Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation

Ying Qiang Shen, Ana Guerra-Librero, Beatriz I. Fernandez-Gil, Javier Florido, Sergio García-López, Laura Martinez-Ruiz, Miguel Mendivil-Perez, Viviana Soto-Mercado, Darío Acuña-Castroviejo, Hector Ortega-Arellano, Victor Carriel, María E. Diaz-Casado, Russel J. Reiter, Iryna Rusanova, Ana Nieto, Luis C. López, Germaine Escames

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47 Scopus citations

Abstract

Head and neck squamous cell carcinoma (HNSCC) clearly involves activation of the Akt mammalian target of rapamycin (mTOR) signalling pathway. However, the effectiveness of treatment with the mTOR inhibitor rapamycin is often limited by chemoresistance. Melatonin suppresses neoplastic growth via different mechanisms in a variety of tumours. In this study, we aimed to elucidate the effects of melatonin on rapamycin-induced HNSCC cell death and to identify potential cross-talk pathways. We analysed the dose-dependent effects of melatonin in rapamycin-treated HNSCC cell lines (Cal-27 and SCC-9). These cells were treated with 0.1, 0.5 or 1 mmol/L melatonin combined with 20 nM rapamycin. We further examined the potential synergistic effects of melatonin with rapamycin in Cal-27 xenograft mice. Relationships between inhibition of the mTOR pathway, reactive oxygen species (ROS), and apoptosis and mitophagy reportedly increased the cytotoxic effects of rapamycin in HNSCC. Our results demonstrated that combined treatment with rapamycin and melatonin blocked the negative feedback loop from the specific downstream effector of mTOR activation S6K1 to Akt signalling, which decreased cell viability, proliferation and clonogenic capacity. Interestingly, combined treatment with rapamycin and melatonin-induced changes in mitochondrial function, which were associated with increased ROS production, increasing apoptosis and mitophagy. This led to increase cell death and cellular differentiation. Our data further indicated that melatonin administration reduced rapamycin-associated toxicity to healthy cells. Overall, our findings suggested that melatonin could be used as an adjuvant agent with rapamycin, improving effectiveness while minimizing its side effects.

Original languageEnglish (US)
Article numbere12461
JournalJournal of pineal research
Volume64
Issue number3
DOIs
StatePublished - Apr 2018

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Keywords

  • apoptosis
  • head and neck cancer cells
  • mTOR
  • melatonin
  • mitochondria
  • mitophagy
  • rapamycin

ASJC Scopus subject areas

  • Endocrinology

Cite this

Shen, Y. Q., Guerra-Librero, A., Fernandez-Gil, B. I., Florido, J., García-López, S., Martinez-Ruiz, L., Mendivil-Perez, M., Soto-Mercado, V., Acuña-Castroviejo, D., Ortega-Arellano, H., Carriel, V., Diaz-Casado, M. E., Reiter, R. J., Rusanova, I., Nieto, A., López, L. C., & Escames, G. (2018). Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation. Journal of pineal research, 64(3), [e12461]. https://doi.org/10.1111/jpi.12461