Abstract | PURPOSE: METHODS AND RESULTS: MTT assay and flow cytometric analysis were used to examine the in vitro antitumor activity of CUDC-907. A BxPC-3-derived xenograft mouse model was used to determine CUDC-907 in vivo efficacy. The TUNEL assay as used to determine apoptosis in tumors in vivo post CUDC-907 treatment. Western blots were used to determine the effect of CUDC-907 on protein levels. Our results show that CUDC-907 decreased viable cells and induced cell death in a concentration-dependent manner. Furthermore, CUDC-907 showed promising in vivo antitumor activity in the BxPC-3-derived xenograft mouse model while exhibiting tolerable toxicity. Furthermore, long-term treatment with CUDC-907 induced phosphorylation of AKT, S6 ( ribosomal protein S6), and ERK (extracellular regulated protein kinase), and inhibition of PI3K (phosphatidylinositol 3-kinase), mTOR ( mammalian target of rapamycin), or ERK significantly enhanced CUDC-907-induced cell death in pancreatic cell lines. CONCLUSION: Taken together, these findings support the clinical development of CUDC-907 for the treatment of pancreatic cancer and identify compensatory activation of mTOR and MEK/ERK as a possible mechanism of resistance to CUDC-907.
|
Authors | Shuang Liu, Shoujing Zhao, Yang Dong, Tingting Wang, Xiaojia Niu, Lijing Zhao, Guan Wang |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 87
Issue 3
Pg. 415-423
(03 2021)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 33392641
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Antineoplastic Agents
- CUDC-907
- Histone Deacetylase Inhibitors
- Morpholines
- Phosphoinositide-3 Kinase Inhibitors
- Pyrimidines
|
Topics |
- Animals
- Antineoplastic Agents
(administration & dosage, pharmacology)
- Apoptosis
(drug effects)
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Female
- Histone Deacetylase Inhibitors
(administration & dosage, pharmacology)
- Humans
- In Situ Nick-End Labeling
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Morpholines
(administration & dosage, pharmacology)
- Pancreatic Neoplasms
(drug therapy, pathology)
- Phosphoinositide-3 Kinase Inhibitors
(administration & dosage, pharmacology)
- Pyrimidines
(administration & dosage, pharmacology)
- Xenograft Model Antitumor Assays
|