Peptide nucleic acids targeting mitochondria enhances sensitivity of lung cancer cells to chemotherapy

摘要

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.