title: Procaspase-3 activation as an anti-cancer strategy: structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3.
abstract: A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivatives where key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.
authors.affiliation: Department of Biochemistry, Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, USA.
authors.forename: Quinn P
authors.initials: QP
authors.lastname: Peterson
authors.forename: Danny C
authors.initials: DC
authors.lastname: Hsu
authors.forename: David R
authors.initials: DR
authors.lastname: Goode
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Novotny
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Totten
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D021381:Protein Transport; D013194:Staining and Labeling; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D000970:Antineoplastic Agents; D002614:Chelating Agents; D005456:Fluorescent Dyes; D006835:Hydrazones; D010879:Piperazines; D053148:Caspase 3; D015032:Zinc