To what extend can melatonin be used
to prevent the spreading of
Adenocarcinoma lung cancer and
metastases?
1st semester project, International Bachelor in Natural Science
Supervisor: Steffen Jørgensen
Group 6:
Angelucci Sara, angelucci@ruc.dk, 73156
Mateo-Tomlinson Lucas, mateotomli@ruc.dk, 74515
Mehmeti Bardhyl, bardhyl@ruc.dk, 74274
Michalska Arianna, michalska@ruc.dk, 73150
Vigell Viveka Hannele, viveka@ruc.dk, 73172
Zangenberg Joni Kristian, jkz@ruc.dk, 73183
Abstract
Cancer is a worldwide known disease, regarded as the main cause of death in 2020.
Within the diverse types of cancer, lung cancer is the most common diagnosed and,
with the highest lethality levels. The report focuses on Adenocarcinoma lung cancer,
and the research question aims to analyse the effectiveness of melatonin, in order to
develop alternative methods to prevent the spreading, as metastases, of the cancer.
Meta-studies, in vivo and in vitro studies had been carried out and melatonin proves
to induce migration of tumor cells, by functioning as oxidative stress and apoptosis
regulator, and to reduce mesenchymal phenotype. To understand how melatonin levels
could affect the tumor in cancer patients during medicine administration, cortisol and
melatonin levels from various studies were compared, and it has been seen that cortisol
lowers melatonin levels, leading to a greater invasiveness of tumor cells. Alternatives to
melatonin were researched, and its precursor tryptophan and serotonin were regarded as
not beneficial because of serotonin’s mitogenic behaviour in tumor cells.
December 17, 2021
1
Contents
1 Dictionary
4
2 Key words
4
3 Introduction
4
4 The aim of the report
5
5 Research
question theme:
the societal effect
5
6 Background
6.1 Lung Cancer . . . . . . . . . . . . .
6.2 Metastases . . . . . . . . . . . . . .
6.3 Adenocarcinoma lung
cancer . . . . . . . . . . . . . . . .
6.4 Melatonin . . . . . . . . . . . . . .
6.4.1 Tryptophan . . . . . . . . .
6.4.2 Effects of melatonin on
Adenocarcinoma lung cancer
6.5 Risks and protective
factors . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
6
6
6
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8
8
10
. . . . . . . . . . . . . . . . . . . . .
10
. . . . . . . . . . . . . . . . . . . . .
11
7 Current treatments
12
8 Methods and results
8.1 Melatonin and cortisol levels on Adenocarcinoma lung cancer patients
compared to healthy individuals . . . . . . . . . . . . . . . . . . . . . . .
8.2 In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3 In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.4 Radio-chemotherapy and melatonin . . . . . . . . . . . . . . . . . . . . .
8.5 Results of studies on the effects of melatonin on Adenocarcinoma lung
cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6 Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.1 Radio-chemotherapy and melatonin . . . . . . . . . . . . . . . . .
12
2
12
13
13
13
14
17
19
9 Discussion:
side effects
9.1 Side effects of melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.2 Could tryptophan be an efficient melatonin
substitute? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
19
21
10 Conclusion
22
11 Perspective Discussion
23
12 Bibliography
24
3
1
NSCLC, carcinoma, mesenchymal transition (EMT), serotonin.
Dictionary
A549 cells - Adenocarcinomic human
alveolar basal epithelial cells, used as
models for the study of lung cancer
and the development of drug therapies
against it.
3
Cancer is a leading cause of death worldwide, accounting for nearly 10 million
deaths in 2020. Amongst the most common is lung cancer, of which 2.21 million cases were diagnosed and 1.80 million deaths recorded. Cancer is also one
of the diseases that most affects the body,
not only physically, but also socially and
emotionally: depression, lack of self esteem due to medicines changing the body
(such as hair loss due to chemotherapy),
are some of the issues carried by cancer.
It is for this reason that we have decided
to focus on this topic, specifically Adenocarcinoma lung cancer, one of the most
common types of lung cancer (Ferlay J et
al., 2020).
Melatonin is an hormone secreted by
the pineal gland. Its scope is to regulate the circadian rhythm (which also
includes the wake-sleep cycle), amongst
many other crucial biological processes.
A study carried out by Chiru et al.
showed that melatonin deficiency may increase the chances of cancer being developed (Chiru et al., 2014). Melatonin deficiency could be caused by different health
conditions such as dementia, type 2 diabetes, severe pain and chronic sleep deprivation. Studies by Hardeland also show
that melatonin secretion and levels lower
gradually as we age (Hardeland, 2012).
Melatonin has been demonstrated by
several studies, such as Pourhanifeh et
al., to reduce the growth of lung cancer
Glycoprotein – Complex molecules
found in the cell membrane, with distinct functions such as cell recognition,
gateways for macromolecules and, receptors for chemical signaling.
Neoplastic disease – An abnormal
growth of cells, more commonly known
as tumor.
TP53 gene - It provides instructions
to make a protein called tumor protein
p53, which acts as a tumor suppressor,
regulating cell division by keeping cells
from proliferating too fast or in an
uncontrolled way.
SCID mice - SCID mean Severe Combined Immunodeficient mice. These mice
lack of T and B cells, which are essential
to the correct functioning of the immune
system.
2
Introduction
Key words
Melatonin, Adenocarcinoma lung cancer,
cancer, lung cancer, tumor, apoptosis,
circadian rhythm, A549 cells, proliferation, chemotherapy, radiotherapy, hormone, wake-sleep cycle, cortisol, tryptophan, in vivo, in vitro, pineal gland,
4
metastases (Pourhanifeh et al., 2019).
