Small-molecule procaspase-3 activation sensitizes cancer to treatment with diverse chemotherapeutics

Rachel C. Botham, Howard S. Roth, Alison P. Book, Patrick J. Roady, Timothy M. Fan, Paul J. Hergenrother

Research output: Contribution to journalArticle

Abstract

Conventional chemotherapeutics remain essential treatments for most cancers, but their combination with other anticancer drugs (including targeted therapeutics) is often complicated by unpredictable synergies and multiplicative toxicities. As cytotoxic anticancer chemotherapeutics generally function through induction of apoptosis, we hypothesized that a molecularly targeted small molecule capable of facilitating a central and defining step in the apoptotic cascade, the activation of procaspase-3 to caspase-3, would broadly and predictably enhance activity of cytotoxic drugs. Here we show that procaspaseactivating compound 1 (PAC-1) enhances cancer cell death induced by 15 different FDA-approved chemotherapeutics, across many cancer types and chemotherapeutic targets. In particular, the promising combination of PAC-1 and doxorubicin induces a synergistic reduction in tumor burden and enhances survival in murine tumor models of osteosarcoma and lymphoma. This PAC-1/doxorubicin combination was evaluated in 10 pet dogs with naturally occurring metastatic osteosarcoma or lymphoma, eliciting a biologic response in 3 of 6 osteosarcoma patients and 4 of 4 lymphoma patients. Importantly, in both mice and dogs, coadministration of PAC-1 with doxorubicin resulted in no additional toxicity. On the basis of the mode of action of PAC-1 and the high expression of procaspase-3 in many cancers, these results suggest the combination of PAC-1 with cytotoxic anticancer drugs as a potent and general strategy to enhance therapeutic response.

Original languageEnglish (US)
Pages (from-to)545-559
Number of pages15
JournalACS Central Science
Volume2
Issue number8
DOIs
StatePublished - Aug 24 2016

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Cell death
Caspase 3
Doxorubicin
Toxicity
Tumors
Chemical activation
Molecules
Pharmaceutical Preparations
Apoptosis

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Small-molecule procaspase-3 activation sensitizes cancer to treatment with diverse chemotherapeutics. / Botham, Rachel C.; Roth, Howard S.; Book, Alison P.; Roady, Patrick J.; Fan, Timothy M.; Hergenrother, Paul J.

In: ACS Central Science, Vol. 2, No. 8, 24.08.2016, p. 545-559.

Research output: Contribution to journalArticle

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