Discovery and canine preclinical assessment of a nontoxic procaspase-3-activating compound

Cancer Res. 2010 Sep 15;70(18):7232-41. doi: 10.1158/0008-5472.CAN-10-0766. Epub 2010 Sep 7.


A critical event in the apoptotic cascade is the proteolytic activation of procaspases to active caspases. The caspase autoactivating compound PAC-1 induces cancer cell apoptosis and exhibits antitumor activity in murine xenograft models when administered orally as a lipid-based formulation or implanted s.c. as a cholesterol pellet. However, high doses of PAC-1 were found to induce neurotoxicity, prompting us to design and assess a novel PAC-1 derivative called S-PAC-1. Similar to PAC-1, S-PAC-1 activated procaspase-3 and induced cancer cell apoptosis. However, S-PAC-1 did not induce neurotoxicity in mice or dogs. Continuous i.v. infusion of S-PAC-1 in dogs led to a steady-state plasma concentration of ∼10 μmol/L for 24 to 72 hours. In a small efficacy trial of S-PAC-1, evaluation of six pet dogs with lymphoma revealed that S-PAC-1 was well tolerated and that the treatments induced partial tumor regression or stable disease in four of six subjects. Our results support this canine setting for further evaluation of small-molecule procaspase-3 activators, including S-PAC-1, a compound that is an excellent candidate for further clinical evaluation as a novel cancer chemotherapeutic.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Dog Diseases / drug therapy*
  • Dog Diseases / enzymology
  • Dog Diseases / pathology
  • Dogs
  • Enzyme Activation / drug effects
  • HeLa Cells
  • Humans
  • Hydrazones / pharmacokinetics
  • Hydrazones / pharmacology*
  • Hydrazones / toxicity
  • Jurkat Cells
  • Lymphoma, B-Cell / drug therapy
  • Lymphoma, B-Cell / enzymology
  • Lymphoma, B-Cell / pathology
  • Lymphoma, B-Cell / veterinary*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Piperazines / toxicity
  • U937 Cells


  • (4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine
  • Hydrazones
  • Piperazines
  • Caspase 3