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Melatonin increases the effect of 5-fluorouracil-based chemotherapy in human colorectal adenocarcinoma cells in vitro

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Abstract

Melatonin has antitumor activity via several mechanisms including its anti-proliferative and pro-apoptotic effects. Moreover, it has been proven that melatonin in combination with chemotherapeutic agents enhances chemotherapy-triggered apoptosis in several types of cancer. Therefore, this study was intended to evaluate whether melatonin is able to strengthen the anti-cancer potential of different chemotherapeutic drugs in human colorectal adenocarcinoma HT–29 cells. We found that treatment with 20 µM cisplatin (CIS) or 1 mM 5-fluorouracil (5-FU) for 72 h induced a decrease in HT-29 cell viability. Furthermore, 1 mM melatonin significantly (P < 0.05) increased the cytotoxic effects of 5-FU. Likewise, simultaneous stimulation with 1 mM melatonin and 1 mM 5-FU significantly (P < 0.05) enhanced the ratio of cells with an overproduction of intracellular reactive oxygen species and substantially augmented the population of apoptotic cells compared to the treatment with 5-FU alone. Nonetheless, melatonin only displayed moderate chemosensitizing effects in CIS-treated HT-29 cells, as suggested by a slight increment in the fraction of early apoptotic cells that was observed only after 48 h. Consistently, co-stimulation of HT-29 cells with 20 µM CIS or 1 mM 5-FU in the presence of 1 mM melatonin further increased caspase-3 activation. Apart from this, the cytostatic activity displayed by CIS due to S phase arrest was not affected by concomitant stimulation with melatonin. Overall, our results indicate that melatonin increases the sensitivity of HT-29 cells to 5-FU treatment and, consequently, the indolamine could be potentially applied to colorectal adenocarcinoma treatment as a potent chemosensitizing agent.

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Acknowledgements

This work was supported by Junta de Extremadura (GR15051). J. Espino holds a research post-doctoral fellowship from Junta de Extremadura (jointly financed by the European Regional Development Fund (ERDF); ref. PO14011). The authors appreciate the technical and human support provided by Facility of Bioscience Applied Techniques of SAIUEx (financed by UEx, Junta de Extremadura, MICINN, FEDER, and FSE).

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  1. Roberto Pariente and Ignacio Bejarano contributed equally to this study.

Authors and Affiliations

  1. Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, 06006, Badajoz, Spain

    Roberto Pariente, Ignacio Bejarano, Ana Beatriz Rodríguez, José Antonio Pariente & Javier Espino

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  1. Roberto Pariente
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  2. Ignacio Bejarano
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Correspondence to Javier Espino.

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Pariente, R., Bejarano, I., Rodríguez, A.B. et al. Melatonin increases the effect of 5-fluorouracil-based chemotherapy in human colorectal adenocarcinoma cells in vitro. Mol Cell Biochem 440, 43–51 (2018). https://doi.org/10.1007/s11010-017-3154-2

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