Melatonin is a ubiquitous molecule present in many living organisms that has stayed constant throughout evolution, suggesting that it plays roles that are critical to life. Melatonin is best known in humans for its role in the circadian rhythm, but it is also involved in other processes, such as reproduction regulation and immune modulation. It is an efficient antioxidant in vitro with anti-inflammatory, anti-aging, and anti-tumor properties [1].
Although its anti-tumor activity was discovered fifty years ago, melatonin’s therapeutic potential in oncology has not yet been fully investigated. This molecule is nevertheless promising given its wide therapeutic window and efficacy in vitro.
In a previous article, we’ve gone into depth on melatonin, its mechanism, and its supplementation. In this article, we will focus on melatonin’s anti-cancer effects.
Melatonin's anti-cancer effects in vitro and in vivo
Pro-oxidant promoting apoptosis
Melatonin is an antioxidant that acts as a radical scavenger more efficiently than glutathione and mannitol in vitro [2]. Melatonin seems to be present in high quantities in the mitochondria [3], which are major organelles in reactive oxygen species (ROS) production [4]. In them, melatonin may contribute to the neutralization of the highly reactive species that form during mitochondrial respiration [5]. On the contrary, in vitro experiments showed that melatonin is able to promote ROS production in cancer cells to initiate apoptosis [6,7]. Zhang and colleagues named this property the “conditional pro-oxidant action of melatonin.” This pro-oxidant activity depends on the cell type observed in vitro, melatonin concentration in the medium culture, and duration of treatment [7].
For example, at high concentrations (0.01-1 mM), melatonin induced moderate cytotoxicity combined with a significant increase in ROS production in several human leukemia cell lines, including Jurkat, MOLT-4, and CMK cells [6]. At the same concentration, melatonin also induced elevated ROS in HL-60 leukemia cells, K562 leukemia cells, or B lymphoblastoid 721.221 cells [8], despite variations in the cell outcomes ranging from apoptosis induction to no viability difference.
Remarkably, high concentrations of melatonin did not cause cytotoxicity in non-tumor cells, such as peripheral blood mononuclear leukocytes [9], neuronal stem cells [10], and primary hepatocytes [11]. The pro-oxidant effects of melatonin at high concentrations seem to be cell-type dependent (i.e., whether it is a cancer or normal cell).
Metabolism modulations
Melatonin can modulate cancer cell metabolism. To meet high energy demands, tumor cells produce ATP via aerobic glycolysis despite the presence of oxygen and functional mitochondria. Instead of entering the mitochondria, pyruvate (the end product of glucose metabolism) undergoes fermentation to lactate in the cytosol before release from tumor cells. This metabolic change, known as the Warburg effect, gives advantages to cancer cells in terms of proliferation and invasion by contributing to tumor micro-environment acidification [12,13].
Blask and colleagues observed that tumors exhibited different metabolic profiles during day and night while growing human breast cancer xenografts in nude rats and that these differences temporally correlated with circulating melatonin levels [14]. Suppressing melatonin release by exposing the rats to light at night showed that the Warburg effect, which is normally interrupted at night, greatly enhanced tumor growth. Melatonin seems to facilitate tumor transition from Warburg metabolism to normal oxidative phosphorylation at night, and this reversal has been confirmed in several melatonin-treated cancer cell lines [15-17].
Chemo-resistance reversion
Melatonin exhibits the potential to overcome the chemo-resistance in cancer cells. Chemo-resistance mechanisms are extremely complex and include enhanced DNA repair, altered cell cycle, and reduced apoptosis. Dauchy and colleagues implanted estrogen receptor-positive breast cancer in nude rats. By exposing the rats to constant light, they suppressed melatonin secretion and observed that tumors exhibited accelerated growth and resistance to tamoxifen, while the tumors in rats expressing melatonin rapidly collapsed. By providing exogenous melatonin to rats without melatonin secretion, tumor insensitivity to tamoxifen could be reversed, thus stopping tumor growth [18]. Other experiments with similar settings showed that exogenous melatonin was able to reverse the cancer cell sensitivity to paclitaxel [19].
Melatonin can also impact the widely used chemotherapies doxorubicin and cisplatin. In hepatocellular carcinoma, melatonin reversed the endoplasmic reticulum stress-induced chemoresistance, influencing key molecular pathways. The reversal of P-glycoprotein-mediated drug efflux, increasing cancer cells’ surviving capacity, and downregulation of genes related to chemo-resistance further highlighted melatonin’s effects [20,21].
Finally, in colorectal cancer cell lines, melatonin was found to reverse resistance to 5-fluorouracil and also enhance its cytotoxicity. Melatonin downregulated thymidylate synthase (the therapeutic target of 5-fluorouracil) and increased microRNA-215-5p expression, leading to chemo-sensitizing effects [22]. These findings underscore the potential of melatonin as a complementary therapeutic agent to address chemo-resistance issues associated with conventional chemotherapies.
