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Halofuginone Sensitizes Lung Cancer Organoids to Cisplatin via Suppressing PI3K/AKT and MAPK Signaling Pathways
Hefei Li1, Yushan Zhang2, Xiaomei Lan3
1Department of Thoracic Surgery, Affiliated Hospital of Hebei University, Baoding, China.
Abstract:
Lung cancer is the leading cause of cancer death worldwide. Cisplatin is the major DNA-damaging anticancer drug that cross-links the DNA in cancer cells, but many patients inevitably develop resistance with treatment. Identification of a cisplatin sensitizer might postpone or even reverse the development of cisplatin resistance. Halofuginone (HF), a natural small molecule isolated from Dichroa febrifuga, has been found to play an antitumor role. In this study, we found that HF inhibited the proliferation, induced G0/G1 phase arrest, and promoted apoptosis in lung cancer cells in a dose-dependent manner. To explore the underlying mechanism of this antitumor effect of halofuginone, we performed RNA sequencing to profile transcriptomes of NSCLC cells treated with or without halofuginone. Gene expression profiling and KEGG analysis indicated that PI3K/AKT and MAPK signaling pathways were top-ranked pathways affected by halofuginone. Moreover, combination of cisplatin and HF revealed that HF could sensitize the cisplatin-resistant patient-derived lung cancer organoids and lung cancer cells to cisplatin treatment. Taken together, this study identified HF as a cisplatin sensitizer and a dual pathway inhibitor, which might provide a new strategy to improve prognosis of patients with cisplatin-resistant lung cancer.
Insights
Halofuginone (HF) inhibits lung cancer cell growth and sensitizes resistant cells to cisplatin. This natural compound may offer a new strategy for treating cisplatin-resistant lung cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Lung cancer is a leading cause of cancer death globally.
- Cisplatin is a primary chemotherapy drug, but resistance is a significant clinical challenge.
- Identifying cisplatin sensitizers is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate the antitumor effects of Halofuginone (HF) in lung cancer.
- To explore the molecular mechanisms underlying HF's action.
- To evaluate HF's potential as a cisplatin sensitizer.
Main Methods:
- Cell proliferation assays, cell cycle analysis, and apoptosis assays were performed.
- RNA sequencing was used to profile transcriptomes of lung cancer cells treated with HF.
- KEGG pathway analysis identified affected signaling pathways.
- Combination therapy with cisplatin and HF was tested in resistant lung cancer models.
Main Results:
- HF inhibited lung cancer cell proliferation, induced G0/G1 phase arrest, and promoted apoptosis.
- Gene expression profiling revealed that PI3K/AKT and MAPK signaling pathways were significantly affected by HF.
- HF demonstrated the ability to sensitize cisplatin-resistant lung cancer cells and organoids to cisplatin treatment.
Conclusions:
- Halofuginone exhibits significant antitumor activity and acts as a cisplatin sensitizer.
- HF targets PI3K/AKT and MAPK signaling pathways.
- HF presents a potential therapeutic strategy for overcoming cisplatin resistance in lung cancer.
