Metronomic docetaxel in PRINT nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer.

Abstract

The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and antiangiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT-docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models (P < 0.05). Individual as well as combination therapies showed significant antiangiogenic, antiproliferative, and proapoptotic effects, and combination therapy had additive effects. Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA has significant antitumor activity in preclinical models of ovarian cancer.

• Authors: Kshipra M Gharpure, Kevin S Chu, Charles J Bowerman, Takahito Miyake, Sunila Pradeep, Selanere L Mangala, Hee-Dong Han, Rajesha Rupaimoole, Guillermo N Armaiz-Pena, Tojan B Rahhal, Sherry Y Wu, J Christopher Luft, Mary E Napier, Gabriel Lopez-Berestein, Joseph M DeSimone, Anil K Sood
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 7 Pg. 1750-7 (Jul 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24755199 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• RNA, Small Interfering
• Taxoids
• Docetaxel
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2

Topics

• Administration, Metronomic
• Animals
• Antineoplastic Agents (administration & dosage, chemistry)
• Cell Line, Tumor
• Docetaxel
• Enhancer of Zeste Homolog 2 Protein
• Female
• Gene Silencing (drug effects)
• Humans
• Mice
• Mice, Nude
• Nanoparticles (administration & dosage, chemistry)
• Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
• Polycomb Repressive Complex 2 (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (administration & dosage, genetics)
• Randomized Controlled Trials as Topic
• Taxoids (administration & dosage, chemistry)