Loading...
Please wait, while we are loading the content...
Similar Documents
MDM2 antagonists synergize with PI3K/mTOR inhibition in well-differentiated/dedifferentiated liposarcomas
| Content Provider | Semantic Scholar |
|---|---|
| Author | Laroche, Audrey Chaire, Vanessa Algéo, Marie-Paule Karanian, Marie Fourneaux, Benjamin |
| Copyright Year | 2017 |
| Abstract | BACKGROUND Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) are characterized by a consistent amplification of the MDM2 gene. The PI3K/AKT/mTOR pathway has been suggested to play also an important role in their tumorigenesis. Our goal was to determine whether combined MDM2 and PI3K/AKT/mTOR targeting is associated with higher anti-tumor activity than single agent alone in preclinical models of WDLPS/DDLPS. METHODS WDLPS/DDLPS cells were exposed to RG7388 (MDM2 antagonist) and BEZ235 (PI3K/mTOR dual inhibitor) after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. Western blotting, histopathology, and tumor volume evolution were used for the assessment of treatment efficacy. RESULTS The PI3K/AKT/mTOR was upregulated in up to 81% of the human WDLPS/DDLPS samples analysed. Treatment with RG7388 and BEZ235 resulted in a greater tumor activity than either drug alone with a significant difference in terms of cell viability after 72h of treatment with RG-73888 alone, BEZ235 alone and a combination of both agents. Consistent with these observations, we found a significant increase in apoptosis with the combination versus the single agent treatment alone. We then analysed the in vivo antitumor activity of RG7388 and BEZ235 in a xenograft model of DDLPS. The combination regimen significantly reduced tumor growth rate in comparison with single agent alone. CONCLUSIONS Our results represent the first in vivo evidence of synergy between MDM2 and PI3K/AKT/mTOR antagonists and represent a strong rationale to evaluate the therapeutic potential of such a combination in WDLPS/DDLPS. |
| Starting Page | 53968 |
| Ending Page | 53977 |
| Page Count | 10 |
| File Format | PDF HTM / HTML |
| PubMed reference number | 28903316v1 |
| Alternate Webpage(s) | https://doi.org/10.18632/oncotarget.16345 |
| DOI | 10.18632/oncotarget.16345 |
| Journal | Oncotarget |
| Volume Number | 8 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Apoptosis BEZ235 Carcinogenesis Cell Differentiation process Cell Survival Dual FRAP1 protein, human Flow Cytometry Histopathology Liposarcoma, Dedifferentiated MDM2 gene MDM2 protein, human MTOR gene Neoplasms Proto-Oncogene Proteins c-akt RG7388 Tumor Volume Western Blotting Xenograft procedure cellular targeting liposarcoma |
| Content Type | Text |
| Resource Type | Article |
