Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cancer is characterized by mutations in apoptotic proteins, preventing programmed cell death and promoting proliferation.
• Caspase-3, a key executioner caspase, exists as an inactive zymogen and is crucial for apoptosis.
• Elevated procaspase-3 concentrations are observed in various cancer types.

Purpose of the Study:

• To identify a small molecule that can directly activate procaspase-3.
• To investigate the therapeutic potential of such a molecule in cancer treatment.

Main Methods:

• Identification of a small molecule, PAC-1, with direct procaspase-3 activating properties.
• In vitro activation of procaspase-3 to caspase-3 by PAC-1.
• Assessment of PAC-1's ability to induce apoptosis in primary colon cancer cells.
• Evaluation of PAC-1's anti-tumor efficacy in three distinct mouse cancer models, including oral administration.

Main Results:

• PAC-1 was identified as a small molecule that directly activates procaspase-3 to caspase-3 in vitro.
• PAC-1 induced apoptosis in cancerous cells in direct proportion to their procaspase-3 concentration.
• PAC-1 demonstrated tumor growth retardation in mouse models, with efficacy observed after oral administration.

Conclusions:

• PAC-1 is the first small molecule capable of directly activating procaspase-3, enabling apoptosis induction even in cells with compromised apoptotic pathways.
• Direct activation of executioner caspases represents a promising anticancer strategy, especially for cancers exhibiting high procaspase-3 levels.