Participation of MT3 melatonin receptors in the synergistic effect of melatonin on cytotoxic and apoptotic actions evoked by chemotherapeutics
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Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant actions. Therefore, melatonin may be useful in the treatment of tumors in association with chemotherapy drugs.
Purpose and methods
This study was performed to study the role of melatonin receptors on the cytotoxicity and apoptosis induced by the chemotherapeutic agents cisplatin and 5-fluorouracil in two tumor cell lines, such as human colorectal cancer HT-29 cells and cervical cancer HeLa cells.
We found that both melatonin and the two chemotherapeutic agents tested induced a decrease in HT-29 and HeLa cell viability. Furthermore, melatonin significantly increased the cytotoxic effect of chemotherapeutic agents, particularly, in 5-fluorouracil-challenged cells. Stimulation of cells with either of the two chemotherapeutic agents in the presence of melatonin further increased caspase-3 activation. Concomitant treatments with melatonin and chemotherapeutic agents augmented the population of apoptotic cells compared to the treatments with chemotherapeutics alone. Blockade of MT1 and/or MT2 receptors with luzindole or 4-P-PDOT was unable to reverse the enhancing effects of melatonin on both cytotoxicity, caspase-3 activation and the amount of apoptotic cells evoked by the chemotherapeutic agents, whereas when MT3 receptors were blocked with prazosin, the synergistic effect of melatonin with chemotherapy on cytotoxicity and apoptosis was reversed.
Our findings provided evidence that in vitro melatonin strongly enhances chemotherapeutic-induced cytotoxicity and apoptosis in two tumor cell lines, namely HT-29 and HeLa cells and, this potentiating effect of melatonin is mediated by MT3 receptor stimulation.
KeywordsMelatonin Colorectal and cervical cancer Chemotherapy Cytotoxicity Apoptosis
The authors appreciate the technical and human support provided by the facility of Bioscience Applied Techniques of SAIUEx (financed by UEx, Junta de Extremadura, MICINN, FEDER, and FSE).
Conflict of interest
R. Pariente declares that he has no conflict of interest. I. Bejarano declares that he has no conflict of interest. J. Espino declares that he has no conflict of interest. A.B. Rodriguez declares that she has no conflict of interest. J.A. Pariente declares that he has no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
This work was supported by Gobierno de Extremadura grants (GR15051). J. Espino holds a research post-doctoral fellowship from Gobierno de Extremadura (jointly financed by the European Regional Development Fund (ERDF); ref. PO14011).
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