. 9 The expression of the a5b1 integrin is related to the tumor stage of gliomas 5 and the integrin signaling pathways were identified as being part of functional networks of GBM. 10 Because of the recent interest in a5b1 integrin, design of specific non peptidic ligands has increased these last years. [11][12][13] Nonpeptidic small a5b1 integrin antagonists were already shown to block angiogenesis and lymphangiogenesis. 14-16 Focusing on brain tumors, we have recently shown that perturbing specifically the function of the a5b1 integrin with the prototypical antagonist SJ749 in U87MG glioma cells triggers cell cycle arrest 6 and decreases cell aggressiveness. 7 In addition, we demonstrated that the ex...

No abstract