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

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.

Melatonin inhibits epithelial‑to‑mesenchymal transition in gastric cancer cells via attenuation of IL‑1β/NF‑κB/MMP2/MMP9 signaling

“…Its anticancer mechanisms include acceleration of tumor cell apoptosis, suppression of tumor cell proliferation, immunostimulation and synergistic activity with other treatments. Recent studies have demonstrated that melatonin notably decreases the risk of death and treatment resistance of multiple malignancies, particularly in breast cancer, colon cancer, melanoma, lung cancer and malignant glioblastoma (7)(8)(9)31,32). A clinical study by Lissoni et al has demonstrated that the regression rate in patients with non-small-cell lung cancer or gastrointestinal cancer receiving combination therapy with chemotherapeutic drugs and melatonin was significantly higher compared with that in the group of patients receiving chemotherapy alone.…”

“…Its biological roles include regulation of the circadian rhythm, as well as antioxidant, anti-aging and immunoregulatory actions. Various studies have reported that melatonin has significant antitumor activity against several types of cancers, such as breast, lung and colorectal cancer (7)(8)(9). Although the exact mechanism remains unknown, the anticancer effects of melatonin may be mediated by multiple pathways, including antagonism of growth factors, induction of tumor cell apoptosis, enhancement of immunity, adjustment of the psychological state, and synergy with other treatments (10)(11)(12)(13)(14).…”

The emergence of melatonin in oncology: Focus on colorectal cancer

“…The addition of melatonin (1 mM for 48 hours) enhanced the in vitro antiproliferative capacity of 5‐FU, as well as its potential for inhibiting the formation of colonies, migration, and invasion. A second published study has demonstrated the significant augmenting effect of melatonin (1 mM for 72 hours) on the cytotoxicity of 5‐FU in human HT‐29 cells . The coadministration of melatonin potentiated significantly the cytotoxicity of 5‐FU, jointly achieving rates of ROS production and apoptosis on HT‐29 cells greater than the drug given separately.…”

“…A second published study has demonstrated the significant augmenting effect of melatonin (1 mM for 72 hours) on the cytotoxicity of 5-FU in human HT-29 cells. 319 The coadministration of melatonin potentiated significantly the cytotoxicity of 5-FU, jointly achieving rates of ROS production and apoptosis on HT-29 cells greater than the drug given separately. Both reports provided compelling evidence of the synergistic interplay between melatonin and 5-FU in CRC.…”

An extract of Hypericum perforatum induces wound healing through inhibitions of Ca2+ mobilizations, mitochondrial oxidative stress and cell death in epithelial cells: Involvement of TRPM2 channels

“…The PI is a membrane-impermeable dye. Hence, the state of the cell determines the ability of PI staining to distinguish between viable and late apoptotic cells (Pariente et al, 2018). At the end of the HP treatment (72 h), treated or resting cells were incubated with 250 μL binding buffer containing 5 μl of V-FITC for 15 min at room temperature in dark and then they were washed twice with 1X PBS, and finally the cells were incubated with 250 μL binding buffer containing 10 μL of PI for 15 min at room temperature in dark.…”