4
ported that anxiety levels associated with
cancer appeared to fluctuate during the
course of treatment in patients, and a
similar trend was also found by a literature review on psychological functioning in cancer patients treated with radiotherapy. Two literature review articles
on age differences in psychological impact
of cancer showed that the detrimental
psychological impact of cancer was less
pronounced in older patients than it was
in younger patients; however, the results
were not conclusive because of methodological limitations within each primary
study (Okamoto et al., 2012). The systematic appraisal revealed that the psychological impact of cancer has been
studied to a considerable extent; however, it did not identify reviews regarding
everyday emotional and psychological aspects of having cancer and strategies patients can use to manage these problems
in everyday life (Okamoto et al., 2012).
Lin and Bauer-Wu concluded in their
integrative review that patients with an
enhanced sense of psycho-spiritual wellbeing can cope more effectively with the
process of terminal illness and to find
meaning in living with cancer and that
psycho-spiritual well-being can be enhanced by prognostic awareness, family
and social support, autonomy, hope and
meaning in life (Lin Assistant Professor Bauer-Wu, 2003). The systematic
appraisal also demonstrated that there
have been many intervention studies conducted in this area. For example, a literature review reported that interventions
on patients’ psychological well-being were
not consistently effective, while another
The aim of the report
The aim of this project is to perform a literature based investigation on
whether ingesting or injecting melatonin
is an effective method of reducing cancer growth in Adenocarcinoma lung cancer and metastases.
The research question is, as the title of
the report states, to what extent can
melatonin be used to prevent the spreading of Adenocarcinoma lung cancer and
metastases?
5
Research
question theme:
the societal effect
According to a conceptual and empirical review on post-traumatic stress disorder (PTSD) following cancer, a considerable proportion of cancer patients suffer
PTSD symptoms, and a literature review
on studies of psychological aspects of
lung cancer showed that lung cancer patients have an elevated risk of psychosocial problems after diagnosis and treatment (Okamoto et al., 2012). One of the
findings of a systematic review on depression in patients with advanced cancer and
amongst mixed hospice populations was
that approximately 15% of palliative care
inpatients experienced major depression
(Okamoto et al., 2012). Regarding the
impact of anxiety, a systematic review re5
literature review suggested that psychosocial interventions could reduce the degree of depression for lung cancer patients.
A Cochrane review of studies on the
QOL (quality of life) of patients with
lung cancer showed that some interventions (e.g., nursing interventions to manage breathlessness, nurse follow-up, counselling) might be effective, although the
evidence was not conclusive (Liu Hengyu
Liu Zihang Mai, 2020). Lin Assistant
Professor Bauer-Wu and Liu Hengyu Liu
Zihang Mai reviews, however, pointed
out methodological limitations with primary studies. In terms of patients’ information needs, only a minority of primary
studies employed previously validated instruments, and very few utilized longitudinal study designs, which made it difficult to assess how patients’ needs and information sources may change over time.
Many of the interventions tested on lung
cancer patients in the trials had a number
of different components, any one or combination of which may or may not have
produced a positive or negative effect.
6
6.1
mas derive from transformed malignant
cells that originate as epithelial cells, or
from tissues composed of epithelial cells.
Thus, line the surface of the body including the outer layer of the skin, organ lining, or glands (Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version
- National Cancer Institute, 2021).
Other types of lung cancers exist, such
as the rare sarcomas of the lung, which
are created by the changing of connective tissues, caused by mesenchymal cells (adult stem cells, such as
in bone marrow). However, this report will focus on analysing Adenocarcinoma lung cancer, thus other types of
cancers will not be explained any further (Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version - National Cancer Institute, 2021).
6.2
Metastases
Tumour cells’ spreading from the primary site to the blood vessels and the
pathways they take are introduced.
Therefore, accurateness of inhibition
processes that melatonin takes will be
understood.
Background
Metastases is the spreading of cancer cells
after the primary tumour is formed. Occurs because metastatic cells can break
free from the primary tumour and adapt
to microenvironments of diverse tissues
(Su et al., 2017).
Lung Cancer
In order to introduce report’s main topic,
general knowledge about the disease is
introduced.
Lung cancer, scientifically known as
Bronchial carcinoma, is a disease caused
by uncontrolled cell growth in tissues, in
this case in the lungs. Lung carcino6
The importance of extracellular matrix
(ECM) components and the interaction
between adjacent cells must be introduced in order to contextualize how
metastases spreads. When the tumor is
formed in the primary site, tumor cells’
lack of adhesiveness in abundance, dissociation from the site occurs. This characteristic is seen in tight junctions (TJ)
and adherens junctions (AJ) (Figure 1)
(Su et al., 2017).
In the first beginning of the migratory process, which occurs in AJ, epithelial to mesenchymal transition (EMT) activates. This term is used the describe
the change of polarity in epithelial cells
in order to adapt to a mesenchymal phenotype (a loosely organized tissue, characterized in tumor cells). Then, vimentin
(glycoproteins that affect cell-cell adhesion related to the correct heart pumping) expression and N-cadherin (protein
from mesenchymal cells that form their
cytoskeleton) production is triggered.
Meanwhile, E-cadherins reduce in
amount (glycoprotein involved in cellcell adhesion, which assures proper tissue
separation, cellular migration, and positioning the cells throughout the development) (Chao et al., 2019). Is important
that E-cadherins expression is in its highest, therefore, migration and metastases
is impeded; whereas if their amount lowers, cancer cells will be greatly invasive
(Su et al., 2017). In EMT, transcription
factors are involved, and thus, enhance
the first stages of metastases by inhibiting E-cadherin synthesis when they bind
to the promoter region of the E-cadherin
(Figure 2) (Chao et al., 2019).
