title: Structure-Activity Relationships of Di-2-pyridylketone, 2-Benzoylpyridine, and 2-Acetylpyridine Thiosemicarbazones for Overcoming Pgp-Mediated Drug Resistance.
abstract: Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) represents a significant impediment to successful cancer treatment. The compound, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), has been shown to induce greater cytotoxicity against resistant cells than their nonresistant counterparts. Herein, the structure-activity relationships of selected thiosemicarbazones are explored and the novel mechanism underlying their ability to overcome resistance is further elucidated. Only thiosemicarbazones with electron-withdrawing substituents at the imine carbon mediated Pgp-dependent potentiated cytotoxicity, which was reversed by Pgp inhibition. Treatment of resistant cells with these thiosemicarbazones resulted in Pgp-dependent lysosomal membrane permeabilization (LMP) that relied on copper (Cu) chelation, reactive oxygen species generation, and increased relative lipophilicity. Hence, this study is the first to demonstrate the structural requirements of these thiosemicarbazones necessary to overcome MDR. We also demonstrate the mechanism that enables the targeting of resistant tumors, whereby thiosemicarbazones "hijack" lysosomal Pgp and form redox-active Cu complexes that mediate LMP and potentiate cytotoxicity.
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Level 5, Blackburn Building (D06), Sydney, New South Wales 2006, Australia.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Stacy
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Level 5, Blackburn Building (D06), Sydney, New South Wales 2006, Australia.
authors.forename: Duraippandi
authors.initials: D
authors.lastname: Palanimuthu
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Level 5, Blackburn Building (D06), Sydney, New South Wales 2006, Australia.
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Level 5, Blackburn Building (D06), Sydney, New South Wales 2006, Australia.
authors.forename: Patric J
authors.initials: PJ
authors.lastname: Jansson
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Level 5, Blackburn Building (D06), Sydney, New South Wales 2006, Australia.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism; D018432:Drug Resistance, Multiple; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D010539:Permeability / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; C033836:2-acetylpyridine thiosemicarbazone; D003300:Copper