Fusaricide is a Novel Iron Chelator that Induces Apoptosis through Activating Caspase-3

Area of Science:

• Natural Product Chemistry
• Cancer Biology
• Molecular Pharmacology

Background:

• Nonsmall cell lung cancer (NSCLC) remains a significant global health challenge with limited effective treatments.
• Identifying novel therapeutic agents with targeted anticancer mechanisms is crucial for improving patient outcomes.
• Endophytic fungi associated with medicinal plants are a rich source of bioactive compounds.

Purpose of the Study:

• To isolate and characterize a novel natural product, fusaricide (FCD), from an endophytic fungus.
• To investigate the anticancer potential of FCD against human NSCLC cell lines.
• To elucidate the molecular mechanisms underlying FCD-induced cytotoxicity, focusing on its role as an iron chelator.

Main Methods:

• Isolation and identification of fusaricide (FCD) from an endophytic fungus (Epicoccum sp.) cultured from Lycium barbarum.
• In vitro proliferation assays using various human NSCLC cell lines and normal cells.
• Apoptosis induction assays, DNA damage assessment, cell cycle analysis, and caspase-3 activity measurement in NCI-H460 cells.
• Iron chelator activity assessment, including measurement of cellular labile iron pool and reversal studies with FeCl3 supplementation.
• Analysis of transferrin receptor 1 (TfR1) and ferritin heavy chain (FTH) expression.

Main Results:

• Fusaricide (FCD) demonstrated potent inhibition of proliferation across multiple human NSCLC cell lines with minimal toxicity to normal cells.
• FCD treatment induced significant apoptosis, DNA damage, and G0/G1 cell cycle arrest in NCI-H460 NSCLC cells.
• FCD functions as an iron chelator, reducing the cellular labile iron pool, which was confirmed by the reversal of apoptosis upon iron supplementation.
• FCD treatment led to the upregulation of TfR1 and downregulation of FTH, indicating modulation of cellular iron homeostasis.

Conclusions:

• Fusaricide (FCD) exhibits promising anticancer properties against human NSCLC.
• The mechanism of FCD-induced apoptosis is dependent on its iron-chelating activity and subsequent disruption of cellular iron homeostasis.
• FCD represents a potential novel therapeutic candidate for the treatment of NSCLC.