Figure 1: Process of how tumor metastases are formed.
Compared to the average, it is unusual that cells acquire
such invasive property. The figure represents how tumor
cells escape from the primary site (which is in the extracellular matrix bounded to the endothelial cells, making
up the barrier between tissues and blood vessels). This
process is known as intravasation. When tumor cells are
in contact with the bloodstream, they begin extravasation,
and proliferate causing metastases. Moreover, plenty of
cells fail the second process and undergo cell death (Su
et al., 2017). Figure taken from the cited article.
When genetic factors are being altered,
oncogenesis is triggered, whereas when
epigenetic alterations occur due to aging, heritable changes affect the gene expression, and consequently, function of
the cell is changed (Paoletti, 2013). Tumor cells are characterized for not being adhesive, have greater invasiveness,
survival and intravasation (escaping of
cancer cells from the primary site into
the blood or lymphatic vessel in the vascular system, larger proliferation, and
even extravasation (escaping of cancer
cells from vessels to the tissues) in other
sites. Therefore, metastases do not occur
randomly, since the spread depends on
haemodynamic factors, being the blood
flow in organs and tissues, and vascular
drainage, determined by the primary site
(Coghlin Murray, 2010).
7
cinoma subtype (Non-Small Cell Lung
Cancer Treatment (PDQ®)–Patient
Version - National Cancer Institute,
2021).
Adenocarcinoma lung cancer
originates in glandular cells that produce
biological compounds such as mucus, and
they tend to grow slower than other lung
cancers (Non-Small Cell Lung Cancer
Treatment (PDQ®)–Patient Version National Cancer Institute, 2021).
Figure 2: Schematic insight into epithelial-mesenchymal
transition (EMT). When epithelial cells lose their characteristics, which are distribution of cell-cell junctions,
they switch into tumor cells (Su et al., 2017). Figure
taken from the cited article.
6.4
Melatonin (also known as N-acetyl-5methoxytryptamine) is a hormone primarily released by the pineal gland (in
the brain) at night, and has long been
associated with control of the sleep–wake
cycle. It is an indolic compound (aromatic heterocyclic organic compound)
and it is also produced in other organs
such as skin, the retina, the gastrointestinal tract, and the lymphocytes (Pourhanifeh et al., 2019). In the pineal gland, our
body starts the production of melatonin
from tryptophan to serotonin, and from
serotonin to melatonin (Figure 3), once it
has gotten a stimulus from the superior
cervical ganglion, stimulated from the
suprachiasmatic nucleus (SCN), which is
stimulated, in turn, from the retina (Figure 4).
The other factor to take into consideration while metastases occurs in NonSmall Cell Lung Cancer (NSCLC), is
that due to the alteration in structure
of the epithelial cells, the cancer cells
can acquire great invasiveness (Su et al.,
2017). Tyrosine kinases (RTKs), enzyme
which transfers a phosphate group from
ATP molecule to other proteins,which are
stimulated and, therefore, activate other
pathways, including mitogen-activated
protein kinase (MAPK). MAPK is significantly invasive since it regulates cells’
proliferation, differentiation and death
and gene expression. When cancer is in
an advanced stage, it leads to metastases
and tumorigenesis and, in some cases,
epithelial cells begin a second round of
EMT (Chao et al., 2019).
6.3
Melatonin
Adenocarcinoma lung
cancer
Adenocarcinoma is a subtype of cancer
that has a glandular origin. Nearly 40%
of lung cancers are part of the Adenocar8
Figure 4: Pathway for melatonin synthesis to start.
Retina gets stimulus either from light or darkness. Light
inhibiting and darkness stimulating melatonin production. The retina sends the message to the suprachiasmatic nucleus, where it continues to superior ganglion,
and finally to the pineal gland, where the melatonin production from tryptophan starts.
Figure 3: Melatonin synthesis pathway and hepatic metabolization, the synthesis from tryptophan to melatonin. The enzymes are written in italic and the derived
molecules are underlined (Amaral Cipolla-Neto, 2018).
Figure taken from the cited article.
Melatonin is produced according to the
light and dark stimuli that the retina
gives (Amaral Cipolla-Neto, 2018). During the dark time norepinephrine quantity (a chemical that gives the starting message for melatonin production) is
higher than in light (Amaral CipollaNeto, 2018). Melatonin produced in the
pineal gland gets secreted into the cerebrospinal fluid and to the bloodstream,
where it goes to all cells needed (Amaral
F, Cipolla-Neto J, 2018).
Melatonin and its precursor tryptophan are both present in a variety of foods, and they may contribute
to melatonin blood levels but otherwise, extrapineal (produced outside the
pineal gland) melatonin rarely enters
the circulation (Pandi-Perumal S, Cardinali D, Reiter R, Brown G, 2020).
This extrapineal melatonin functions lo-
cally as a a cell protector in antioxidative processes, immunomodulation,
and haematopoiesis (the process through
which blood cells are produced). Moreover, through receptor-dependent and
receptor-independent mechanisms, melatonin has important oncostatic (that
halts the spread of cancer) properties (Li
et al., 2017) most important being the
apoptotic pathway ragulating that will be
discussed more in section 6.4.2(Effects of
melatonin on adenocarsinoma lung cancer). It also has anti-inflammatory effects caused by its ability to stimulate
monocyte/macrophage, lymphocyte, and
natural killer cells to increase immunosurveillance (Pourhanifeh et al., 2019).
