title: Bruceantin inhibits multiple myeloma cancer stem cell proliferation.
abstract: Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM.
authors.affiliation: a School of Pharmaceutical Sciences , University of Geneva, University of Lausanne, Rue Michel Servet , Geneva , Switzerland.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Issa
authors.affiliation: a School of Pharmaceutical Sciences , University of Geneva, University of Lausanne, Rue Michel Servet , Geneva , Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Berndt
authors.affiliation: b Laboratoire CRRET, Faculté des Sciences et Technologie , Université Paris Est Créteil , Créteil Cedex , France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Carpentier
authors.affiliation: c Arnold & Marie Schwartz College of Pharmacy and Health Sciences , Long Island University , Brooklyn , NY , USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
authors.affiliation: a School of Pharmaceutical Sciences , University of Geneva, University of Lausanne, Rue Michel Servet , Geneva , Switzerland.
authors.forename: Muriel
authors.initials: M
authors.lastname: Cuendet
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D036702:Quassins / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D036702:Quassins; C002550:bruceantin
keywords: Bruceantin; cancer stem cells; cell death; multiple myeloma; notch; proliferation