title: Sanguinarine suppresses basal-like breast cancer growth through dihydrofolate reductase inhibition.
abstract: Basal-like breast cancer (BLBC) remains a great challenge because of its clinically aggressive nature and lack of effective targeted therapy. We analyzed the potential anti-neoplastic effects of sanguinarine, a natural benzophenanthridine alkaloid, against BLBC cells. Sanguinarine treatment resulted in a reduction of cell migration, in a dose-dependent inhibition of cell viability and in the induction of cell death by apoptosis in both human (MDA-MB-231 cells) and mouse (A17 cells) in vitro models of BLBC. In vivo experiments demonstrated that oral administration of sanguinarine reduced the development and growth of A17 transplantable tumors in FVB syngeneic mice. Western blotting analysis revealed that suppression of BLBC growth by sanguinarine was correlated with a concurrent upregulation of p27 and downregulation of cyclin D1 and with the inhibition of STAT3 activation. In addition, we identified sanguinarine as a potent inhibitor of dihydrofolate reductase (DHFR), able to impair enzyme activity even in methotrexate resistant MDA-MB-231 cells. These results provide evidence that sanguinarine is a promising anticancer drug for the treatment of BLBC.
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Kalogris
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Garulli
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Pietrella
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gambini
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pucciarelli
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Lucci
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Tilio
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Maria Elexpuru
authors.initials: ME
authors.lastname: Zabaleta
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bartolacci
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Andreani
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Giangrossi
authors.affiliation: Aging Research Centre, G. d'Annunzio University, Chieti 66100, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: Division of Experimental Oncology 2, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy. Electronic address: cristina.marchini@unicam.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Marchini
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy. Electronic address: augusto.amici@unicam.it.
authors.forename: Augusto
authors.initials: A
authors.lastname: Amici
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009336:Necrosis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009368:Neoplasm Transplantation; D018295:Neoplasms, Basal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011897:Random Allocation; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D005493:Folic Acid Antagonists; D007546:Isoquinolines; D009363:Neoplasm Proteins; C005705:sanguinarine; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate
keywords: Apoptosis; Basal-like breast cancer; Dihydrofolate reductase (DHFR); Mice; STAT3; Sanguinarine