The timing of caffeic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines

Cisplatin is a widely used chemotherapeutic drug showing high efficiency in the treatment of primary tumors such as ovarian, testicular and cervical cancers. The major drawback of cisplatin is tumor resistance either acquired or intrinsic. Many mechanisms are involved in the resistance, among them is the Nrf2 pathway which regulates glutathione related enzymes. Caffeic acid, a non-toxic polyphenol which is abundant in many foods modulates glutathione S-transferase (GST) and glutathione reductase (GSR) activity, these enzymes were shown to be involved in resistance of cells towards cisplatin. Caffeic acid induces the Nrf2 pathway and can also inhibit the activity of GST and GSR. Our findings demonstrate that the co-treatment of cancer cells with cisplatin and caffeic acid can enhance cisplatin cytotoxicity and increases the amount of platinum bound to nuclear DNA. However, 6 h of pre incubation with caffeic acid prior to cisplatin treatment led to acquired resistance to cisplatin and reduced DNA binding. In conclusion, the enzyme inhibitory action of caffeic acid is dominant when the two agents are co-administered leading to increased cytotoxicity, and the Nrf2 induction is dominant when the cells are treated with caffeic acid prior to cisplatin treatment leading to resistance. The use of caffeic acid as adjuvant for cisplatin should be carefully examined due to different pharmacokinetic profiles of caffeic acid and cisplatin. Thus, it is questionable if the two agents can reach the tumors at the right time frame in vivo.