TY - JOUR
T1 - Antitumor activity of NAX060
T2 - A novel semisynthetic berberine derivative in breast cancer cells
AU - Pierpaoli, Elisa
AU - Fiorillo, Gaetano
AU - Lombardi, Paolo
AU - Salvatore, Carmela
AU - Geroni, Cristina
AU - Piacenza, Francesco
AU - Provinciali, Mauro
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Breast cancer (BC) is the most common malignancy and the most common cause of cancer death in elderly women. We recently demonstrated that innovative compounds structurally related to and semisynthetically derived from the plant alkaloid berberine represent a promising unexplored resource for novel therapeutic tools in BC therapy. In this study, we analyzed the effectiveness of new 13-dichlorophenylalkyl berberine semisynthetic derivatives (NAX060, NAX103, NAX111, and NAX114) on the viability of BC cell lines. Our results demonstrated that the new compounds effectively inhibited the growth of a variety of human BC cell lines. In particular, the viability of HER-2 overexpressing SK-BR-3 cells was significantly reduced by the treatment with NAX060, the most active compound, in a dose and time-dependent manner. In the same tumor cell line, NAX060 induced a strong increase in sub-G1 population while G0/G1 and G2/M phase cells remarkably decreased. NAX060 withdrawal after 72 h of treatment resulted in an irreversible cell proliferation arrest and increasing cell death. Real-time PCR analyses showed that NAX060 induced the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p21WAF1, p27, p16INK4a, and PAI-1. Furthermore, the HER-2 protein expression and phosphorylation, as well as the level of heparanase expression, were remarkably reduced on SK-BR-3 cells. NAX060 was effective also on HER-2 negative tumor cells, and, in particular, on human triple-negative MDA-MB-231 cells. These data suggest a potential therapeutic effect of NAX060 compound in the management of BC malignancies. Interestingly, NAX060 may represent a new useful tool also in triple-negative BC.
AB - Breast cancer (BC) is the most common malignancy and the most common cause of cancer death in elderly women. We recently demonstrated that innovative compounds structurally related to and semisynthetically derived from the plant alkaloid berberine represent a promising unexplored resource for novel therapeutic tools in BC therapy. In this study, we analyzed the effectiveness of new 13-dichlorophenylalkyl berberine semisynthetic derivatives (NAX060, NAX103, NAX111, and NAX114) on the viability of BC cell lines. Our results demonstrated that the new compounds effectively inhibited the growth of a variety of human BC cell lines. In particular, the viability of HER-2 overexpressing SK-BR-3 cells was significantly reduced by the treatment with NAX060, the most active compound, in a dose and time-dependent manner. In the same tumor cell line, NAX060 induced a strong increase in sub-G1 population while G0/G1 and G2/M phase cells remarkably decreased. NAX060 withdrawal after 72 h of treatment resulted in an irreversible cell proliferation arrest and increasing cell death. Real-time PCR analyses showed that NAX060 induced the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p21WAF1, p27, p16INK4a, and PAI-1. Furthermore, the HER-2 protein expression and phosphorylation, as well as the level of heparanase expression, were remarkably reduced on SK-BR-3 cells. NAX060 was effective also on HER-2 negative tumor cells, and, in particular, on human triple-negative MDA-MB-231 cells. These data suggest a potential therapeutic effect of NAX060 compound in the management of BC malignancies. Interestingly, NAX060 may represent a new useful tool also in triple-negative BC.
KW - apoptosis, senescence
KW - Berberine
KW - breast cancer
KW - HER-2
KW - NAX060
UR - http://www.scopus.com/inward/record.url?scp=85052860378&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052860378&partnerID=8YFLogxK
U2 - 10.1002/biof.1440
DO - 10.1002/biof.1440
M3 - Article
C2 - 30178609
AN - SCOPUS:85052860378
VL - 44
SP - 443
EP - 452
JO - BioFactors
JF - BioFactors
SN - 0951-6433
IS - 5
ER -