The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity.

Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic\r\nregimens for several malignancies; however, the main limitations are chemoresistance and ototoxic\r\nside effects. In this study we used two different polyphenols, curcumin and ferulic acid as adjuvant\r\nchemotherapeutics evaluating (1) in vivo their antioxidant effects in protecting against cisplatin\r\nototoxicity and (2) in vitro the transcription factors involved in tumor progression and cisplatin\r\nresistance. We reported that both polyphenols show antioxidant and oto-protective activity in the\r\ncochlea by up-regulating Nrf-2/HO-1 pathway and downregulating p53 phosphorylation. However, only\r\ncurcumin is able to influence inflammatory pathways counteracting NF-κB activation. In human cancer\r\ncells, curcumin converts the anti-oxidant effect into a pro-oxidant and anti-inflammatory one. Curcumin\r\nexerts permissive and chemosensitive properties by targeting the cisplatin chemoresistant factors\r\nNrf-2, NF-κB and STAT-3 phosphorylation. Ferulic acid shows a biphasic response: it is pro-oxidant at\r\nlower concentrations and anti-oxidant at higher concentrations promoting chemoresistance. Thus,\r\npolyphenols, mainly curcumin, targeting ROS-modulated pathways may be a promising tool for cancer\r\ntherapy. Thanks to their biphasic activity of antioxidant in normal cells undergoing stressful conditions\r\nand pro-oxidant in cancer cells, these polyphenols probably engage an interplay among the key factors\r\nNrf-2, NF-κB, STAT-3 and p53.