REGISTRO DOI: 10.69849/revistaft/ni10202503091555
Christiane Nazareth Silva; Vitória Feitoza Souza; Lívia Helene da Costa Rabelo; Kelly Teles Lima da Silva; Paulo Henrique de Franco Alcântara; João de Sousa Pinheiro Barbosa
SUMMARY
OBJECTIVE: To analyze the efficacy of the use of Melatonin in the treatment of breast cancer. METHODOLOGY: Integrative review of scientific studies in English indexed in the following databases: PubMed, Lilacs and SciELO. RESULTS: Melatonin has been shown to be an excellent hormone with inhibitory and oxidizing effects on cancer cells, especially in breast tumors, as well as potentiating chemotherapy treatments, acting as an adjuvant in cancer treatment. Melatonin has also been shown to be effective in reducing the symptoms associated with cancer treatment and the disease itself. Finally, the protective effect of melatonin against breast cancer was also observed. CONCLUSION: Scientific studies have therefore shown that melatonin plays a role in the treatment of breast cancer in isolation and in combination, potentiating the effects of chemotherapy or leading to apoptosis of cancer cells.
KEYWORDS: Breast. Cancer. Chemotherapy. Melatonin. Treatment.
INTRODUCTION
Malignant neoplasms are a worldwide public health problem. In the last decade, there has been a 20% increase in incidence and it is expected that by 2030 there will be more than 25 million new cases. At the same time, melatonin is a hormone secreted by the pineal gland whose main physiological function is to provide information about the photoperiod of the day, and can be considered a physiological sleep regulator, reaching higher plasma levels during the night1 . In addition to this role, the hormone has been shown to have an inhibitory and oxidizing effect on cancer cells2 through mechanisms related to membrane receptors linked to the melatonin 1 receptor (MT1)9 . In this sense, as breast cancer is the most prevalent tumor in the Brazilian population4 and is the most prevalent and deadliest cancer in the world5 , this literature review aims to analyze the efficacy of the use of Melatonin in the treatment of breast cancer, as well as its association with other drugs and the future projections of this therapy.
METHODS
This study is a literature review on the therapeutic potential of melatonin in the treatment of breast cancer. As a review, there was no need for ethics committee approval. The searches were carried out in the PubMed, SciELO and Lilacs databases. The OCEBM “The Oxford Levels of Evidence 2”6 was used to evaluate the articles. The first step in selecting the articles was to exclude studies with a level of evidence lower than 2C, as well as any type of review methodology (such as systematic reviews and review articles). After this, the remaining articles had to meet the required criteria: I) presence of the Health Sciences Descriptors7 : “Breast”, “Cancer” and “Melatonin” in the keywords; II) year of publication not exceeding 5 years; III) methodology applied with 2C as the minimum level of evidence. The results obtained were experimental and analytical studies from 2018 to 2022, of which 20 were selected because they best fit the theme and level of evidence.
RESULTS AND DISCUSSION
Melatonin is a hormone secreted by the pineal gland whose main physiological function is to provide information about the photoperiod of the day, and can be considered a physiological sleep regulator, reaching higher plasma levels during the night1 . In addition, it is a molecule whose antitumor and antioxidant effects are known2 . However, increased exposure to artificial light can deregulate the physiological secretion of this hormone.
In this sense, it was observed that nocturnal light pollution from permanent sources (cities, towns, industries and gas flares) proved to be a risk factor for breast cancer after periods of exposure of more than one year.8 Exposure to cumulative light pollution over five years has been shown to be a risk factor for breast cancer.8 Especially at night, exposure to light disrupts the circadian cycle and leads to suppression of nocturnal melatonin.9 The association of nocturnal light with excessive expression of the STAT3 factor (signal transducer and activator of transcription 3) has been described, together with inhibition of the anti-tumor factor, which promotes both the appearance of breast carcinoma and the resistance of this cancer to treatment with Paclitaxel.9
In in vitro studies, the findings indicate that treatment of breast cancer cells with melatonin increased the inhibitory effect of melatonin on cell growth, through apoptosis and autophagy.10 It was concluded that melatonin can adjust the balance of expression of markers that play a role in cell death mechanisms and significantly promote these mechanisms.10 Therefore, melatonin can inhibit the growth of breast cancer cells by inducing cell death.10
In addition to increased light incidence and sleep dysregulation, the presence of Bisphenol A (BPA), a synthetic compound widely used in food and plastic packaging, is another risk factor for breast cancer.3 It can mimic estrogen and interact with its receptor (ER), promoting neoplastic factors that can result in ER+ tumor cells (they use estrogen to grow).3 Trials have shown that melatonin considerably prevents BPA-derived cell proliferation.3 Results of the positive regulation of MT1 (melatonin receptor 1) by melatonin in ER+ breast tumors indicate that MT1, mediated by melatonin, may be related to blocking the proliferation of breast cancer cells.3
In addition, the data showed that melatonin is a molecule with significant anticancer activities with the potential to optimize the management of breast cancer by overcoming resistance to antiangiogenic drugs.11 Melatonin is a molecule with potential for use as an adjuvant in cancer chemotherapy, which may have implications for designing clinical trials using chemotherapy drugs in combination with melatonin. 12
