title: Dual small-molecule targeting of procaspase-3 dramatically enhances zymogen activation and anticancer activity.
abstract: Combination anticancer therapy typically consists of drugs that target different biochemical pathways or those that act on different targets in the same pathway. Here we demonstrate a new concept in combination therapy, that of enzyme activation with two compounds that hit the same biological target, but through different mechanisms. Combinations of procaspase-3 activators PAC-1 and 1541B show considerable synergy in activating procaspase-3 in vitro, stimulate rapid and dramatic maturation of procaspase-3 in multiple cancer cell lines, and powerfully induce caspase-dependent apoptotic death to a degree well exceeding the additive effect. In addition, the combination of PAC-1 and 1541B effectively reduces tumor burden in a murine lymphoma model at dosages for which the compounds alone have minimal or no effect. These data suggest the potential of PAC-1/1541B combinations for the treatment of cancer and, more broadly, demonstrate that differentially acting enzyme activators can potently synergize to give a significantly heightened biological effect.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Botham
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Fan
authors.forename: Isak
authors.initials: I
authors.lastname: Im
authors.forename: Luke B
authors.initials: LB
authors.lastname: Borst
authors.forename: Levent
authors.initials: L
authors.lastname: Dirikolu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D006835:Hydrazones; D010879:Piperazines; D053148:Caspase 3