Investigating procaspase-3 as a potential therapeutic target in canine osteosarcoma

Apoptosis is a specialized, active form of cell death that is important in both health and disease. It is responsible for maintaining regulated development and tissue homeostasis and participates in the elimination of aged, damaged, or displaced cells. Apoptosis is also an inherent tumor suppressive mechanism, and the ability of cancer cells to evade death is widely acknowledged as one of the hallmarks of cancer development. In tumor cell populations, disruptions in apoptosis commonly occur through modulation of key players in the apoptotic cascade. The central role of capsase-3 as an executioner of apoptosis makes it an ideal drug target for circumventing such upstream disruptions and restoring effective apoptosis in cancer cells. This work investigates the use of PAC-1, a newly developed procaspase-3 activating compound, in the treatment of canine osteosarcoma. Procaspase-3 is expressed in osteosarcoma cells, and furthermore, greater expression is seen in malignant canine osteoblasts than normal osteoblasts. Exposing cells to PAC-1 results in the activation of procaspase-3 to caspase-3, increased caspase-3 catalytic activity, and induction of apoptosis in osteosarcoma cells. The greatest degree of activity is seen after 48 hours of exposure to the PAC-1. Additionally, a large proportion of spontaneous primary and metastatic tumors express procaspase-3 to a varying degree, and the pattern of expression appears to be conserved within patients from primary to metastatic lesions. In conclusion, the study’s findings support future investigation of PAC-1 as a personalized anticancer treatment strategy for osteosarcoma