title: Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma.
abstract: Berberine (BBR) is a natural isoquinoline alkaloid with proven antiangiogenic and anticancer activities. We recently demonstrated that BBR and its synthetic derivative 13-(4-chlorophenylethyl)berberine iodide, NAX014, exert antiproliferative activity against HER2-overexpressing breast cancer cells, inducing apoptosis, modulating the expression of cell cycle checkpoint molecules involved in cell senescence, and reducing both HER2 expression and phosphorylation on tumor cells. In this study, we examined the anticancer properties of BBR and NAX014 in a transgenic mouse model which spontaneously develops HER2-positive mammary tumors. Repeated intraperitoneal injections of a safety dose (2.5mg/kg) of NAX014 delayed the development of tumors, reducing both the number and size of tumor masses. In vivo sidestream dark field videomicroscopy revealed a significant lower vessel density in mammary tumors from NAX014-treated mice in comparison with the control group. Immunohistochemical evaluation using CD34 antibody confirmed the reduced vessel density in NAX014 group. Statistically significant increase of senescence associated β-galactosidase and p16 expression, and reduced expression of heparanase were observed in tumors from NAX014-treated mice than in tumors from control animals. Finally, NAX014 treatment decreased the level of perforine and granzyme mRNA in mammary tumors. Berberine did not show any statistically significant modulation in comparison with control mice. The results of the present study indicate that NAX014 is more effective than BBR in exerting anticancer activity delaying the development of mammary tumors in mice transgenic for the HER-2/neu oncogene. The antitumor efficacy of NAX014 is mainly related to its effect on tumor vascular network and on induction of tumor cell senescence.
authors.affiliation: Advanced Technology Center for Aging Research, Scientific Technological Area, IRCCS- INRCA, Via Birarelli 8, 60121 Ancona, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pierpaoli
authors.affiliation: Department of Biomedical Sciences and Public Health, Anesthesia and Intensive Care Unit, Polytechnic University of Marche Region, via Tronto 10/a, 60020 Torrette di Ancona, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Damiani
authors.affiliation: Experimental Animal Models for Aging Unit, Scientific Technological Area, IRCCS- INRCA, via Birarelli 8, 60121 Ancona, Italy.
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Orlando
authors.affiliation: Department of Molecular and Clinical Sciences, Histology, Polytechnic University of Marche Region, via Tronto 10/a, 60020 Torrette di Ancona, Italy.
authors.forename: Guendalina
authors.initials: G
authors.lastname: Lucarini
authors.affiliation: Advanced Technology Center for Aging Research, Scientific Technological Area, IRCCS- INRCA, Via Birarelli 8, 60121 Ancona, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bartozzi
authors.affiliation: Naxospharma, via Di Vittorio 70, 20026 Novate Milanese, Italy and Aesis Therapeutics, Incubatore JCube, via della Barchetta 1, 60035 Jesi, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lombardi
authors.affiliation: Aesis Therapeutics, Incubatore JCube, via della Barchetta 1, 60035 Jesi, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Salvatore
authors.affiliation: Aesis Therapeutics, Incubatore JCube, via della Barchetta 1, 60035 Jesi, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Geroni
authors.affiliation: Department of Biomedical Sciences and Public Health, Anesthesia and Intensive Care Unit, Polytechnic University of Marche Region, via Tronto 10/a, 60020 Torrette di Ancona, Italy.
authors.forename: Abele
authors.initials: A
authors.lastname: Donati
authors.affiliation: Advanced Technology Center for Aging Research, Scientific Technological Area, IRCCS- INRCA, Via Birarelli 8, 60121 Ancona, Italy, Experimental Animal Models for Aging Unit, Scientific Technological Area, IRCCS- INRCA, via Birarelli 8, 60121 Ancona, Italy, m.provinciali@inrca.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Provinciali
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001599:Berberine / Q000008:administration & dosage* / Q000031:analogs & derivatives; D001600:Berberine Alkaloids / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: D020533:Angiogenesis Inhibitors; D001599:Berberine; D001600:Berberine Alkaloids; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D001616:beta-Galactosidase; C000603985:13-(4-chlorophenylethyl)berberine; C000614131:CDKN2A protein, human