Dual small-molecule targeting of procaspase-3 dramatically enhances zymogen activation and anticancer activity

Rachel C. Botham, Timothy M. Fan, Isak Im, Luke B. Borst, Levent Dirikolu, Paul J. Hergenrother

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1312-1319
Number of pages8
JournalJournal of the American Chemical Society
Volume136
Issue number4
DOIs
StatePublished - Jan 29 2014

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Enzyme Precursors
Caspase 3
targeting
cancer
Enzymes
Chemical activation
enzyme
Molecules
Enzyme Activators
tumor
maturation
Tumors
drug
Enzyme Activation
Cells
Caspases
Tumor Burden
Lymphoma
Neoplasms
Cell Line

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Dual small-molecule targeting of procaspase-3 dramatically enhances zymogen activation and anticancer activity. / Botham, Rachel C.; Fan, Timothy M.; Im, Isak; Borst, Luke B.; Dirikolu, Levent; Hergenrother, Paul J.

In: Journal of the American Chemical Society, Vol. 136, No. 4, 29.01.2014, p. 1312-1319.

Research output: Contribution to journalArticle

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AU - Hergenrother, Paul J.

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