Epithelial-mesenchymal transition inhibition
Melatonin has emerged as a potent regulator in impeding epithelial-mesenchymal transition (EMT), a reversible process crucial in carcinomas. EMT enhances tumor cell invasiveness, mobility, and resistance to genotoxic treatments, promoting metastasis. Melatonin showed great efficacy in limiting EMT, thereby combating metastasis development by interfering with required molecular events, such as preventing changes in cell polarity, upregulating adhesion molecules, and resisting cytoskeletal changes [23,24]. Melatonin inhibited kinases and interfered with vimentin, hindering cellular migration. It also impeded matrix metalloproteinases, limiting the breakdown of the extracellular matrix and making invasion more difficult [25].
Melatonin and human cancers
Melatonin secretion is reduced in lung cancer
In the context of non-small cell lung cancer (NSCLC), the circadian profiles of melatonin, cortisol, and their ratio were meticulously examined across different disease stages. Seventeen healthy subjects, alongside patients with lung cancer in stages I, II, III, and IV, underwent comprehensive 24-hour melatonin and cortisol profiling. While the circadian rhythm of melatonin persisted in all groups, patients with lung cancer exhibited diminished melatonin levels and an altered cortisol secretion pattern, particularly in advanced stages. The melatonin/cortisol ratio decreased significantly in stage III and IV cancer patients [26].
Another study investigating melatonin, tryptophan (a melatonin precursor), and 6-sulfatoxymelatonin in advanced-stage NSCLC patients revealed substantial reductions in them compared to healthy subjects. Following standard chemotherapy, a progressive decline in these biomarkers was observed. These findings highlight the intricate interplay between melatonin, the neuroendocrine system, and lung cancer, suggesting that both the disease and its treatment may progressively impact melatonin secretion [27].
Melatonin in clinical trials
The effects of melatonin and low-dose interleukin-2 (IL-2) on tumor progression and survival in patients with untreatable metastatic solid tumors were assessed in a clinical trial with 846 patients. Patients were randomized into three groups and received the best supportive care alone, supportive care and melatonin, or melatonin and subcutaneous low-dose IL-2. The addition of melatonin to supportive care led to a significant increase in disease stabilization and survival time compared to supportive care alone. Additionally, a combination of IL-2 and melatonin resulted in further improvements in the percentage of tumor regression and 3-year survival compared to melatonin alone. IL-2 and melatonin may help control neoplastic growth and extend survival in patients with metastatic solid tumors, particularly when no other conventional anti-cancer therapy is available [28].
Another clinical trial assessed the effects of a combination regimen consisting of somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide, in 23 patients with advanced lung adenocarcinoma. The median overall survival was 95 days combined with mild side effects (including diarrhea, nausea, vomiting, and drowsiness). Both respiratory and general symptoms improved, particularly in patients surviving more than 95 days. This combined regimen showed the potential to improve disease-related symptoms in patients with late-stage lung adenocarcinoma [29].
The effects of concomitant melatonin administration on the efficacy and toxicity of various chemotherapies in the treatment of metastatic solid tumors were also assessed. A total of 370 patients with NSCLC or gastrointestinal tumors were randomized and received either chemotherapy alone or chemotherapy and melatonin (chemotherapy varied based on the cancer type). Results showed a significantly higher overall tumor regression rate in patients concomitantly treated with melatonin compared to those receiving chemotherapy alone. Additionally, patients receiving melatonin showed a significantly higher 2-year survival rate. These findings underscore melatonin’s potential to enhance the effectiveness of standard anti-cancer chemotherapies [30].
Similarly, another clinical trial involving 100 patients with NSCLC assessed the effects of concomitant melatonin administration with chemotherapy (cisplatin and etoposide). Patients were randomized and received chemotherapy alone or chemotherapy and melatonin. Results showed that patients concomitantly treated with melatonin presented significantly higher overall tumor regression rates and 5-year survival outcomes. Additionally, with melatonin, chemotherapy was better tolerated, highlighting its potential to enhance chemotherapy efficacy in both survival and quality of life [31].
Conclusion
The multiple actions of melatonin involve numerous signaling pathways and transcription factors, making it a promising agent in counteracting cancer progression, limiting metastasis, and potentially enhancing the efficacy of anti-cancer therapies. Further studies are needed to fully comprehend melatonin’s modes of action and its anti-cancer effects as well as explore its potential as a concomitant therapy in cancer treatment.
However, if you’d like to use melatonin for what it’s best known for (i.e., helping with the timing of your circadian rhythms and sleep), then give Tro Zzz a try! It’s our buccal troche formulated for sleep that has melatonin as one of its main ingredients to help you fall asleep, stay asleep, and wake up feeling refreshed.
References
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