title: Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells.
abstract: Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multidrug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density.
authors.affiliation: Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Surgery, Munich Medical Center, Campus Grosshadern, LMU, Munich, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schwarz
authors.affiliation: Institute of Molecular Immunology, Helmholtz Center for Environment and Health, Munich, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Mysliwietz
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.affiliation: Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Camaj
authors.affiliation: Department of Surgery, Munich Medical Center, Campus Grosshadern, LMU, Munich, Germany.
authors.forename: Qi
authors.initials: Q
authors.lastname: Bao
authors.affiliation: Department of Surgery, Munich Medical Center, Campus Grosshadern, LMU, Munich, Germany.
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Jauch
authors.affiliation: Department of Surgery, Munich Medical Center, Campus Grosshadern, LMU, Munich, Germany.
authors.forename: Makus
authors.initials: M
authors.lastname: Guba
authors.affiliation: Institute of Molecular Immunology, Helmholtz Center for Environment and Health, Munich, Germany.
authors.forename: Joachim Walter
authors.initials: JW
authors.lastname: Ellwart
authors.affiliation: Clinical Biochemistry Group, Medical Clinic and Policlinic IV, Munich Medical Center, Campus Innenstadt, LMU, Munich, Germany.
authors.forename: Peter Jon
authors.initials: PJ
authors.lastname: Nelson
authors.affiliation: Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Christiane Josephine
authors.initials: CJ
authors.lastname: Bruns
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D033721:Equilibrative Nucleoside Transporter 1 / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058985:Side-Population Cells / Q000187:drug effects; D014700:Verapamil / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D014700:Verapamil