9
6.4.1
totic pathways and the proliferation of
tumour cells (Figure 5) (Pourhanifeh et
al., 2019). Melatonin up-regulates bax
expression, a protein that functions as
an apoptotic activator. This leads to the
leak of cytochrome C, a small hemeprotein that is known for its function in ATP
synthesis inside mitochondria, and its
part in apoptotic pathway when outside
mitochondria. Once the cytochrome C
gets outside of the mitochondria, it starts
reacting with APAF-1 (an apoptotic protease Activation factor 1). Apoptosomes
are formed, activating the enzyme procaspase 9 followed by the activation of
caspase-9, -3 and -7, finally leading to the
cancer cells death, apoptosis.
Tryptophan
Tryptophan is an amino acid that our
body needs to create several important
molecules, including serotonin and melatonin. Other compounds it acts as a
precursor of are kynurenine, auxin and
niacin. Humans cannot produce it by
themselves, so it needs to be administrated from the diet or by supplementation. Low tryptophan levels can influence
melatonin levels, leading to detrimental
effects.
Although melatonin is synthesized in
pineal cells (pinealocytes) from tryptophan, pineal tryptophan concentrations
do not control melatonin synthesis. The
activation is produced by sympathetic
nerve endings that terminate on pinealocytes (Fernstrom J, 2016). Therefore,
the increase in tryptophan levels in the
pineal gland might not lead to higher concentrations of melatonin. On the other
hand, tryptophan levels impact the melatonin synthesis in the enterochromaffin
(EC) cells throughout the gastrointestinal differently. It has been reported that
the EC cells are the major source of Ltryptophan-induced increase of circulating melatonin, being made 400-500 times
more than in the pineal gland (Chen,
Fichna J, Bashashati M, Li Y, Storr M,
2011) (Pandi-Perumal S, Cardinali D,
Reiter R, Brown G, 2020).
6.4.2
Figure 5: Melatonin up-regulates bax expression, starting
the apoptotic pathway, which leads to the leaking of cytochrome C. Once the cytochrome C is out of the mithocondria, it reacts with APAF-1(an apoptotic protease Activation factor 1), and apoptosomes are formed.
Through reinforcing the therapeutic effects and reducing the side effects of
chemotherapies and radiation, melatonin
has shown the potential to be utilized as
an adjuvant for cancer therapies, which
will be analysed more in depth in further section (Li et al., 2017). Among
Effects of melatonin on
Adenocarcinoma lung cancer
In NSCLC, melatonin works as a metastasis inhibitor as well as an oxidative
stress regulator. It affects the apop10
its factors, the ability to prevent cancer, with an inhibitory effect involving
both independent mechanisms and membrane receptor-dependent at initiation,
promotion, progression, and malignant
metastasis phases, can be highlighted
(Menéndez-Menéndez Martínez-Campa,
2018).
Patients with Adenocarcinoma lung
cancer (the same is for patients affected
by other types of cancer) are known
to have abnormal and unbalanced levels of hormones. In these tumour conditions, endogenous melatonin levels are
lower than they should be, thus the patients lose the circadian rhythm (Wang
et al., 2018). Also, some NSCLC cells
(including Adenocarcinoma lung cancer
cells) might have the KRAS mutation,
which is known for its infamous attribute
of making the cancer cells quickly gain
resistance against almost every kind of
therapy used to eradicate the cancer
cells, thus rendering the KRAS mutationbearing NSCLC cells the hardest to treat.
Recent studies have shown it may be
vulnerable to immunotherapy. Furthermore, these studies have shown that if
immunotherapy and melatonin get combined, metastases spread and growth will
slow down or even completely shut down
(Chao et al., 2019).
6.5
ing prevalence are achieved, lung cancer will remain among the top causes of
death. Other risk factors include alcohol, air pollution such as emissions rich
in various polycyclic aromatic hydrocarbon compounds, which is estimated to
cause 11% of lung cancer cases in Europe; and occupational exposure, by exposing workers in several work settings
to carcinogens, leading to an increased
risk of lung cancers (Molina et al., 2008).
Familial clustering of lung cancer has
been reported repeatedly in the past 60
years, giving enough evidence to suggest
a hereditary base to disease development.
An increased risk of lung cancer was
found in the carriers of TP53 germline
sequence variations (it provides instructions to make a protein called tumor protein p53, acting as a tumor suppressor,
regulating cell division), and carriers who
smoked cigarettes are three times more
likely to develop lung cancer than carriers
who did not. Cured meat (sausage, cured
pork, pressed duck), deep-fried cooking,
have been associated with an increased
lung cancer risk (Molina et al., 2008).
Among the protective factors, physical activity is said to lower about a 13%
to 30% the chance of developing lung
cancer (Molina et al., 2008). Lung cancer screening in individuals at risk could
interrupt, prevent, or delay lung cancer
progression; however, no current guidelines recommend mass screening for early
detection of lung cancer. Diet and food
supplements play an important role, such
as fruit and vegetables, lutein, zeaxanthin, lycopene, vitamins C and E, and
-carotene displayed a certain protective
Risks and protective
factors
Both smoking and passive smoking are
among the risk factors that could increase
the chance of developing lung cancer,
and unless radical reductions in smok11
trend (Molina et al., 2008).
