title: Inhibition of carbonic anhydrase IX in glioblastoma multiforme.
abstract: Carbonic anhydrase IX (CAIX) is a transmembrane enzyme upregulated in several types of tumors including glioblastoma multiforme (GBM). GBM is among the most aggressive tumors among gliomas. Temozolomide (TMZ) therapy combined with surgical or radiation approaches is the standard treatment but not effective in long term. In this study we tested the treatment with acetazolamide (ATZ), an inhibitor of CAIX, alone or combined with TMZ. The experiments were performed in 2D and 3D cultures (spheroids) using glioblastoma U251N and human brain tumor stem cells (BTSCs). Several proteins implicated in tumor cell death were also investigated. The key results from these studies suggest the following: (1) Cell death of human glioblastoma spheroids and BTSC is significantly increased with combined treatment after 7 days, and (2) the effectiveness of ATZ is significantly enhanced against BTSC and U251N when incorporated into nano-carriers. Collectively, these results point toward the usefulness of nano-delivery of CAIX inhibitors and their combination with chemotherapeutics for glioblastoma treatment.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Abdolali
authors.initials: A
authors.lastname: Amiri
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal H3A 2B4, Quebec, Canada.
authors.forename: Phuong Uyen
authors.initials: PU
authors.lastname: Le
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Moquin
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Gayane
authors.initials: G
authors.lastname: Machkalyan
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal H3A 2B4, Quebec, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrecca
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada; Kalgene Pharmaceuticals, Innovation Park at Queens University, Kingston K7L 3N6, Ontario, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Gillard
authors.affiliation: Kalgene Pharmaceuticals, Innovation Park at Queens University, Kingston K7L 3N6, Ontario, Canada.
authors.forename: Nathan
authors.initials: N
authors.lastname: Yoganathan
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada. Electronic address: dusica.maysinger@mcgill.ca.
authors.forename: Dusica
authors.initials: D
authors.lastname: Maysinger
mesh_terms: D000086:Acetazolamide / Q000008:administration & dosage / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D000071231:Carbonic Anhydrase IX / Q000037:antagonists & inhibitors*; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage / Q000737:chemistry*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D008823:Micelles; D018874:Spheroids, Cellular; D000077204:Temozolomide; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D004337:Drug Carriers; D008823:Micelles; D003606:Dacarbazine; D053148:Caspase 3; D000071231:Carbonic Anhydrase IX; D000086:Acetazolamide; D000077204:Temozolomide
keywords: Acetazolamide; Brain tumor stem cells; Carbonic anhydrase IX; Drug delivery system; Glioblastoma spheroid; Temozolomide