title: 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.affiliation: Authors' Affiliations: Departments of Gynecology Oncology, Experimental Therapeutics Program and.
authors.forename: Kshipra M
authors.initials: KM
authors.lastname: Gharpure
authors.affiliation: Pharmaceutical Sciences, and.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Chu
authors.affiliation: Chemistry, Lineberger Comprehensive Cancer Center;
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Bowerman
authors.affiliation: Authors' Affiliations: Departments of Gynecology Oncology.
authors.forename: Takahito
authors.initials: T
authors.lastname: Miyake
authors.affiliation: Authors' Affiliations: Departments of Gynecology Oncology.
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center (MDACC);
authors.forename: Selanere L
authors.initials: SL
authors.lastname: Mangala
authors.affiliation: Authors' Affiliations: Departments of Gynecology Oncology, Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center (MDACC); Department of Immunology, School of Medicine, Konkuk University, South Korea.
authors.forename: Hee-Dong
authors.initials: HD
authors.lastname: Han
authors.affiliation: Authors' Affiliations: Departments of Gynecology Oncology, Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas; Departments of.
authors.forename: Rajesha
authors.initials: R
authors.lastname: Rupaimoole
authors.affiliation: Authors' Affiliations: Departments of Gynecology Oncology.
authors.forename: Guillermo N
authors.initials: GN
authors.lastname: Armaiz-Pena
authors.affiliation: Pharmaceutical Sciences, and.
authors.forename: Tojan B
authors.initials: TB
authors.lastname: Rahhal
authors.affiliation: Authors' Affiliations: Departments of Gynecology Oncology.
authors.forename: Sherry Y
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Chemistry, Lineberger Comprehensive Cancer Center;
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Luft
authors.affiliation: Frank Hawkins Kenan Institute of Private Enterprises;
authors.forename: Mary E
authors.initials: ME
authors.lastname: Napier
authors.affiliation: Experimental Therapeutics, and Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center (MDACC);
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Chemistry, Chemical and Biomolecular Engineering; and Department of Pharmacology, Eshelman School of Pharmacy; Lineberger Comprehensive Cancer Center; Carolina Center of Cancer Nanotechnology Excellence; Institute for Nanomedicine; and Institute for Advanced Materials, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: DeSimone
authors.affiliation: Authors' Affiliations: Departments of Gynecology Oncology, Cancer Biology; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center (MDACC); asood@mdanderson.org.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D000077143:Docetaxel; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
references.citation: Cancer Biol Ther. 2009 Aug;8(16):1596-603
references.pmid: 19738426
references.citation: Nat Rev Cancer. 2003 Jul;3(7):502-16
references.pmid: 12835670
references.citation: Anticancer Drugs. 2011 Nov;22(10):1030-3
references.pmid: 21970854
references.citation: Cancer Sci. 2011 Mar;102(3):530-9
references.pmid: 21205084
references.citation: Nanomedicine. 2013 Jul;9(5):686-93
references.pmid: 23219874
references.citation: Cancer Res. 2007 Feb 15;67(4):1757-68
references.pmid: 17308118
references.citation: Cancer Cell. 2010 Aug 9;18(2):185-97
references.pmid: 20708159
references.citation: J Clin Invest. 2000 Apr;105(8):R15-24
references.pmid: 10772661
references.citation: Cancer Lett. 2013 Aug 9;336(1):53-60
references.pmid: 23603558
references.citation: Mol Cancer Ther. 2010 Apr;9(4):985-95
references.pmid: 20371710
references.citation: Mol Cancer Ther. 2010 Apr;9(4):996-1006
references.pmid: 20371722
references.citation: Cancer Res. 2000 Apr 1;60(7):1878-86
references.pmid: 10766175
references.citation: Cancer Res. 2007 Jan 1;67(1):281-8
references.pmid: 17210709
references.citation: J Clin Invest. 2000 Apr;105(8):1045-7
references.pmid: 10772648
references.citation: J Natl Cancer Inst. 1990 Jan 3;82(1):4-6
references.pmid: 1688381
references.citation: J Gastroenterol Hepatol. 2011 Jan;26(1):19-27
references.pmid: 21175789
references.citation: Cancer Chemother Pharmacol. 2013 Jul;72(1):13-33
references.pmid: 23475105
references.citation: Carcinogenesis. 2010 Sep;31(9):1576-83
references.pmid: 20668008
references.citation: Lancet Oncol. 2001 Dec;2(12):733-40
references.pmid: 11902515
references.citation: Nat Rev Cancer. 2004 Jun;4(6):423-36
references.pmid: 15170445
references.citation: Nano Lett. 2011 Feb 9;11(2):808-13
references.pmid: 21265552