7
In fact, several negative studies have
compared standard chemotherapy double
tand targeted therapy (including agents
such as EGFR inhibitors, a substance
that blocks the activity of a protein
called epidermal growth factor receptor,
antisense molecules, and immune modulators) to first-line regimens (Molina et
al., 2008).
Current treatments
Surgical resection remains the single most
consistent and successful option for cure
for patients, predicated on achieving a
complete resection. The cancer must
be completely resectable and the patient
must be able to tolerate the proposed surgical intervention, for this option to be
feasible. Among the issues of resectability, the preoperative staging including
imaging studies and biopsy are found,
whereas issues of operability include the
evaluation of operative approaches and
patient factors that minimize surgical
risk and morbidity. Lobectomy is the current criterion standard for resectable tumours (Molina et al., 2008).
Chemotherapy is beneficial for palliation in patients with locally advanced
and metastatic disease. There is a sense
that the use of traditional chemotherapeutic agents has reached a therapeutic
plateau, although chemotherapy is appropriate for many patients with lung
cancer (Molina et al., 2008). A metaanalysis conducted in 1995 used updated
data on patients from 52 randomized
clinical trials to compare outcomes after
surgery alone without comes of surgery
followed by chemotherapy. The metaanalysis showed a 5-year survival benefit of borderline significance for patients
receiving platinum-based chemotherapy
(Molina et al., 2008).
Previous attempts to combine
chemotherapy and targeted therapy in
lung cancer have been unsuccessful.
8
8.1
Methods and results
Melatonin and cortisol
levels
on
Adenocarcinoma
lung
cancer
patients compared to
healthy individuals
Cortisol, being the antagonist of melatonin (cortisol is a hormone produced
by the adrenal glands, specially in the
fasciculated area of their cortical portion; it is a steroid-type hormone, deriving from cholesterol, that belongs to the
category of glucocorticoids), plays a vital role in the sleep-wake cycle as well
(Mazzoccoli et al., 2005). It is known
that serum endogenous (produced/ secreted/ originated from and inside the organism) melatonin levels vary in humans
from age to age. Therefore, studies aimed
to analyse the correlation between melatonin and cortisol levels, and the impact
it has on cancer patients (Jung Ahmad,
2006).
Mazzoccoli et al. seeked to analyze
melatonin secretion levels are in each
lung cancer stage. The collection of
blood samples was carried out every four
12
hours for 24 hours from 17 healthy subjects (mean age=68.8), 17 lung cancer
I-II stage subjects (mean age=67.2), 17
lung cancer III-IV stage subjects (mean
age=69.5). Hence, melatonin and cortisol serum levels were analyzed (Mazzoccoli et al., 2005).
8.2
(protein required for TJ to have a proper
adhesiveness) in A549 cells.Therefore,
immunofluorescence detection was carried out using 96 well plates. Before the
immunofluorescence, a controlled group
was treated with DMSO, and melatonin
groups were made according to the different concentration (0.1mM to 2mM).
After 7 days, the samples were prepared for the immunofluorescences assay. Throughout the preparation process, A549 cells were incubated with goat
anti-human occludin primary antibodies
overnight (Zhou et al., 2014).
In vitro studies
A study carried out by Zhou Q et al.
seeks to investigate melatonin’s ability
to regulate cell proliferation in the A549
cell line by interaction among proteins located in the tight junctions (TJ). The
used compound was prepared in vitro,
where A549 cells were cultured with different melatonin concentrations (0.1, 0.5,
0.75, 1.0, 2.5, 5.0 mmol/L). Thus, were
incubated for 4 hours (Zhou Q, Gui S,
Zhou Q et al., 2014).
The same team did a wound healing assay to assess the migration of A549 cells
when in contact with melatonin. The experiment was done by adding A549 cells
to 12 well plates and grown to cover the
plates fully. Then, a line was scraped in
the cell culture, in order to add DMSO
(dimethyl sulfoxide) and different melatonin concentrations (0.1mM, 0.75mM,
2.5mM and 5mM). 0h, 12h and 24h the
cultures were photographed with a 10x
photomicroscope (Zhou Q, Gui S, Zhou
Q et al., 2014).
The prior experiment was repeated
but this time using a JNK pathway inhibitor (SP600125) and a MAPK activator PMA (Phorbol-12-myristate-13acetate) to investigate whether JNK
pathway is related to A549 cells’ migration ability by analysing occludin levels
8.3
In vivo studies
Another research by Chao et al., aimed
to show that apoptosis is induced in cancer cells and EMT phenotype was attenuated. In order to prove the statement, in
vivo study was carried out in six to eight
years old male SCID mice by injecting
A549-Luc cells in their lung. After two
weeks, three groups of mice were separated, one of them being the controlled
group. The other two groups of mice were
administered with melatonin, one of the
groups with 5mg, and the other one with
20mg. Weekly, cancer progression in each
mouse was compared in the eighth week
(Chao et al., 2019).
8.4
Radio-chemotherapy and
melatonin
Melatonin’s effect on tumor cells when
patients are on treatment, analysis of
side effects and 1-year survival.
