Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma

Elisa Pierpaoli, Elisa Damiani, Fiorenza Orlando, Guendalina Lucarini, Beatrice Bartozzi, Paolo Lombardi, Carmela Salvatore, Cristina Geroni, Abele Donati, Mauro Provinciali

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 (2.5 mg/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.

Original languageEnglish
Pages (from-to)1169-1179
Number of pages11
JournalCarcinogenesis
Volume36
Issue number10
DOIs
Publication statusPublished - Aug 16 2015

Fingerprint

Berberine
Breast Neoplasms
Neoplasms
Cell Aging
Transgenic Mice
13-(4-chlorophenylethyl)berberine
Galactosidases
Granzymes
Video Microscopy
Cell Cycle Checkpoints
Intraperitoneal Injections
Oncogenes
Alkaloids
Blood Vessels
Phosphorylation
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Medicine(all)

Cite this

Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. / Pierpaoli, Elisa; Damiani, Elisa; Orlando, Fiorenza; Lucarini, Guendalina; Bartozzi, Beatrice; Lombardi, Paolo; Salvatore, Carmela; Geroni, Cristina; Donati, Abele; Provinciali, Mauro.

In: Carcinogenesis, Vol. 36, No. 10, 16.08.2015, p. 1169-1179.

Research output: Contribution to journalArticle

Pierpaoli, Elisa ; Damiani, Elisa ; Orlando, Fiorenza ; Lucarini, Guendalina ; Bartozzi, Beatrice ; Lombardi, Paolo ; Salvatore, Carmela ; Geroni, Cristina ; Donati, Abele ; Provinciali, Mauro. / Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. In: Carcinogenesis. 2015 ; Vol. 36, No. 10. pp. 1169-1179.
@article{4206069ed644446bb6b73ef14fdb90ad,
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 (2.5 mg/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.",
author = "Elisa Pierpaoli and Elisa Damiani and Fiorenza Orlando and Guendalina Lucarini and Beatrice Bartozzi and Paolo Lombardi and Carmela Salvatore and Cristina Geroni and Abele Donati and Mauro Provinciali",
year = "2015",
month = "8",
day = "16",
doi = "10.1093/carcin/bgv103",
language = "English",
volume = "36",
pages = "1169--1179",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

T1 - Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma

AU - Pierpaoli, Elisa

AU - Damiani, Elisa

AU - Orlando, Fiorenza

AU - Lucarini, Guendalina

AU - Bartozzi, Beatrice

AU - Lombardi, Paolo

AU - Salvatore, Carmela

AU - Geroni, Cristina

AU - Donati, Abele

AU - Provinciali, Mauro

PY - 2015/8/16

Y1 - 2015/8/16

N2 - 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 (2.5 mg/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.

AB - 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 (2.5 mg/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.

UR - http://www.scopus.com/inward/record.url?scp=84943773879&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943773879&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgv103

DO - 10.1093/carcin/bgv103

M3 - Article

C2 - 26168818

AN - SCOPUS:84943773879

VL - 36

SP - 1169

EP - 1179

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 10

ER -