Ammonium chloride enhances cisplatin cytotoxicity through DNA double-strand breaks in human cervical cancer cells

Cisplatin (cis-diamminedichloroplatinum II, CDDP) acts as a therapeutic agent by initiating cellular apoptosis. However, side-effects and drug resistance limit the clinical use of cisplatin. Numerous studies have focused on the drug-target interactions, cellular pharmacology and pharmacokinetics of cisplatin. Newly developed treatment strategies are needed in order to be used in combination with cisplatin, with the aim to minimize toxicity and to circumvent cisplatin resistance. Ammonium chloride (NH4Cl) is widely used in various areas, but its use as a combination agent with cisplatin for the treatment of cancer cells has not been previously reported. In the present study, we showed that NH4Cl could be potentially used as an effective agent in cisplatin combination treatment of HeLa human cervical cancer (HCC) cells. Cisplatin was found to inhibit cell growth, as well as to induce cell apoptosis and DNA double-strand breaks. In addition, treatment with NH4Cl increased the rate of cell apoptosis and the activation of caspase-3. Particularly, we found that NH4Cl treatment increased cisplatin-induced phosphorylation of H(2)AX. In conclusion, our data indicate that NH4Cl enhances cisplatin cytotoxicity through increased DNA damage in HeLa HCC cells.