Mitochondrial targeting and anticancer cell killing by arylurea-fatty acids containing in-chain sulfur atoms

Area of Science:

• Biochemistry
• Mitochondrial Biology
• Cancer Therapeutics

Background:

• Arylureido-fatty acids induce cancer cell death by targeting tumor cell mitochondria, generating reactive oxygen species (ROS), and activating endoplasmic reticulum (ER)-stress.
• These compounds uncouple electron transport and ATP production via proton transfer across the inner mitochondrial membrane.
• Simple arylureas like CTU have low potency, limiting their anticancer drug development potential.

Purpose of the Study:

• To evaluate the mitochondrial targeting and anticancer activities of CTU analogues with in-chain sulfur heteroatoms.
• To identify a lead molecule for further preclinical development as a novel anticancer agent.

Main Methods:

• Synthesis and evaluation of CTU analogues with sulfur heteroatoms at the 3- or 13-positions.
• Assessment of mitochondrial targeting, ROS generation, ER-stress activation, and cancer cell death.
• Measurement of ATP production and proton transport across the inner mitochondrial membrane.

Main Results:

• 3-thiaCTU substitution optimally impaired ATP production and induced cell death in MDA-MB-231 breast cancer cells.
• 13-thia substitution did not enhance, and in some cases attenuated, the anticancer effects of 3-thiaCTU.
• The 3-sulfur atom incorporation was crucial for potent anticancer activity and proton transport disruption.

Conclusions:

• 3-thiaCTU is a lead molecule with significant potential for preclinical development as a novel anticancer therapeutic.
• The position of the sulfur heteroatom critically influences the compound's efficacy in targeting cancer cell mitochondria.
• This study highlights the therapeutic potential of specifically designed arylureido-fatty acids for cancer treatment.