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Updated: Dec 26, 2025
A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Fucoidan increased the sensitivity to gefitinib in lung cancer cells correlates with reduction of TGFβ-mediated Slug
Wei-Lun Qiu1, Ai-Jung Tseng1, Hsien-Yeh Hsu2
1Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.
Abstract:
Gefitinib is a first tyrosine kinase inhibitor (TKI) designed with an EGFR tyrosine kinase for lung cancer targeted therapy. However, some lung cancer patients with wild-type EGFR (wtEGFR) or acquired secondary EGFR mutation showed lower response rate of gefitinib. In this study, we examined the efficacy of fucoidan on altering gefitinib-sensitivity on TKI-resistant lung cancer A549 and H1975 cells. We found that the simultaneous administration of fucoidan and gefitinib synergistically inhibited lung cancer cell viability via activating apoptotic response. Moreover, we found that fucoidan effectively downregulated expressions of mesenchymal-like molecules. Mechanistically, we demonstrated that fucoidan altered the gefitinib-inhibitory rate may result from induction of proteasome-dependent Slug degradation. Abolishment of TGFβ signaling enhanced gefitinib-inhibited cell viability and reduced N-cadherin, Twist and Slug levels. Moreover, knockdown of Slug contributed the increasing the gefitinib-sensitivity of H1975 cells. Our study is the first to find that fucoidan alters the gefitinib-sensitive of TKI-resistant cells by reduction of TGFβ receptor-mediated expressions of mesenchymal-like molecules and induction of Slug degradation. Together, our current results indicate that combination of fucoidan and gefitinib may be a potential and effective therapeutic strategy in gefitinib non-sensitive lung cancer.
Insights
Fucoidan enhances gefitinib effectiveness in resistant lung cancer by promoting apoptosis and reducing mesenchymal traits. This combination therapy shows promise for patients unresponsive to gefitinib alone.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gefitinib, an EGFR tyrosine kinase inhibitor (TKI), is a targeted therapy for lung cancer.
- Resistance to gefitinib occurs in lung cancer patients with wild-type EGFR or acquired mutations, limiting treatment efficacy.
Purpose of the Study:
- To investigate the efficacy of fucoidan in overcoming gefitinib resistance in lung cancer cells.
- To elucidate the underlying mechanisms by which fucoidan modulates gefitinib sensitivity.
Main Methods:
- Assessing the synergistic effects of fucoidan and gefitinib on lung cancer cell viability and apoptosis.
- Analyzing the expression of mesenchymal markers and key signaling pathway components (e.g., TGFβ, Slug).
- Utilizing proteasome inhibition and gene knockdown (Slug) to explore mechanistic pathways.
Main Results:
- Simultaneous administration of fucoidan and gefitinib synergistically inhibited lung cancer cell viability by activating apoptosis.
- Fucoidan downregulated mesenchymal-like molecules and induced proteasome-dependent Slug degradation.
- Blocking TGFβ signaling enhanced gefitinib's effect and reduced mesenchymal markers; Slug knockdown increased gefitinib sensitivity.
Conclusions:
- Fucoidan alters gefitinib sensitivity in TKI-resistant lung cancer cells by reducing TGFβ receptor-mediated mesenchymal gene expression and inducing Slug degradation.
- The combination of fucoidan and gefitinib presents a potential therapeutic strategy for gefitinib-insensitive lung cancer.
