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.
Melatonin 5-fluorouracil Apoptosis Reactive oxygen species Colon cancer
This is a preview of subscription content, log in to check access.
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).
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
Scholefield JH, Steele RJ, British Society For Gastroenterology, Association of Coloproctology for Great Britain and Ireland (2002) Guidelines for follow up after resection of colorectal cancer. Gut 51:V3–V5CrossRefPubMedPubMedCentralGoogle Scholar
Trivedi PP, Jena GB, Tikoo KB, Kumar V (2016) Melatonin modulated autophagy and Nrf2 signaling pathways in mice with colitis-associated colon carcinogenesis. Mol Carcinog 55:255–267. doi:10.1002/mc.22274CrossRefPubMedGoogle Scholar
García-Navarro A, González-Puga C, Escames G et al (2007) Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture. J Pineal Res 43:195–205CrossRefPubMedGoogle Scholar
Kos-Kudla B, Ostrowska Z, Kozlowski A et al (2002) Circadian rhythm of melatonin in patients with colorectal carcinoma. Neuro Endocrinol Lett 23:239–242PubMedGoogle Scholar
Schernhammer ES, Laden F, Speizer FE et al (2003) Night-shift work and risk of colorectal cancer in the nurses’ health study. J Natl Cancer Inst 95:825–828CrossRefPubMedGoogle Scholar
Naziroglu M, Karaoğlu A, Aksoy AO (2004) Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats. Toxicology 195:221–230CrossRefPubMedGoogle Scholar
Sakallı Çetin E, Nazıroğlu M, Çiğ B et al (2017) Selenium potentiates the anticancer effect of cisplatin against oxidative stress and calcium ion signaling-induced intracellular toxicity in MCF-7 breast cancer cells: involvement of the TRPV1 channel. J Recept Signal Transduct Res 37:84–93. doi:10.3109/10799893.2016.1160931CrossRefPubMedGoogle Scholar
Koşar PA, Nazıroğlu M, Övey İS, Çiğ B (2016) Synergic effects of doxorubicin and melatonin on apoptosis and mitochondrial oxidative stress in MCF-7 breast cancer cells: involvement of TRPV1 channels. J Membr Biol 249:129–140. doi:10.1007/s00232-015-9855-0CrossRefPubMedGoogle Scholar
Pariente R, Pariente JA, Rodríguez AB, Espino J (2016) Melatonin sensitizes human cervical cancer HeLa cells to cisplatin-induced cytotoxicity and apoptosis: effects on oxidative stress and DNA fragmentation. J Pineal Res 60:55–64. doi:10.1111/jpi.12288CrossRefPubMedGoogle Scholar
Fan L-L, Sun G-P, Wei W et al (2010) Melatonin and doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines. World J Gastroenterol 16:1473–1481CrossRefPubMedPubMedCentralGoogle Scholar
Plaimee P, Weerapreeyakul N, Barusrux S, Johns NP (2015) Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Prolif 48:67–77. doi:10.1111/cpr.12158CrossRefPubMedGoogle Scholar
Casado-Zapico S, Rodriguez-Blanco J, García-Santos G et al (2010) Synergistic antitumor effect of melatonin with several chemotherapeutic drugs on human Ewing sarcoma cancer cells: potentiation of the extrinsic apoptotic pathway. J Pineal Res 48:72–80. doi:10.1111/j.1600-079X.2009.00727.xCrossRefPubMedGoogle Scholar
Espino J, Rodríguez AB, Pariente JA (2013) The inhibition of TNF-α-induced leucocyte apoptosis by melatonin involves membrane receptor MT1/MT2 interaction. J Pineal Res 54:442–452. doi:10.1111/jpi.12042CrossRefPubMedGoogle Scholar
Espino J, González-Gómez D, Moreno D et al (2013) Tempranillo-derived grape seed extract induces apoptotic cell death and cell growth arrest in human promyelocytic leukemia HL-60 cells. Food Funct 4:1759–1766. doi:10.1039/c3fo60267bCrossRefPubMedGoogle Scholar
Cassidy J, Saltz L, Twelves C et al (2011) Efficacy of capecitabine versus 5-fluorouracil in colorectal and gastric cancers: a meta-analysis of individual data from 6171 patients. Ann Oncol 22:2604–2609. doi:10.1093/annonc/mdr031CrossRefPubMedGoogle Scholar
Wang L-H, Li Y, Yang S-N et al (2014) Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signalling. Br J Cancer 110:341–352. doi:10.1038/bjc.2013.752CrossRefPubMedGoogle Scholar
Cos S, Garcia-Bolado A, Sánchez-Barceló EJ (2001) Direct antiproliferative effects of melatonin on two metastatic cell sublines of mouse melanoma (B16BL6 and PG19). Melanoma Res 11:197–201CrossRefPubMedGoogle Scholar
Madhu P, Reddy KP, Reddy PS (2015) Melatonin reduces oxidative stress and restores mitochondrial function in the liver of rats exposed to chemotherapeutics. J Exp Zool A Ecol Genet Physiol 323:301–308. doi:10.1002/jez.1917CrossRefPubMedGoogle Scholar
Wei J-Y, Li W-M, Zhou L-L et al (2015) Melatonin induces apoptosis of colorectal cancer cells through HDAC4 nuclear import mediated by CaMKII inactivation. J Pineal Res 58:429–438. doi:10.1111/jpi.12226CrossRefPubMedGoogle Scholar
Wang J, Guo W, Chen W et al (2013) Melatonin potentiates the antiproliferative and pro-apoptotic effects of ursolic acid in colon cancer cells by modulating multiple signaling pathways. J Pineal Res 54:406–416. doi:10.1111/jpi.12035CrossRefPubMedGoogle Scholar
Ju H-Q, Li H, Tian T et al (2016) Melatonin overcomes gemcitabine resistance in pancreatic ductal adenocarcinoma by abrogating nuclear factor-κB activation. J Pineal Res 60:27–38. doi:10.1111/jpi.12285CrossRefPubMedGoogle Scholar
Gao Y, Xiao X, Zhang C et al (2017) Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways. J Pineal Res 62:e12380. doi:10.1111/jpi.12380CrossRefGoogle Scholar