Discovery and canine preclinical assessment of a nontoxic procaspase-3-activating compound.
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.
Peterson
Quinn P
QP
Departments of Biochemistry, Chemistry, Veterinary Biosciences, and Veterinary Clinical Medicine, University of Illinois, Urbana, IL 61801, USA.
Hsu
Danny C
DC
Novotny
Chris J
CJ
West
Diana C
DC
Kim
Dewey
D
Schmit
Joanna M
JM
Dirikolu
Levent
L
Hergenrother
Paul J
PJ
Fan
Timothy M
TM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D004283:Dog Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D006835:Hydrazones / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D019169:Jurkat Cells; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000662:veterinary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D020298:U937 Cells
C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D006835:Hydrazones; D010879:Piperazines; D053148:Caspase 3
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