title: Novel Mechanism of Cytotoxicity for the Selective Selenosemicarbazone, 2-Acetylpyridine 4,4-Dimethyl-3-selenosemicarbazone (Ap44mSe): Lysosomal Membrane Permeabilization.
abstract: Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up-regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant thiosemicarbazones. Furthermore, Cu-Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-L-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure-activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent.
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Sydney, Level 5, Blackburn Building (D06)New South Wales 2006, Australia.
authors.forename: Zaynab
authors.initials: Z
authors.lastname: Al-Eisawi
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Sydney, Level 5, Blackburn Building (D06)New South Wales 2006, Australia.
authors.forename: Christian
authors.initials: C
authors.lastname: Stefani
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Sydney, Level 5, Blackburn Building (D06)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 , Sydney, Level 5, Blackburn Building (D06)New South Wales 2006, Australia.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Arvind
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Sharpe
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Maram T
authors.initials: MT
authors.lastname: Basha
authors.affiliation: School of Chemistry, University of New South Wales , Sydney, New South Wales 2052, Australia.
authors.forename: George M
authors.initials: GM
authors.lastname: Iskander
authors.affiliation: School of Chemistry, University of New South Wales , Sydney, New South Wales 2052, Australia.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Sydney, Level 5, Blackburn Building (D06)New South Wales 2006, Australia.
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Kovacevic
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Sydney, Level 5, Blackburn Building (D06)New South Wales 2006, Australia.
authors.forename: Darius J R
authors.initials: DJ
authors.lastname: Lane
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Sydney, Level 5, Blackburn Building (D06)New South Wales 2006, Australia.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sahni
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 , Sydney, Level 5, Blackburn Building (D06)New South Wales 2006, Australia.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Sydney, Level 5, Blackburn Building (D06)New South Wales 2006, Australia.
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D005293:Ferritins / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D051907:Lysosomal Membrane Proteins / Q000187:drug effects*; D008247:Lysosomes / Q000187:drug effects*; D008706:Methemoglobin / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010539:Permeability; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011990:Receptors, Transferrin / Q000187:drug effects; D012664:Semicarbazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000607645:2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone; D000970:Antineoplastic Agents; D000975:Antioxidants; D007502:Iron Chelating Agents; D051907:Lysosomal Membrane Proteins; D011725:Pyridines; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; D012664:Semicarbazones; D005293:Ferritins; D008706:Methemoglobin; D007501:Iron