title: Cancer Cell Mitochondria Targeting by Pancratistatin Analogs is Dependent on Functional Complex II and III.
abstract: Enhanced mitochondrial stability and decreased dependence on oxidative phosphorylation confer an acquired resistance to apoptosis in cancer cells, but may present opportunities for therapeutic intervention. The compound pancratistatin (PST) has been shown to selectively induce apoptosis in cancer cells. However, its low availability in nature has hindered its clinical advancement. We synthesized PST analogs and a medium-throughput screen was completed. Analogs SVTH-7, -6, and -5 demonstrated potent anti-cancer activity greater than PST and several standard chemotherapeutics. They disrupted mitochondrial function, activated the intrinsic apoptotic pathway, and reduced growth of tumor xenografts in vivo. Interestingly, the pro-apoptotic effects of SVTH-7 on cancer cells and mitochondria were abrogated with the inhibition of mitochondrial complex II and III, suggesting mitochondrial or metabolic vulnerabilities may be exploited by this analog. This work provides a scaffold for characterizing distinct mitochondrial and metabolic features of cancer cells and reveals several lead compounds with high therapeutic potential.
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Dennis
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Pignanelli
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tarade
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Tyler
authors.initials: T
authors.lastname: Gilbert
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Megan
authors.initials: M
authors.lastname: Noel
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Fadi
authors.initials: F
authors.lastname: Mansour
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Adams
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dowhayko
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Kyle
authors.initials: K
authors.lastname: Stokes
authors.affiliation: Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada.
authors.forename: Sergey
authors.initials: S
authors.lastname: Vshyvenko
authors.affiliation: Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada.
authors.forename: Tomas
authors.initials: T
authors.lastname: Hudlicky
authors.affiliation: Department of Chemistry, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
authors.forename: James
authors.initials: J
authors.lastname: McNulty
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Siyaram
authors.initials: S
authors.lastname: Pandey
mesh_terms: D047151:Amaryllidaceae Alkaloids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D047151:Amaryllidaceae Alkaloids; D000970:Antineoplastic Agents; D007546:Isoquinolines; D017382:Reactive Oxygen Species; C044997:pancratistatin; D042963:Electron Transport Complex II; D020169:Caspases; D014450:Electron Transport Complex III