Dual Small-Molecule Targeting of Procaspase‑3 Dramatically Enhances Zymogen Activation and Anticancer Activity

• Published in: Journal of the American Chemical Society Vol. 136; no. 4; pp. 1312 - 1319
• Main Authors: Botham, Rachel C, Fan, Timothy M, Im, Isak, Borst, Luke B, Dirikolu, Levent, Hergenrother, Paul J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 29.01.2014
• Subjects: Activation; Animals; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols - chemistry; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Biochemistry; Biotechnology; Cancer; Caspase 3 - metabolism; Cell Proliferation - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; Enzymes; HL-60 Cells; Humans; Hydrazones - chemistry; Hydrazones - pharmacology; Lymphoma - drug therapy; Lymphoma - pathology; Mice; Mice, Inbred C57BL; Molecular Structure; Pathways; Piperazines - chemistry; Piperazines - pharmacology; Structure-Activity Relationship; Therapy; Tumor Cells, Cultured
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja4124303

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.