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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Peptide nucleic acids targeting mitochondria enhances sensitivity of lung cancer cells to chemotherapy
Sheng-Song Chen1, Xiao-Yun Tu1, Li-Xia Xie1
1Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University Nanchang, China.
Abstract:
Acquired resistance to chemotherapy is a major limitation for the successful treatment of lung cancer. Previously, we and others showed that formation of tumor spheres is associated with chemotherapy resistance in lung cancer cells, but the underlying mechanisms remained largely unknown. In the current study, we show that mitochondrial activity is significantly higher in A549 tumor spheres versus monolayer cells, establishing mitochondria as a putative target for antitumor therapy. To this end, we designed a peptide nucleic acids (PNAs) coupled with triphenylphosphonium (TPP) to target the displacement loop (D-loop) regulatory region of mitochondrial DNA (PNA-mito). Treatment with PNA-mito significantly disrupted mitochondrial gene expression, inhibited membrane potential and mitochondria fusion, resulting in proliferation inhibition and cell death. Consistently, in mouse xenograft models, PNA-mito could efficiently inhibit mitochondrial gene expression and block tumor growth. Treatment with a low dose of PNA-mito could significantly enhance the chemotoxicity of cisplatin (CDDP) in drug-resistant A549 tumor spheres. These results establish mitochondria-targeting PNAs as a novel strategy to enhance the accumulative therapeutic outcome of lung cancer.
Insights
Mitochondria-targeting peptide nucleic acids (PNAs) overcome chemotherapy resistance in lung cancer. This novel approach inhibits tumor growth and enhances cisplatin efficacy in resistant cells.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Acquired chemotherapy resistance is a significant challenge in lung cancer treatment.
- Tumor sphere formation in lung cancer cells is linked to chemotherapy resistance, but mechanisms are unclear.
- Elevated mitochondrial activity in tumor spheres suggests mitochondria as a therapeutic target.
Purpose of the Study:
- To investigate the role of mitochondria in chemotherapy-resistant lung cancer.
- To develop and evaluate mitochondria-targeting peptide nucleic acids (PNAs) for lung cancer therapy.
- To assess the efficacy of PNAs in combination with chemotherapy.
Main Methods:
- Mitochondrial activity was compared between A549 tumor spheres and monolayer cells.
- Peptide nucleic acids coupled with triphenylphosphonium (PNA-mito) were designed to target mitochondrial DNA.
- PNA-mito treatment effects on mitochondrial gene expression, membrane potential, and fusion were analyzed.
- In vivo efficacy was tested using mouse xenograft models.
- Combination therapy with PNA-mito and cisplatin (CDDP) was evaluated in drug-resistant cells.
Main Results:
- Mitochondrial activity was significantly higher in A549 tumor spheres compared to monolayer cells.
- PNA-mito treatment disrupted mitochondrial gene expression, reduced membrane potential, and inhibited mitochondrial fusion.
- PNA-mito treatment led to proliferation inhibition and cell death in vitro.
- In vivo, PNA-mito inhibited mitochondrial gene expression and suppressed tumor growth.
- Low-dose PNA-mito enhanced the chemotoxicity of cisplatin in resistant lung cancer cells.
Conclusions:
- Mitochondria are a viable therapeutic target for overcoming chemotherapy resistance in lung cancer.
- Mitochondria-targeting PNAs (PNA-mito) are effective in inhibiting lung cancer cell proliferation and tumor growth.
- PNA-mito represents a novel strategy to enhance the therapeutic outcomes of lung cancer treatment, particularly in combination with chemotherapy.
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