Identification of new compounds that trigger apoptosome-independent caspase activation and apoptosis

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Identifying alternative pathways for caspase activation is crucial for developing novel anticancer therapies.
• The apoptosome pathway is a key regulator of programmed cell death (apoptosis).

Purpose of the Study:

• To screen a chemical library for compounds that activate apoptosis independently of the apoptosome.
• To identify and characterize novel molecules that induce cell death through alternative apoptotic routes.

Main Methods:

• Screening of the National Cancer Institute's Developmental Therapeutics Program
• challenge set
• chemical library against cells with mutated caspase-9.
• Assaying for apoptosis induction and characterizing the molecular players involved in the identified pathway.
• Investigating the role of the ubiquitin-proteasome system and specific proteins like Noxa and Smac.

Main Results:

• Two compounds, F6 and G5, were identified that induce apoptosis via an apoptosome-independent pathway.
• These compounds inhibit ubiquitin isopeptidases, targeting the ubiquitin-proteasome system.
• The identified pathway involves Bcl-2, Noxa up-regulation, Smac stabilization, and the death receptor pathway.

Conclusions:

• Chemical library screening in cancer cells with specific apoptotic defects can reveal compounds targeting alternative cell death pathways.
• Compounds F6 and G5 represent valuable tools for dissecting novel apoptotic mechanisms and hold potential for anticancer drug development.