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Evaluation of Hedgehog Pathway Inhibitors as a Therapeutic Option for Uterine Leiomyosarcoma Using the Xenograft Model.
- Source :
-
Reproductive sciences (Thousand Oaks, Calif.) [Reprod Sci] 2022 Mar; Vol. 29 (3), pp. 781-790. Date of Electronic Publication: 2021 Oct 12. - Publication Year :
- 2022
-
Abstract
- Uterine leiomyosarcoma (LMS) contributes to a significant proportion of uterine cancer deaths. It is a rare and high-risk gynecological cancer. LMS is challenging to the treatment due to the resistance of several therapies. The activation of the Hedgehog (HH) pathway has been reported in several types of female cancers. Uterine LMS presents an upregulation of the crucial HH signaling pathway members such as SMO and GLI1. Although targeting the HH pathway exhibited a potent inhibitory effect on the phenotype of uterine LMS in vitro, the effect of the HH inhibitors on LMS growth in vivo has not been identified. The present study aimed to assess the effect of Hedgehog pathway inhibitors (SMO-LDE225 and GLI-Gant61) as a therapeutic option in the xenograft model of uterine LMS. The results demonstrated that LDE225 treatment did not show any inhibitory effect on LMS tumor growth; however, treatment with GLI inhibitor (Gant61) induced a remarkable tumor regression with a significant decrease in Ki67 expression, compared to control (pā<ā0.01). Moreover, administration of Gant61 decreased the expression of GLI1, GLI target genes BMP4 and c-MYC (pā<ā0.05), indicating that the HH pathway is implicated in the LMS experimental model. In conclusion, our studies demonstrate for the first time that GLI inhibitor (Gant61), but not SMO inhibitor (LDE225), shows a potent inhibitory effect on LMS tumor growth and concomitantly suppresses the expression of GLI1- and GLI-targeted genes using the xenograft model of uterine LMS.<br /> (© 2021. The Author(s).)
- Subjects :
- Animals
Cell Line, Tumor
Female
Humans
Leiomyosarcoma metabolism
Mice
Mice, Nude
Phenotype
Signal Transduction
Uterine Neoplasms metabolism
Xenograft Model Antitumor Assays
Biphenyl Compounds pharmacology
Hedgehog Proteins antagonists & inhibitors
Hedgehog Proteins metabolism
Leiomyosarcoma drug therapy
Pyridines pharmacology
Pyrimidines pharmacology
Uterine Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1933-7205
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Reproductive sciences (Thousand Oaks, Calif.)
- Publication Type :
- Academic Journal
- Accession number :
- 34642915
- Full Text :
- https://doi.org/10.1007/s43032-021-00731-y