Molecular targets for anticancer redox chemotherapy and cisplatin-induced ototoxicity: the role of curcumin on pSTAT3 and Nrf-2 signalling

• Published in: British journal of cancer Vol. 113; no. 10; pp. 1434 - 1444
• Main Authors: Fetoni, A R, Paciello, F, Mezzogori, D, Rolesi, R, Eramo, S L M, Paludetti, G, Troiani, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.11.2015; Nature Publishing Group
• Subjects: 631/67/1059/99; 631/67/1536; 631/80/86; 692/700/565/2194; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cisplatin - administration & dosage; Cisplatin - adverse effects; Curcumin - administration & dosage; Curcumin - pharmacology; Drug Resistance; Drug Resistance, Neoplasm - drug effects; Epidemiology; Evoked Potentials, Auditory, Brain Stem - drug effects; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Hearing Loss - chemically induced; Hearing Loss - prevention & control; Humans; Male; Molecular Medicine; NF-E2-Related Factor 2 - metabolism; Oncology; Phosphorylation - drug effects; Rats; Rats, Wistar; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; Translational Therapeutics; polyphenols; cochlea; human oral squamous cell carcinoma; chemotherapeutic adjuvant; otoprotection; heme oxigenase-1; pro-/antioxidant effect
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2015.359

Background: In oncology, an emerging paradigm emphasises molecularly targeted approaches for cancer prevention and therapy and the use of adjuvant chemotherapeutics to overcome cisplatin limitations. Owing to their safe use, some polyphenols, such as curcumin, modulate important pathways or molecular targets in cancers. This paper focuses on curcumin as an adjuvant molecule to cisplatin by analysing its potential implications on the molecular targets, signal transducer and activator of transcription 3 (STAT3) and NF-E2 p45-related factor 2 (Nrf-2), in tumour progression and cisplatin resistance in vitro and the adverse effect ototoxicity in vivo . Methods: The effects of curcumin and/or cisplatin treatment have been evaluated in head and neck squamous cell carcinoma as well as in a rat model of cisplatin-induced ototoxicity by using immunofluorescence, western blot, and functional and morphological analysis. Results: This study demonstrates that curcumin attenuates all stages of tumour progression (survival, proliferation) and, by targeting pSTAT3 and Nrf-2 signalling pathways, provides chemosensitisation to cisplatin in vitro and protection from its ototoxic adverse effects in vivo. Conclusions: These results indicate that curcumin can be used as an efficient adjuvant to cisplatin cancer therapy. This treatment strategy in head and neck cancer could mediate cisplatin chemoresistance by modulating therapeutic targets (STAT3 and Nrf2) and, at the same time, reduce cisplatin-related ototoxic adverse effects.