13
Several studies were gathered in one
to compute percentages on how effective melatonin is on radio-chemotherapy
treated cancer patients. Data was collected helped by an electronic search in
several databases from inception until the
latest updates from 2011. This was analyzed by conducting randomized controlled trials (RCTs), to compare melatonin’s efficiency in tumor and side effect
attenuation. The followed criteria were
the followed:
8.5
Results of studies on
the effects of melatonin
on Adenocarcinoma lung
cancer
Melatonin and cortisol levels on
Adenocarcinoma lung cancer patients compared to healthy individuals
Jung Ahmad have observed that young
to middle aged people have a high secretion rate of melatonin (54-75 pg/mL),
whereas the age goes up, the levels of
melatonin get lower (18-40 pg/mL) (Jung
Ahmad, 2006). There was also found that
endogenous and exogenous (produced, secreted, or originated from outside the
organism) half-life of melatonin in the
serum is different. Endogenous melatonin in the serum has a half-life of 3060 minutes meanwhile the half-life of exogenous melatonin is lower, about 1248 minutes. This is because 50% to
70% of the endogenous melatonin in the
blood is reversibly bonded to albumin
(protein present in the blood serum) and
glycoproteins. Thus, endogenous melatonin is capable of being stored, whereas
exogenous melatonin is completely excreted out of the system. Melatonin
is metabolized in the liver (through cytochrome P450/enzyme CYP1A2 which
is a member of the cytochrome P450 superfamily of enzymes that catalyze reactions such as synthesis of lipids and drug
metabolism), and no more than 10% of
melatonin goes unmetabolized, therefore,
it does not put a strain on the excretory
system (Jung Ahmad, 2006).
-Studies had to be controlled and random.
-The participants were pathologyconfirmed malignancy patients, where all
ages, genders and tumor stages were not
excluded during sampling process.
-Details about tumor attenuation, 1 year
survival, and side effects of chemoradiotherapy were to be analyzed.
-Trials had to use melatonin in the
current treatment of radiotherapy and
chemotherapy.
Out of the 988 results from databases, 74
articles were analyzed in depth by two investigators, who also extracted data and
after approval of the 8 final RCTs, a
meta-study was carried out. In each of
those RCTs, 20mg of melatonin dose was
used orally.
14
Table 1: Melatonin and cortisol secretion values were compared to find a possible dependence on one another. Melatonin
levels in healthy individuals is observed to be higher than cortisol levels. The more advanced stage of cancer it is, the
lower melatonin levels, and the higher in cortisol levels are (Mazzoccoli et al., 2005). Table taken from the cited article.
Table 2: Chronobiological data derived from the best-fitting sine curves. Results of the tests of melatonin and cortisol
levels on healthy and diseased individuals have been compared proving even further that the more advanced the stage of
cancer it is, the lower melatonin level, the higher cortisol levels and disrupted cicardian rhithmicity of both (Mazzoccoli
et al., 2005). Table taken from the cited article.
Mazzocoli et al. noticed different levels
in melatonin and cortisol secretion levels
between these subjects, as shown in table
1 and 2. As the stage of the cancer advances, melatonin levels decrease and cortisol levels increase, leading to a change
in the melatonin/cortisol ratio (Mazzoccoli et al., 2005)
Melatonin levels are lower in the IIIIV lung cancer stage, but these lung cancer patients still maintain the circadian
rhythm of melatonin secretion, although
melatonin levels in the body are not high
enough. It cannot be said the same
for circadian rhythm of cortisol secretion,
which does not follow the proper timing of when cortisol should be secreted,
as shown in figure 6 (Mazzoccoli et al.,
2005).
This altered pattern of cortisol secretion leads to lower levels of melatonin secretion. It was concluded that
it was because of a change in the
CNS (Central Nervous System) regulatory mechanisms.
The regulatory
mechanisms that are compromised are:
the pineal gland, down-regulating the
processes of hypothalamus-hypophysis15
adrenal axis, and melatonin, which directly inhibits the function glucocorticoid
receptors (also known as GR or GCR, receptors to which glucocorticoids bind and
modulate immune response processes).
This leads to a lowering in cortisol levels and its effects (Rosa Maria Sainz
et al., 1999). On the other hand, the
adrenal corticosteroids (in this case cortisol) down-regulate the pineal gland activity/melatonin secretion. Dexamethasone is a corticosteroid synthesized by
our own body, with anti-inflammation
and immunosuppressant properties, also
used to treat conditions associated with
NSCLC and other diseases. It is administered to most Adenocarcinoma lung
cancer patients. This compound, upregulates glucocorticoid receptors, therefore, it increases self-induced apoptosis in
T-cells and alters the cortisol secretion
(Rosa Maria Sainz et al., 1999).
The study concludes that anomalies of these two neuro-endocrine compounds are present in Adenocarcinoma
lung cancer patients, and that it is necessary to regulate melatonin levels through
medication without altering even further
the secretion of cortisol. Dexamethasone is an example of an efficient antiinflammatory medication used to treat
complications that are associated with
NSCLC, but exposure to it, leads to
altered melatonin/cortisol secretion levels. Administration of such medications
should be done in a way that does not
bring imbalances in melatonin/cortisol
secretion ratio, and by doing that the risk
of spreading of already existing metastases is lowered along with the risk of a
Figure 6: 24-hour profiles of serum melatonin and cortisol levels in healthy subjects and lung cancer patients
at various stages of disease were analyzed. And assuring
the prior tables outcomes, cortisol levels are found to be
higher in more advanced lung cancer patients compared
to healthy individuals (Mazzoccoli et al.). Figure taken
from the cited article.
neoplastic disease (the abnormal growth
of cells), more commonly known as tumor
being born (Mazzoccoli et al., 2005).
16
cells turned back into epithelial cells.
Bioluminiscence records and dissection outcomes support that 20mg intake was the most effective one in order to attenuate tumour cells’ invasion
(Figure 9). The study also analyzed Ncharderin levels in the different melatonin
intakes (Figure 10). Antibody production is observed to be lower in mice that
were administered with 20mg dosage.
