Proteasome versus Thioredoxin Reductase Competition as Possible Biological Targets in Antitumor Mixed...

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Development of novel anticancer agents is crucial for effective colorectal cancer therapy.
• Gold compounds have shown potential in cancer treatment, but their mechanisms and stability require further investigation.

Purpose of the Study:

• To synthesize and characterize novel gold(III) derivatives with dithiocarbamate and thiolate ligands.
• To evaluate their anticancer activity, stability, and mechanism of action in colon cancer models.

Main Methods:

• Synthesis and characterization of new gold(III) mixed ligand complexes.
• In vitro anticancer activity assays against colon cancer cell lines and differentiated enterocytes.
• Stability studies in phosphate-buffered saline and resistance to reducing agents.
• Enzyme inhibition assays (thioredoxin reductase and proteasome).
• Apoptosis pathway analysis, including mitochondrial membrane potential, cytochrome c release, and caspase-3 activation.

Main Results:

• Synthesized gold(III) derivatives exhibit high anticancer activity against colon cancer cells with minimal toxicity to normal enterocytes.
• The complexes demonstrate good stability in physiological conditions and resistance to reduction.
• Compounds interact with thioredoxin reductase and inhibit proteasomal activity, indicating a dual mechanism.
• Apoptosis is induced via the intrinsic pathway, involving mitochondrial dysfunction and caspase activation.

Conclusions:

• Novel gold(III) dithiocarbamate complexes possess significant anticancer potential for colorectal cancer.
• The proteasome is identified as a key molecular target for these compounds in cancer cells.
• These findings support the development of these gold complexes as a new therapeutic strategy for colorectal cancer.