title: Antitumor effect of novel berberine derivatives in breast cancer cells.
abstract: Breast cancer is the most common malignancy and the most common cause of cancer death in elderly women. Chemoprevention with dietary compounds and their synthetic analogs has emerged as an attractive strategy to prevent carcinogenic progression to invasive cancer. In this study, we investigated the efficacy of some new synthetic derivatives of berberine, a phytochemical isolated from Barberry and other plants, to induce growth arrest of HER-2/neu overexpressing SK-BR-3 breast cancer cells. Supplementation with berberine or with the synthetic derivatives NAX012, NAX013, NAX014, and NAX035 exerted a dose- and time-dependent inhibition of SK-BR-3 cell viability, with a greater effectiveness of NAX012 and NAX014 compounds with respect to berberine. This cytotoxic effect was related to an increased number of apoptotic cells that reached 71.6% and 68.4% after 72 h treatment with 50 µM of NAX012 and NAX014, respectively, compared with 44.2% of berberine. Real-time PCR analyses showed that berberine, NAX012 and NAX014 compounds increased the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p53, p21(WAF1) , p16(INK4a) , and PAI-1, already after 24 h of 50 µM treatments. Furthermore, berberine, NAX012 and NAX014, all reduced both HER-2/neu expression and phosphorylation on tumor cells, the NAX014 compound showing the higher effectiveness. These results provide novel information on the mechanisms involved in the anticancer effects of berberine and demonstrate the greater effectiveness of NAX012 and NAX014 analogs in inducing apoptosis and cellular senescence in HER-2/neu overexpressing tumor cell lines.
authors.affiliation: Advanced Technology Center for Aging Research, Scientific Technological Area, INRCA-IRCCS, Ancona, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pierpaoli
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Arcamone
authors.forename: Franco
authors.initials: F
authors.lastname: Buzzetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Lombardi
authors.forename: Carmela
authors.initials: C
authors.lastname: Salvatore
authors.forename: Mauro
authors.initials: M
authors.lastname: Provinciali
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001600:Berberine Alkaloids / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001600:Berberine Alkaloids; D018719:Erb-b2 Receptor Tyrosine Kinases; C000603985:13-(4-chlorophenylethyl)berberine; C508053:ERBB2 protein, human
keywords: Her-2/neu; apoptosis; berberine; breast cancer; senescence