Shortly, 20mg administration was proved
to be the most efficient tumour suppressor (Chao et al., 2019).
In vitro studies
The study by Zhou Q et al. analysed the
inhibition rates after 4 hours have passed
(table 3). Inhibition was 66.65% higher in
5.00 mmol/L concentration compared to
0.1 mmol/L concentration. Therefore, it
was concluded that a high dose of melatonin alone can inhibit the proliferations
of A549 cells (Zhou Q, Gui S, Zhou Q et
al., 2014).
In the wound healing assay Zhou Q
et al. carried out, results show that high
concentration of melatonin can inhibit
the migration of A549 cells almost completely supporting the results of the MTT
assay (Figure 7) (Zhou et al., 2014).
When the same method was executed
with the JNK pathway inhibitor, the controlled group showed no occludin proteins
on the cell surface, whereas both 0.1mM
and 2mM melatonin groups showed an up
regulation of occludin proteins on the cell
surface (Figure 8). Zhou Q et al. concluded that PMA could downplay the effects of melatonin and SP600125. Therefore, SP600125 was able to inhibit the migration of A549 cells, suggesting that the
JNK pathway plays a role in the migration of A549 cells (Zhou et al., 2014).
8.6
Metastases
Effects of melatonin on metastases and
analysis of its inhibitory actions.
Melatonin was shown to inhibit the invasiveness of cancer by regulating those
cells which oversee the adhesion in TJ
and AJ by impeding tumour cells to
break free from the primary site. EMT
and migration is slowed down when
melatonin interferes in the transcription
factors, since they negatively affect Ecadherin’s expression. Meanwhile, vimentin’s production shuts down, therefore, mesenchymal phenotype on cells is
suppressed (Su et al., 2017).
In vivo studies
In the research Chao et al. carried out,
mice with 0mg, 5mg, and 20mg dosages
were administered, and outcomes were
analyzed and compared.
It was observed that EMT phenotype
decreased due to the suppression of the
regulators of A549 cells by melatonin’s
main receptors. Therefore, mesenchymal
17
Table 3: inhibition rates are analysed after culturing A549 adenocarcinoma lung cancer cells in in vitro studies. The
content shows considerable larger inhibition in 5.00 mmol/L concentration rather than in 0.1 mmol/L concentration.
Table taken from the cited article (Zhou Q, Gui S, Zhou Q et al., 2014).
Figure 7: (A) photographies with photomicroscope were done in order to compare A549 cell migration at different concentrations of melatonin groups within 24h. It is observed that the higher concentration of melatonin is, the migration
level is lower. (B) Empirical data of the experiment was displayed into a bar plot. Data shows DMSO cell culture has
0.9 migration ratio within 24h whereas 5.0mM melatonin concentration has 0.2mM migration ration within 24 h. Figures
taken from the cited article (Zhou et al., 2014).
18
Figure 8: in order to assess the correlation between JNK pathway and A549 cells’ invasion, an immunofluorescence is
carried out. It can be observed that in picture (A) there are any occludin proteins. Moreover, in pictures (B) which is
the 0.1mM group and (C)which is 2mM group, occludin proteins are present on the cell surface (thus can be seen as little
dots surrounding the cell). Figures taken from the cited article (Zhou et al., 2014).
8.6.1
Radio-chemotherapy
melatonin
9
and
Wang et al. represented the trial quality, where patients’ status was updated,
usage of placebo was analyzed and the
loss of participants. General information
about each study, study groups’ characteristics and baseline, melatonin dosages,
types of tumors, intervention, and results
in table 4 were described (Wang et al.,
2012).
In this study it was concluded that
melatonin is an efficient source to prevent neoplastic diseases, it has protected healthy cells from radiation and
chemotherapy related damage due to its
antioxidant property, and therefore, significantly attenuate side effects of treatment and prolonged survival.
9.1
Discussion:
side effects
Side effects of melatonin
Even though a limited number of meta
studies have been conducted, melatonin
causes very few side effects when looking
at its short-term consumption (3 months
at low dosages).
Two studies found no adverse effects
of exogenous melatonin in several clinical
trials, and comparative trials found the
adverse effects headaches, dizziness, nausea, and drowsiness were reported about
equally for both melatonin and a placebo
control (Buscemi et al., 2006). This suggests that melatonin might not have as
much of a drowsiness-like effect as people think it does, and it indicates that
it might be due to a psychosomatic phenomenon more than anything.
In addition, prolonged-release melatonin is safe with long-term use of up
to 12 months (Lyseng-Williamson KA,
2012).
19
Figure 9: (A) After tumour cells were injected into mice, each weeks’ bioluminescence record was done to compare the
difference between 0mg, 5mg and 20mg dosages. (B) After those 8 weeks, the mice were sacrificed to photograph the lungs
and the livers and reach to a conclusion. 20mg dosage was the most effective way to attenuate migration of cancer cells,
whereas the effect of 5mg, which is the usual quantity used in sleep pills, was much less effective as we can see in picture
(B) in the dissection (Chao et al., 2019). Figures taken from the cited article.
Figure 10: to argue the attenuation of migration levels of cancer cells, N-cadherin’s antibody levels were analysed from
the dissections taken from the lung of the scarified mice. Melatonin treated mice shown a better response toward tumour
cells rather than the controlled group. This occurs due to the signalling cascades, reducing EMT phenotype and further
dispersion of migrative cells (Chao et al., 2019). Figures taken from the cited article.
