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 language | English (US) |
|---|---|
| Pages (from-to) | 1312-1319 |
| Number of pages | 8 |
| Journal | Journal of the American Chemical Society |
| Volume | 136 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jan 29 2014 |
Fingerprint
ASJC Scopus subject areas
- Catalysis
- Chemistry(all)
- 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 journal › Article
}
TY - JOUR
T1 - Dual small-molecule targeting of procaspase-3 dramatically enhances zymogen activation and anticancer activity
AU - Botham, Rachel C.
AU - Fan, Timothy M.
AU - Im, Isak
AU - Borst, Luke B.
AU - Dirikolu, Levent
AU - Hergenrother, Paul J.
PY - 2014/1/29
Y1 - 2014/1/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84893487711&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893487711&partnerID=8YFLogxK
U2 - 10.1021/ja4124303
DO - 10.1021/ja4124303
M3 - Article
C2 - 24383395
AN - SCOPUS:84893487711
VL - 136
SP - 1312
EP - 1319
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 4
ER -