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Updated: Jun 9, 2026
Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Discovery and canine preclinical assessment of a nontoxic procaspase-3-activating compound
Quinn P Peterson1, Danny C Hsu, Chris J Novotny
1Departments of Biochemistry, Chemistry, Veterinary Biosciences, and Veterinary Clinical Medicine, University of Illinois, Urbana, IL 61801, USA.
Abstract:
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 micromol/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.
Insights
A new compound, S-PAC-1, effectively triggers cancer cell apoptosis and shows antitumor activity without causing neurotoxicity. This procaspase-3 activator is a promising candidate for novel cancer chemotherapy.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Apoptosis is regulated by caspase activation.
- PAC-1 activates caspases and induces cancer cell apoptosis but causes neurotoxicity.
- Developing safer, effective caspase activators is crucial for cancer therapy.
Purpose of the Study:
- To design and evaluate S-PAC-1, a novel PAC-1 derivative with reduced neurotoxicity.
- To assess S-PAC-1's efficacy and safety as a potential cancer chemotherapeutic.
Main Methods:
- S-PAC-1 was synthesized and tested for procaspase-3 activation and cancer cell apoptosis induction.
- Neurotoxicity was evaluated in mice and dogs.
- Pharmacokinetics and preliminary efficacy were assessed in dogs with lymphoma.
Main Results:
- S-PAC-1 activated procaspase-3 and induced cancer cell apoptosis.
- S-PAC-1 demonstrated no neurotoxicity in preclinical models.
- In a canine lymphoma trial, S-PAC-1 was well tolerated and showed partial tumor regression or stable disease in 4 of 6 subjects.
Conclusions:
- S-PAC-1 is a safe and effective procaspase-3 activator with potential as a cancer chemotherapeutic.
- The canine model is suitable for further evaluation of S-PAC-1 and similar compounds.
- S-PAC-1 warrants further clinical investigation for cancer treatment.
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