Sonic hedgehog signaling pathway inhibitors: evaluation of in vitro effects on uterine leiomyomas and leiomyosarcomas

Leiomyoma (LM) and leiomyosarcoma (LMS) are uterine mesenchymal tumors. Uterine LM is a benign tumor commonly affecting women at reproductive age whereas LMS are rare tumors represent 7% of all soft tissue sarcomas and 40% of all uterine sarcomas. These neoplasms have variable clinical behavior and their definitive diagnosis occurs only after surgery. Several studies have shown that aberrant activation of the Sonic hedgehog (SHH) signaling pathway plays an important role in cell proliferation and differentiation. In a previous study of our group, we found a hyperexpression of SMO and GLI1 proteins in LMS, compared to LM and no expression in myometrium (MM). The aim of this work was to evaluate, in vitro, inhibitors of the Sonic hedgehog signaling pathway in LM and LMS. For this purpose, MM, LM and LMS cell lines were evaluated for basal expressions of SHH pathway components and major targets. The effect of SMO (GDC0449 and LDE225) and GLI (Gant58 and Gant61) inhibitors in gene and protein expression levels were determined by q-PCR and Western Blot analysis respectively. Proliferation, migration, invasion and apoptosis assays were also performed. Our results showed that among the inhibitors tested, LDE225 and Gant61 were the most promising. Both had an inhibitory effect on LMS cell proliferation, they induced inhibition of SMO, GLI1, GLI2 and GLI3 expression, inhibited migration and invasion mechanisms, and increased apoptotic index. These effects together suggest the potential use of these drugs for specific target therapy in LMS via SHH blockade (AU)