First-In-Class Thiosemicarbazone Metal Complexes Targeting the Sigma-2 Receptor (S2R) as an Innovative Strategy...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Pancreatic cancer has a high incidence and low survival rate, necessitating novel therapeutic strategies.
• The sigma-2 receptor (S2R) is implicated in tumor progression and represents a therapeutic target.
• Thiosemicarbazones (TSCs) are a class of compounds investigated for their anti-cancer properties.

Purpose of the Study:

• To synthesize and evaluate copper(II) and platinum(II) complexes of FA4, a sigma-2 receptor-targeting thiosemicarbazone.
• To compare the efficacy of these novel complexes against pancreatic cancer models.
• To investigate the mechanism of action of the most potent compound.

Main Methods:

• Synthesis of FA4-metal complexes (Cu(II) and Pt(II)) and control TSC 1-metal complexes.
• In vitro cytotoxicity assays to determine efficacy.
• Apoptosis assays and analysis of endoplasmic reticulum (ER) and mitochondrial stress.
• In vivo studies using a preclinical PANC-1 pancreatic cancer model.

Main Results:

• FA4-copper complexes demonstrated significantly higher in vitro cytotoxicity compared to FA4-platinum complexes and control TSCs.
• FA4-copper induced apoptotic cell death through ER and mitochondrial stress, exhibiting greater potency than FA4 alone.
• In vivo studies confirmed that FA4-copper was more effective than FA4, TSC 1, and TSC 1-copper in a preclinical pancreatic cancer model.

Conclusions:

• FA4-copper complexes represent a promising therapeutic strategy for pancreatic cancer.
• Targeting the sigma-2 receptor with FA4-copper warrants further clinical investigation.
• The induction of ER and mitochondrial stress is a key mechanism for FA4-copper's anti-cancer activity.