Upregulation of phosphatase and tensin homolog is essential for the effect of 4-aminopyridine on A549/CDDP cells.

4-aminopyridine (4-AP), a voltage-gated potassium channel blocker, was revealed to possess pro-apoptotic properties in various types of cancer cells. The present study aimed to explore the effect of 4-AP on a cisplatin (DDP) resistant lung cancer cell line A549/CDDP and the underlying mechanism by which it had an effect. In the present study, an MTT assay and cell cycle analysis were used to determine that 4-AP inhibited cell growth in vitro and a tumorigenesis assay in nude mice determined that 4-AP also inhibited cell growth in vivo. 4-AP induced cell apoptosis of A549/CDDP cells observed by electron microscopy and Annexin V-APC/7-ADD analysis. In addition, 4-AP enhanced the sensitivity of A549/CDDP cells to DDP as revealed by an MTT assay. Mechanistically, 4-AP upregulated the phosphatase and tensin homolog (PTEN) and modulated the phosphoinositide 3-kinase/protein kinase B signaling pathway and its downstream cell cycle factors, including cyclin D1, cyclin-dependent kinase 4 and p21, as well as apoptosis-associated proteins B-cell lymphoma 2, pro-caspase 9, pro-caspase 3, cleaved caspase 9 and cleaved caspase 3. The effects of 4-AP on cell growth and apoptosis were reversed by PTEN silencing. In conclusion, the results indicated that 4-AP inhibited cell growth, induced apoptosis and sensitized A549/CDDP cells to DDP via the upregulation of PTEN. 4-AP may be a potential therapeutic agent for patients with DDP resistance.