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.
Highlights
Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic regimens for several malignancies; the main limitations are chemoresistance and ototoxic side effects
Auditory Brainstem Responses (ABRs) thresholds did not differ among control animals and animals treated with the most effective curcumin (200 mg/kg) or Ferulic acid (FA) (600 mg/kg) dosage (Fig. 1A)
The major results indicated that polyphenols administrated in conjunction with cisplatin can exert both anti-oxidant and pro-oxidant effects; the polyphenolic compounds show different mechanisms of action depending on cell context and dosage
Summary
Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic regimens for several malignancies; 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. A strong antioxidant is Ferulic acid (FA), widely studied even for its otoprotectant, antimicrobial, anti-arrhythmic, antithrombotic, antidiabetic and immuno-stimulant properties[25,28,29] This phenolic acid gained attention for its potential role as an adjuvant therapy for several free radical-induced diseases, as ototoxicity, neurodegenerative disorders and cancer, considering that FA was proposed as a novel antioxidant compound endowed with a strong cytoprotective activity due to both the ability to scavenge free radicals and activate cell stress response[28]. The relationship between cytotoxicity, oxidative stress and inflammation and the possible implications among a) Nrf-2 that controls a cellular defensive response[30], b) NF-κB a master regulator of the inflammatory process, responsible for the widespread systemic inflammatory process[31] and for tumor resistance[32] and c) p53 that mediates the induction of apoptosis[33]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
