In Preclinical Model of Ovarian Cancer, the SGK1 Inhibitor SI113 Counteracts the Development of Paclitaxel Resistance and Restores Drug Sensitivity.
Journal
Translational oncology
ISSN: 1936-5233
Titre abrégé: Transl Oncol
Pays: United States
ID NLM: 101472619
Informations de publication
Date de publication:
Aug 2019
Aug 2019
Historique:
received:
08
04
2019
revised:
08
05
2019
accepted:
09
05
2019
pubmed:
5
6
2019
medline:
5
6
2019
entrez:
5
6
2019
Statut:
ppublish
Résumé
Ovarian cancer is the second most common gynecological malignancy worldwide. Paclitaxel is particularly important in the therapy of ovarian carcinomas, but the treatment efficacy is counteracted by the development of resistance to chemotherapy. The identification of target molecules that can prevent or control the development of chemoresistance might provide important tools for the management of patients affected by ovarian cancer. Serum- and glucocorticoid-regulated kinase 1 (SGK1) appears to be a key determinant of resistance to chemo- and radiotherapy. Specifically, SGK1 affects paclitaxel sensitivity in RKO colon carcinoma cells by modulating the specificity protein 1 (SP1)-dependent expression of Ran-specific GTPase-activating protein (RANBP1), a member of the GTP-binding nuclear protein Ran (RAN) network that is required for the organization and function of the mitotic spindle. SGK1 inhibition might thus be useful for counteracting the development of paclitaxel resistance. Here, we present in vitro data obtained using ovarian carcinoma cell lines that indicate that the SGK1 inhibitor SI113 inhibits cancer cell proliferation, potentiates the effects of paclitaxel-based chemotherapy, counteracts the development of paclitaxel resistance, and restores paclitaxel sensitivity in paclitaxel-resistant A2780 ovarian cancer cells. The results were corroborated by preclinical studies of xenografts generated in nude mice through the implantation of paclitaxel-resistant human ovarian cancer cells. The SGK1 inhibitor SI113 synergizes with paclitaxel in the treatment of xenografted ovarian cancer cells. Taken together, these data suggest that SGK1 inhibition should be investigated in clinical trials for the treatment of paclitaxel-resistant ovarian cancer.
Identifiants
pubmed: 31163384
pii: S1936-5233(19)30169-X
doi: 10.1016/j.tranon.2019.05.008
pmc: PMC6545392
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1045-1055Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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