Proteasome inhibitor lactacystin enhances cisplatin cytotoxicity by increasing endoplasmic reticulum stress-associated apoptosis in HeLa cells.

Cisplatin is commonly used as a therapeutic agent, despite its known adverse side effects and the occurrence of drug resistance. The development of novel methods for combination therapy with cisplatin is required in order to circumvent these limitations of cisplatin alone. The proteasome inhibitor lactacystin (LAC) has been indicated to produce anti-tumor effects, and has previously been used as an antitumor agent in cancer treatment research; however, its effects in combination with cisplatin treatment are unknown. In the current study, the effects of LAC in combination with cisplatin treatment were investigated in HeLa human cervical cancer (HCC) cells. The results demonstrated that cisplatin treatment inhibited cell growth and induced cell apoptosis. HeLa cell exposure to cisplatin induced endoplasmic reticulum (ER) stress-associated apoptosis, and LAC treatment increased levels of cell apoptosis and the activation of caspase-3. Specifically, LAC treatment increased the cisplatin-induced expression of PDI, GRP78, CHOP, cleaved caspase-4 and cleaved caspase-3. Together, these data indicate that LAC is able to enhance cisplatin cytotoxicity by increasing ER stress-associated apoptosis in HeLa cells.