Glioblastoma multiforme is the most commonly diagnosed malignant primary brain tumor in adults. Invasive behavior is the pathol. hallmark of malignant gliomas; consequently, its inhibition was suggested as a therapeutic strategy. Tumor cell-derived gelatinases (matrix metalloproteinase-2, matrix metalloproteinase-9) can be considered prime factors in glioma invasiveness: their expression correlates with the progression and the degree of malignancy. Thus, broad spectrum matrix metalloproteinase inhibitors (MMP inhibitors) were included in clin. trials. In the present study, the invasiveness, viability and progression of the human glioma cell line U87MG were investigated following treatment with N-O-iso-Pr sulfonamido-based hydroxamates (compds. 1 and 2) as MMP-2 inhibitors used at nanomolar concn. A std. broad spectrum MMP-inhibitor belonging to the classical tertiary sulfonamido-based hydroxamates family (CGS_27023A) was used too. The compds. 1 and 2 resulted in potent inhibition of cell invasiveness without affecting viability. In some clin. trials, the combined therapy of temozolomide (an alkylating agent used in glioma treatment) plus marimastat (a broad spectrum MMP inhibitor) has provided evidence of the importance of MMPs to tumor progression and invasiveness. On this basis, the effect on U87MG cells of a combined treatment with temozolomide, plus each of the 2 MMP inhibitors at nanomolar concn., was investigated. The obtained data demonstrated the inhibition of cell invasiveness and viability after treatment. These results can help in developing clin. combined therapy using MMP inhibitors that, at low doses, increase the anticancer efficacy of chemotherapeutic drugs, probably without causing the side effects typical of broad-spectrum MMP inhibitors.
Inhibition of metalloproteinases derived from tumours: new insights in the treatment of human glioblastoma
DA POZZO, ELEONORA;COSTA, BARBARA;NUTI, ELISA;ORLANDINI, ELISABETTA;DA SETTIMO PASSETTI, FEDERICO;ROSSELLO, ARMANDO;MARTINI, CLAUDIA
2010-01-01
Abstract
Glioblastoma multiforme is the most commonly diagnosed malignant primary brain tumor in adults. Invasive behavior is the pathol. hallmark of malignant gliomas; consequently, its inhibition was suggested as a therapeutic strategy. Tumor cell-derived gelatinases (matrix metalloproteinase-2, matrix metalloproteinase-9) can be considered prime factors in glioma invasiveness: their expression correlates with the progression and the degree of malignancy. Thus, broad spectrum matrix metalloproteinase inhibitors (MMP inhibitors) were included in clin. trials. In the present study, the invasiveness, viability and progression of the human glioma cell line U87MG were investigated following treatment with N-O-iso-Pr sulfonamido-based hydroxamates (compds. 1 and 2) as MMP-2 inhibitors used at nanomolar concn. A std. broad spectrum MMP-inhibitor belonging to the classical tertiary sulfonamido-based hydroxamates family (CGS_27023A) was used too. The compds. 1 and 2 resulted in potent inhibition of cell invasiveness without affecting viability. In some clin. trials, the combined therapy of temozolomide (an alkylating agent used in glioma treatment) plus marimastat (a broad spectrum MMP inhibitor) has provided evidence of the importance of MMPs to tumor progression and invasiveness. On this basis, the effect on U87MG cells of a combined treatment with temozolomide, plus each of the 2 MMP inhibitors at nanomolar concn., was investigated. The obtained data demonstrated the inhibition of cell invasiveness and viability after treatment. These results can help in developing clin. combined therapy using MMP inhibitors that, at low doses, increase the anticancer efficacy of chemotherapeutic drugs, probably without causing the side effects typical of broad-spectrum MMP inhibitors.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
