Original articleAspirin plus sorafenib potentiates cisplatin cytotoxicity in resistant head and neck cancer cells through xCT inhibition

•Aspirin and sorafenib synergized to induce head and neck cancer (HNC) cell death.•Aspirin plus sorafenib induced cystine-glutamate antiporter (xCT) inhibition, GSH depletion, and ROS accumulation.•Inhibition of xCT increased the cytotoxic effects of aspirin plus sorafenib.•The combination enhanced the cytotoxicity of cisplatin in resistant HNC in vitro and in vivo.

The nonsteroidal anti-inflammatory drug aspirin and the multikinase inhibitor sorafenib have both shown experimental and clinical anticancer activities. The present study investigated whether aspirin and sorafenib synergize to potentiate cisplatin treatment in resistant head and neck cancer (HNC) cells. The effects of aspirin, sorafenib and cisplatin, and combinations thereof were assessed by measuring cell viability, death, glutathione (GSH) and reactive oxygen species (ROS) levels, protein and mRNA expression, genetic inhibition and overexpression of cystine-glutamate antiporter (xCT) and tumor xenograft mouse models. Even at low concentrations, aspirin plus sorafenib synergized to induce cell death of cisplatin-resistant HNC cells. The combination of aspirin and sorafenib induced xCT inhibition, GSH depletion, and ROS accumulation in cancer cells. Genetic and pharmacological inhibition of xCT potentiated the cytotoxic effects of aspirin plus sorafenib; this effect was diminished by xCT overexpression. Low-dose aspirin plus sorafenib enhanced the cytotoxicity of cisplatin in resistant HNC cells through xCT inhibition and oxidant and DNA damage. The in vivo effects of aspirin plus sorafenib on cisplatin therapy were also confirmed in resistant HNC xenograft models, in terms of growth inhibition, GSH depletion, and increased γH2AX formation and apoptosis in tumors. Aspirin and sorafenib synergize to potentiate the cytotoxicity of cisplatin in resistant HNC cells. This therapeutic strategy may help to eliminate resistant HNC.

Graphical abstractA proposed model of cisplatin-induced cytotoxicity enhanced by the combination of aspirin and sorafenib in cisplatin-resistant head and neck cancer cells.Download high-res image (211KB)Download full-size image