Researchers have discovered that a compound called cytochalasin H (CyH), isolated from a mangrove-derived fungus, can significantly enhance the effectiveness of the lung cancer drug gefitinib in non-small-cell lung cancer (NSCLC) cells. The study found that CyH inhibits the activation of the epidermal growth factor receptor (EGFR) and the expression of programmed cell death ligand 1 (PD-L1) in NSCLC cells, leading to increased sensitivity to gefitinib. This could be a promising strategy for improving the treatment of EGFR-driven lung cancers, which often develop resistance to EGFR-targeted therapies.
Mangrove Fungi Offer Promising Cancer-Fighting Compounds
Mangrove ecosystems, located at the interface between land and ocean, are home to a diverse array of microorganisms, including fungi, that have evolved to thrive in the unique saline and acidic environment. These microbes often produce secondary metabolites with novel structures and biological activities that differ from those found in terrestrial microorganisms. Researchers have been increasingly exploring these mangrove-derived compounds as a source of potential therapeutic agents, including for the treatment of cancer.
Cytochalasin H Inhibits EGFR and PD-L1 in Lung Cancer Cells
In a previous study, the research team isolated a compound called cytochalasin H (CyH) from a mangrove-derived endophytic fungus and found that it inhibited the proliferation of NSCLC cells. In the current study, they investigated the effects of CyH on the activation of EGFR and the expression of PD-L1 in NSCLC cell lines.
The researchers found that CyH significantly inhibited the activation of EGFR and the expression of PD-L1 in NSCLC cells, including those with EGFR mutations. This is significant because EGFR activation and PD-L1 expression have been shown to mediate resistance to the EGFR-targeted drug gefitinib in NSCLC.
CyH Enhances Sensitivity to Gefitinib in NSCLC Cells
The researchers then investigated the effects of combining CyH with gefitinib on NSCLC cell proliferation. They found that CyH dramatically enhanced the inhibitory effects of gefitinib on the proliferation of NSCLC cells, including those with EGFR mutations that confer resistance to gefitinib.
Fig. 2
Further experiments showed that CyH increased the inhibitory effect of gefitinib on EGFR activation and PD-L1 expression in the NSCLC cells. This suggests that CyH’s ability to inhibit these two key mechanisms of resistance may be the reason it enhances the effectiveness of gefitinib.
CyH Promotes Gefitinib’s Anti-Tumor Effects in NSCLC Xenografts
To validate these findings in vivo, the researchers established NSCLC xenograft tumors in mice and tested the effects of CyH and gefitinib, alone and in combination. They found that CyH significantly enhanced the inhibitory effects of gefitinib on tumor growth, as well as the expression of the proliferation marker Ki-67 and the levels of p-EGFR and PD-L1 within the tumors.
Table 1 Comparison of IC50 values.
These results further confirm that CyH can increase the sensitivity of NSCLC cells to gefitinib by suppressing EGFR activation and PD-L1 expression, leading to improved anti-tumor effects.
Potential Mechanisms Involving the JAK/STAT Pathway
The researchers also investigated the potential mechanisms by which CyH inhibits PD-L1 expression. They found that CyH significantly inhibited the activation of the JAK/STAT signaling pathway in NSCLC cells. This pathway has been previously linked to the upregulation of PD-L1, suggesting it may be involved in the effects of CyH on PD-L1 expression.
Implications and Future Directions
The findings of this study indicate that the mangrove-derived compound CyH has the potential to significantly improve the effectiveness of the EGFR-targeted drug gefitinib in the treatment of NSCLC, particularly in EGFR-driven lung cancers that often develop resistance to EGFR-targeted therapies.
By inhibiting both EGFR activation and PD-L1 expression, CyH appears to overcome two key mechanisms of resistance to gefitinib. This suggests that the combination of CyH and gefitinib could be a promising strategy for enhancing the treatment of NSCLC patients, especially those with EGFR-mutant tumors.
Further research is needed to fully elucidate the mechanisms by which CyH exerts its effects and to explore the potential clinical applications of this mangrove-derived compound. Nevertheless, this study highlights the value of exploring natural products, such as those from unique ecosystems like mangroves, as a source of novel therapeutic agents for the treatment of cancer.
Author credit: This article is based on research by Guihong Zhang, Jiao Liu, Sanzhong Li, Tianyu Wang, Li Chen, Huan Li, Qingkai Ding, Xiangyong Li, Shaoping Zhu, Xudong Tang.
For More Related Articles Click Here
