RRC ID 63551
Author Kawata Y, Nagasaka K, Oda K, Makii C, Takeuchi M, Oki S, Honjo H, Kojima M, Miyagawa Y, Taguchi A, Tanikawa M, Sone K, Hiraike H, Matsumoto Y, Wada-Hiraike O, Ayabe T, Osuga Y, Fujii T.
Title Effect of murine double-minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys.
Journal Cancer Sci
Abstract Advanced clear cell carcinomas originating from both ovaries and kidneys with cancerous peritonitis have poor prognoses. Murine double-minute 2 (MDM2) is a potential therapeutic target for clear cell ovarian carcinomas with WT TP53. Herein, we characterized the antiangiogenic and antitumor effects of the MDM2 inhibitors DS-3032b and DS-5272 in 6 clear cell ovarian carcinoma cell lines and 2 clear cell renal carcinoma cell lines, as well as in clear cell ovarian carcinomas s.c. xenograft and ID8 (murine ovarian cancer cells with WT TP53) cancer peritonitis mouse models. In clear cell ovarian carcinoma s.c. xenograft mouse models, DS-3032b significantly reduced WT TP53 clear cell ovarian carcinoma- and clear cell renal carcinoma-derived tumor volumes. In ID8 mouse models, DS-5272 significantly inhibited ascites production, reduced body weight, and significantly improved overall survival. Additionally, DS-5272 reduced the tumor burden of peritoneal dissemination and decreased CD31+ cells in a dose-dependent manner. Furthermore, DS-5272 significantly decreased vascular endothelial growth factor concentrations in both sera and ascites. Combined therapy with MDM2 inhibitors and everolimus showed synergistic, and dose-reduction potential, for clear cell carcinoma treatment. Our findings suggest that MDM2 inhibitors represent promising molecular targeted therapy for clear cell carcinomas, thereby warranting further studies to evaluate the efficacy and safety of dual MDM2/mTOR inhibitors in clear cell carcinoma patients.
Volume 111(10)
Pages 3824-3834
Published 2020-10-1
DOI 10.1111/cas.14583
PMID 32713096
PMC PMC7541011
MeSH Adenocarcinoma, Clear Cell / drug therapy Adenocarcinoma, Clear Cell / genetics Adenocarcinoma, Clear Cell / pathology Animals Apoptosis / drug effects Carcinoma, Renal Cell / drug therapy* Carcinoma, Renal Cell / genetics Carcinoma, Renal Cell / pathology Cell Cycle / drug effects Cell Proliferation / drug effects Disease Models, Animal Everolimus / pharmacology Female Heterografts Humans Imidazoles / pharmacology Kidney / drug effects* Kidney / metabolism Kidney / pathology Mice Ovarian Neoplasms / drug therapy* Ovarian Neoplasms / genetics Ovarian Neoplasms / pathology Peritonitis / drug therapy Peritonitis / genetics Peritonitis / pathology Platelet Endothelial Cell Adhesion Molecule-1 / genetics Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors Proto-Oncogene Proteins c-mdm2 / genetics* TOR Serine-Threonine Kinases / genetics Thiazoles / pharmacology
IF 4.966
Human and Animal Cells JHOC-7(RCB1688) JHOC-9(RCB2226)