Discovery and Canine Preclinical Assessment of a Nontoxic Procaspase-3–Activating Compound

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 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. Cancer Res; 70(18); 7232-41. ©2010 AACR.

Ochratoxin A mediates MAPK activation, modulates <i>IL-2</i> and <i>TNF-α</i> mRNA expression and induces apoptosis by mitochondria-dependent and mitochondria-independent pathways in human H9 T cells

“…Activation of caspase-3 is one of the critical steps in the execution of programmed cell death; it commonly occurs in apoptosis of different cell types, resulting from specific cleavage of procaspase-3 and release of the active fragment into the cytosol (Peterson et al, 2010). It appeared that OTA activated caspase-3 in a dose-dependent manner following 24-hr incubation (Fig.…”

Procaspase-3 Activating Therapeutic Agents in Cancer Therapy

“…This type of cell death is currently in focus of different research groups around the word. Small molecules to target different proteins including procaspase-3 and IAP'S are studied extensively now a days and one of these small molecules S-PAC-1 is been studied in phase I clinical trials (Peterson et al, 2010).…”

“…PAC-1 was found to be neurotoxic in chicken CGN (Aziz et al, 2010) and dogs (Peterson et al, 2010). The neurotoxic properties of PAC-1 raised challenges for its use as an anticancer drug and led to the development of S-PAC-1, which contains a polar sulfonamide on the benzyl ring of PAC-1.…”

“…The neurotoxic properties of PAC-1 raised challenges for its use as an anticancer drug and led to the development of S-PAC-1, which contains a polar sulfonamide on the benzyl ring of PAC-1. This compound is believed to have a similar procaspase-3 activating ability, but because it cannot cross the blood-brain barrier, it is not neurotoxic in mice or dogs (Peterson et al, 2010).…”

The immunological, biochemical and molecular bases of canine senescence and carcinogenesis: a review

“…On the other hand, many similarities are found between human and canine cancers, including histologic appearance, tumour genetics, molecular targets, biological and clinical behaviour, and response to therapy (Peterson et al 2010). The studies of Peterson et al (2010) showed that in lymphoma, the most common cancer of humans and canines, evaluation of PAC-1 in canine lymphoma may provide important information for human cancer therapy. It is known that a small molecule of PAC-1, enhances procaspase-3 activity in vitro, and induces death in cancer cells by apoptosis thereby inhibiting antitumour activity (Peterson et al 2009).…”