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 | Rachel C Botham, Timothy M Fan, Isak Im, Luke B Borst, Levent Dirikolu, Paul J Hergenrother |
Journal | Journal of the American Chemical Society
(J Am Chem Soc)
Vol. 136
Issue 4
Pg. 1312-9
(Jan 29 2014)
ISSN: 1520-5126 [Electronic] United States |
PMID | 24383395
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
|
Chemical References |
- (4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine
- Hydrazones
- Piperazines
- Caspase 3
|
Topics |
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(chemistry, pharmacology)
- Apoptosis
(drug effects)
- Caspase 3
(metabolism)
- Cell Proliferation
(drug effects)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- Enzyme Activation
(drug effects)
- HL-60 Cells
- Humans
- Hydrazones
(chemistry, pharmacology)
- Lymphoma
(drug therapy, pathology)
- Mice
- Mice, Inbred C57BL
- Molecular Structure
- Piperazines
(chemistry, pharmacology)
- Structure-Activity Relationship
- Tumor Cells, Cultured
|