Table 4: analysis of melatonin’s effectiveness on radiochemotherapy treatment supported by a meta-study. Outcomes
of the side effects were compared side-by-side between a melatonin group and a controlled group. In comparison to the
controlled group, positive outcomes have been observed from the RCTs, which include 1-year survival, and significant
decrease on cancer side-effects. This table is based on data from the cited article (Wang et al., 2012).
20
This study was conducted on patients
older or equal to 55 years of age, elucidating that even on a “weaker” population immunity wise, melatonin doesn’t
cause many notable side effects. Although not recommended for long-term
use beyond this. However, this was since
26% of the melatonin used in this study
contained serotonin, a hormone that can
have harmful effects even at low levels.
Low-dose melatonin is safer, and a better
alternative, than many prescriptions and
over-the-counter sleep aids if a sleeping
medication must be used for an extended
period.
There is emerging evidence that the
timing of taking exogenous melatonin in
relation to food is also a crucial factor.
Specifically, taking exogenous melatonin
shortly after a meal is correlated with impaired glucose tolerance, possibly causing
symptoms like a dry mouth, feeling very
thirsty, and a frequent need to urinioSastre and colleagues recommend waiting
at least 2 hours after the last meal before
taking a melatonin supplement (Garaulet
M et al., 2020).
As for negative side effects, melatonin
can cause nausea, next-day grogginess,
and irritability (Bauer B, 2020). In the
elderly, it can cause reduced blood flow
hypothermia (however, this research is
not very reliable due to the age of the
studies investigating this). In terms of
giving the melatonin to a person with
other autoimmune disorders, evidence is
conflicting (Terry PD et al., 2009).
Furthermore, there are additional
safety concerns for an older population;
the 2015 guidelines by the American
Academy of Sleep Medicine recommend
against melatonin use by people with dementia, as melatonin may stay active in
older people longer than in younger people and cause daytime drowsiness.
In terms of immunological related side
effects, while it is known that melatonin
interacts with the immune system, the
details of those interactions are unclear.
An anti-inflammatory effect seems to be
the most relevant. There have been few
trials designed to judge the effectiveness
of melatonin in disease treatment. Most
existing data are based on small, incomplete trials. Any positive immunological effect is thought to be the result of
melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells (Carillo-Vico A et
al., 2005).
9.2
Could tryptophan be an
efficient melatonin
substitute?
Tryptophan has been reported to be relatively safe but occasional side effects such
as tremor, nausea, and dizziness have
been reported occurring when taken,
mainly at higher doses (70-200mg/kg)
alone or with a drug that enhances serotonin function (Fernstrom J, 2012). An
increase in tryptophan levels leads to a
serotonin increase. Serotonin has been
shown to be a mitogenic factor for a wide
range of non-tumoral and tumoral cells
in culture and specific receptor subtypes
have been associated with the progression of solid tumors. Therefore, serotonin might be involved in one or more
21
fundamental stages of their progression,
growth of the primary tumor, invasion,
and dissemination up to metastasis (Sarrouilhe D, Mesnil, M, 2019). In rare
cases, as the result of too much serotonin,
the “serotonin syndrome” occurs, showing symptoms like delirium, myoclonus,
hyperthermia, and coma (Fernstrom J,
2012).
L-Tryptophan has as well been linked
to eosinophilia-myalgia syndrome (EMS).
The FDA (U.S. Food and Drug Administration) recalled tryptophan supplements
in 1989 after more than 1500 people who
took them reported becoming sick. EMS
causes sudden and severe muscle pain,
nerve damage, skin changes, and other
debilitating symptoms. However, the
EMS cases were traced back to a manufacturer whose tryptophan supplements
were tainted. Because of this, the medical
problems were due to contamination of
the supplements rather than tryptophan
itself (Woolf A, 1989).
There is still a need for further research on tryptophan, serotonin, and
melatonin safety but the studies this far
show fewer side effects from melatonin
supplement intake than from tryptophan
or serotonin. Based on the studies this
far melatonin is more effective and safer
when gotten as a supplement or from the
diet as melatonin than when synthesized
in the body from supplemental tryptophan or serotonin.
10
hibitory action is proved to be efficient.
Melatonin decreases cancer cell migration by lowering mesenchymal phenotype, leading to metastases inhibition,
and by being oxidative stress regulator.
Cortisol and melatonin levels were found
to depend on one another, which leads
to question high cortisol level medicines,
since melatonin is being inhibited by it,
and therefore, lead to tumor cells’ greater
invasiveness. In vivo and in vitro studies have a few attractive features: 20mg
melatonin dosage has shown successful
outcomes within eight weeks on reducing cancer cell migration on Adenocarcinoma lung Cancer, N-cadherin antibody
levels had been significantly lowered, and
attenuate radiochemotherapy side-effects
on patients. Tryptophan, amino acid
from which melatonin is derived, failed
to be an alternative for melatonin since
it triggers serotonin production, which
possesses migratory properties. Sideeffects produced by melatonin do rarely
occur, even when high dosages are administered, but long-period intakes should be
avoided. After all the data analysis, it
can be said that melatonin is an effective
and more economically convenient source
than current treatments and preventions
utilized. Moreover, the number of studies
is still not enough to prove its efficiency
until it is not put in practice, and it is
an alternative that should be taken into
consideration.
Conclusion
It can be concluded, to answer our
research question, that melatonin’s in22
11
Perspective
sion
Discus-
Melatonin diffusors are already used, and
they directly target lungs. So further investigation should be considered to test
effectiveness of this in Adenocarcinoma
Lung Cancer, since it directly targets the
lungs.
23
12
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