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

Abstract

Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic regimens for several malignancies; however, the main limitations are chemoresistance and ototoxic side effects. In this study we used two different polyphenols, curcumin and ferulic acid as adjuvant chemotherapeutics evaluating (1) in vivo their antioxidant effects in protecting against cisplatin ototoxicity and (2) in vitro the transcription factors involved in tumor progression and cisplatin resistance. We reported that both polyphenols show antioxidant and oto-protective activity in the cochlea by up-regulating Nrf-2/HO-1 pathway and downregulating p53 phosphorylation. However, only curcumin is able to influence inflammatory pathways counteracting NF-κB activation. In human cancer cells, curcumin converts the anti-oxidant effect into a pro-oxidant and anti-inflammatory one. Curcumin exerts permissive and chemosensitive properties by targeting the cisplatin chemoresistant factors Nrf-2, NF-κB and STAT-3 phosphorylation. Ferulic acid shows a biphasic response: it is pro-oxidant at lower concentrations and anti-oxidant at higher concentrations promoting chemoresistance. Thus, polyphenols, mainly curcumin, targeting ROS-modulated pathways may be a promising tool for cancer therapy. Thanks to their biphasic activity of antioxidant in normal cells undergoing stressful conditions and pro-oxidant in cancer cells, these polyphenols probably engage an interplay among the key factors Nrf-2, NF-κB, STAT-3 and p53. Cisplatin chemotherapy has been a mainstay of cancer treatment 1. In general, cisplatin is considered a cytotoxic drug which kills cancer cells by the formation of intra-and inter-strand DNA crosslinks as well as cisplatin DNA adducts 2-4. The molecular mechanisms of action are complex and involve multiple events that include induction of oxidative stress as characterized by reactive oxygen species (ROS) production and lipid peroxidation, inflammation by activating pro-inflammatory factors, induction of p53-dependent signaling pathways 5. However, cisplatin chemotherapy is also associated with substantial side effects that include ototoxic damage 6-9. Elevation of hearing threshold, mainly for the higher frequencies, has been reported in 22 to 75% of adult patients 10 and 26 to 90% of pediatric patients 11 ; it results in significant and permanent hearing loss that is especially debilitating in young children 11. A growing body of research is dedicated to elucidate the molecular mechanisms implicated in cisplatin toxicity and resistance, including oxidative stress and inflammation 4,12-15. Still, the molecular mechanisms underlying the enhanced sensitivity or resistance to cisplatin-induced apoptosis and cisplatin adverse effects are poorly understood. In the present research we considered that combination therapies of cisplatin with other drugs have become challenging in the treatment of human cancers to overcome drug resistance and reduce the undesirable side effects. Currently, natural products or nutraceuticals are...

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