Cancer Stem Cells (CSCs) are known to be essential factors in the formation of Vasculogenic Mimicry (VM), one of the most important causes of breast cancer metastasis and drug resistance.13 The study showed that melatonin and the chemotherapy drug apatinib reduced the survival rate of CSCs in a dose and time dependent manner. 13 Apatinib, melatonin and the combination of apatinib and melatonin inhibited the proliferation of breast CSCs. MV formation was decreased in the MDA-MB-231 cancer cell line treated with apatinib and the combination of apatinib and melatonin. 13
Tamoxifen is used to prevent and treat estrogen receptor positive (ER+) breast cancer.14 However, its chronic use can increase the risk of uterine cancer and induce tamoxifen resistance.14 Thus, new melatonin-tamoxifen drug conjugates could be promising for treating breast cancer and could help offset the adverse effects of tamoxifen alone due to the presence of melatonin.14 Five drug conjugates (linked C2, C4, C5, C9 and C15) were synthesized for their effects on breast cancer cells (MCF-7, tamoxifen-resistant MCF-7, mouse mammary carcinoma, MDA-MB-231 and BT-549).14 The C4 and C5 conjugates demonstrated the most favorable pharmacological characteristics in terms of their binding profiles (affinity for ESR1 (Gene) and MT1R (melatonin receptor) and their potency/efficacy to inhibit the viability and migration of breast cancer cells in four phenotypically diverse invasive ductal cell lines.14
Triple negative breast cancer (TNBC) is an aggressive cancer that is insensitive to hormonal therapies and targets the human epidermal growth factor receptor 2 (HER2).2 HER2 is expressed in 25-30% of breast cancer cases; it is associated with the progression and unfavorable evolution of this cancer.15 Melatonin decreases the stability and destroys the HER2 protein by promoting its endocytosis and lysosomal degradation.15
Also with regard to the actions of melatonin as an adjuvant to breast cancer treatment, it has been observed that melatonin increases the cytotoxic effect of Neratinib, a drug used as an adjuvant treatment for breast cancer, on the HER2 receptor in breast cancer cells.15 The combined use of melatonin and neratinib effectively blocks the growth of HCC1954 tumor xenografts.15 In addition, the potentiating actions of melatonin on the tumor-killing ability of the ligand 2-(3,5-diphenylpyrazol-1-yl)-2-thiazoline (PtDPhPzTn) have also been verified in TNBC cells.2 Co-stimulation of TNBC cells with PtDPhPzTn and melatonin substantially increased apoptosis and markedly improved anti-migratory action.2 Thus, PtDPhPzTn and melatonin can potentially be applied to the treatment of breast cancer as powerful synergistic agents. 2
The individual use of famotidine and melatonin induces very low frequencies of apoptosis which was not significantly different from the control.16 When combined with radiation, there was a decrease in the frequency of apoptosis in leukocytes from normal and breast cancer patients.16 The effect of famotidine was more pronounced than melatonin.16 Melatonin, despite its potent antioxidant properties, does not significantly affect radiation-induced apoptosis in leukocytes derived from normal individuals; however, it has a moderately significant protective effect on leukocytes derived from breast cancer patients.16
However, one study also showed that mice with jet lag (placed in altered light cycle conditions) had significantly fewer circulating tumor cells (CTCs) in their bloodstream than the control group with a normal light-dark schedule.17 Afterwards, the researchers examined the effect of melatonin supplementation on cancer intravasation and found that the melatonin group had significantly more CTCs than the control mice.17 The authors concluded that the greatest release of CTCs occurs during sleep, circadian rhythm disruption (CRD) decreases CTCs and melatonin administration can increase the rate of CTCs, contrasting with the literature.17
Regarding the evaluation of the improvement of symptoms associated with breast cancer treatment, melatonin optimized the scores obtained in the Trail Making Test (TMT A-B) – used to evaluate cognitive performance -, improved episodic memory (immediate and delayed), recognition in the Rey Auditory-Verbal Learning Test (RAVLT), a test used to evaluate episodic declarative memory, and increased verbal fluency in the orthographic COWAT (Controlled Oral Word Association Test).1 In addition, the results suggest a neuroprotective effect of melatonin to counteract the adverse effects during Adjuvant Chemotherapy for Breast Cancer (ACBC) on cognitive function, sleep quality and depressive symptoms.1 In addition, it was observed that the prolonged use of melatonin, even after the completion of adjuvant therapies in women with breast cancer, decreased the levels of fatigue associated with the malignant disease and its treatments.18
CONCLUSION
In short, melatonin is a hormone synthesized naturally in the body and is considered a physiological sleep regulator. In addition, its antioxidant properties have demonstrated significant effects in the treatment of breast cancer by inhibiting neoplastic cell growth. From the articles analyzed, melatonin has been studied in isolation or as an adjuvant. In the first case, some studies showed that there was an inhibitory effect on the cell growth of tumor cells, since melatonin can adjust the balance of expression of markers that play a role in apoptosis mechanisms, inhibiting the growth of breast cancer cells; however, other studies showed that its role alone was not of great importance. In the second case, its greater efficacy has been demonstrated by combining melatonin with other standard chemotherapy drugs for breast cancer therapy, such as the combination of melatonin with apatinib, neratinib and famotidine, which has been shown to act as a synergistic and potentiating agent for these drugs. Finally, melatonin has a neuroprotective effect against the adverse consequences of chemotherapy, improving sleep quality and cognitive functions. More studies are therefore needed to further the subject studied here.
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