Miltirone-induced apoptosis in cisplatin-resistant lung cancer cells through upregulation of p53 signaling pathways.

The active ingredients of natural plants are important sources of antitumor agents. Miltirone is a major effective ingredient in traditional Chinese medicine and it is considered to have anti-infection and immunosuppressive activities. Clinically, it is often used for the treatment of arthritis and immune diseases. The effect of miltirone on cisplatin-resistant lung cancer cells has not been investigated to date. The present study aimed to examine the anticancer effect of miltirone in cisplatin-resistant lung cancer cells. Treatment with miltirone suppressed cell viability and induced apoptosis in HCC827 and A549 platinum-resistant lung cancer cells. It was also revealed that miltirone increased caspase-3/8 activity as well as B-cell lymphoma 2-associated X-protein, apoptosis-inducing factor (AIF), p53 and poly(ADP-ribose) polymerase (PARP) protein expression, whereas it inhibited mitochondrial reactive oxygen species (ROS) generation and matrix metalloproteinase (MMP)-2/9 protein expression in HCC827 and A549 platinum-resistant lung cancer cells. The results of the present study demonstrated that miltirone induces apoptosis in cisplatin-resistant lung cancer cells through ROS-p53, AIF, PARP and MMP2/9 signaling pathways.