Chemoresistance is commonly found in treating cancer patients. Acetaminophen enhances the cytotoxicity of cisplatin in human liver cancer cells by depleting glutathione and increasing production of toxic metabolites in vitro. The objective of this study was to investigate potential molecular mechanisms for chemoenhancement in non-hepatic cells. Human ovarian carcinoma SKOV3 cells were treated with cisplatin or paclitaxel with or without acetaminophen in vitro. Cellular mitochondrial membrane potential and reactive oxygen species concentration was measured by using JC-1 and DHR123 stain, respectively. Cellular platinum level was analyzed using ICP-MS. Apoptosis and signaling pathways were examined by immunoblotting and immunohistochemical analyses. A 2 h incubation with acetaminophen (10 mM) decreased cellular glutathione levels and increased mitochondrial membrane potential without affecting reactive oxygen species. Overnight acetaminophen treatment increased reactive oxygen species and enhanced both cisplatin- and paclitaxel-induced apoptosis. In contrast, the combination of acetaminophen with cisplatin but not paclitaxel blocked nuclear translocation of nrf2, a transcription factor that has been implicated in regulation of the antioxidant response. Pretreatment with acetaminophen for 2 h did not affect cellular platinum uptake when compared to cisplatin alone. Regardless of different oxidative stress pathways involved between cisplatin and paclitaxel, the addition of acetaminophen enhanced the cytotoxic effects of both chemotherapeutic drugs in human ovarian carcinoma cells. Our results suggest that acetaminophen could be used as a chemoenhancing adjuvant for conventional chemotherapy drugs in treating ovarian and other malignancies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4904. doi:1538-7445.AM2012-4904