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Melatonin uses in oncology: Breast cancer prevention and reduction of the side effects of chemotherapy and radiation

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Introduction: The possible oncostatic properties of melatonin on different types of neoplasias have been studied especially in hormone-dependent adenocarcinomas. Despite the promising results of these experimental investigations, the use of melatonin in breast cancer treatment in humans is still uncommon. Areas covered: This article reviews the usefulness of this indoleamine for specific aspects of breast cancer management, particularly in reference to melatonin's antiestrogenic and antioxidant properties: i) treatments oriented to breast cancer prevention, especially when the risk factors are obesity, steroid hormone treatment or chronodisruption by exposure to light at night (LAN); ii) treatment of the side effects associated with chemo- or radiotherapy. Expert opinion: The clinical utility of melatonin depends on the appropriate identification of its actions. Because of its SERM (selective estrogen receptor modulators) and SEEM (selective estrogen enzyme modulators) properties, and its virtual absence of contraindications, melatonin could be an excellent adjuvant with the drugs currently used for breast cancer prevention (antiestrogens and antiaromatases). The antioxidant actions also make melatonin a suitable treatment to reduce oxidative stress associated with chemotherapy, especially with anthracyclines, and radiotherapy.
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1. Introduction
2. Why hormone-dependent
breast tumors are susceptible
to prevention or treatment
with melatonin?
3. Properties of melatonin
potentially useful in the
prevention and treatment of
hormone-dependent breast
cancer
4. Breast cancer risk factors
5. Breast cancer preventive
therapy
6. Melatonin and breast cancer
preventive therapy
7. Melatonin treatment of the
side effects of radio and
chemotherapy
8. Beneficial effects of
melatonin for symptoms
associated with breast cancer
or its treatment
9. Conclusion
10. Expert opinion
Review
Melatonin uses in oncology: breast
cancer prevention and reduction of
the side effects of chemotherapy
and radiation
Emilio J Sanchez-Barcelo
, Maria D Mediavilla, Carolina Alonso-Gonzalez &
Russel J Reiter
University of Cantabria, Department of Physiology & Pharmacology, Santander, Spain
Introduction: The possible oncostatic properties of melatonin on different types
of neoplasias have been studied especially in hormone-dependent adenocarci-
nomas. Despite the promising results of these experimental investigations, the
use of melatonin in breast cancer treatment in humans is still uncommon.
Areas covered: This article reviews the usefulness of this indoleamine for spe-
cific aspects of breast cancer management, particularly in reference to mela-
tonin’s antiestrogenic and antioxidant properties: i) treatments oriented to
breast cancer prevention, especially when the risk factors are obesity, steroid
hormone treatment or chronodisruption by exposure to light at night (LAN);
ii) treatment of the side effects associated with chemo- or radiotherapy.
Expert opinion: The clinical utility of melatonin depends on the appropriate
identification of its actions. Because of its SERM (selective estrogen receptor
modulators) and SEEM (selective estrogen enzyme modulators) properties,
and its virtual absence of contraindications, melatonin could be an excellent
adjuvant with the drugs currently used for breast cancer prevention (anties-
trogens and antiaromatases). The antioxidant actions also make melatonin a
suitable treatment to reduce oxidative stress associated with chemotherapy,
especially with anthracyclines, and radiotherapy
Keywords: breast cancer, chemo prevention, chemotherapy, melatonin, radiotherapy, SEEM,
SERM
Expert Opin. Investig. Drugs [Early Online]
1. Introduction
Melatonin (N-acetyl-5-methoxytryptamine) is an indolic compound secreted
mainly by the pineal gland during the dark hours at night. The circadian pattern
of pineal melatonin secretion is regulated by the biological clock which resides
in mammals within the hypothalamic suprachiasmatic nucleus (SCN). A compre-
hensive review of the physiology of this functionally diverse molecule can be found
in a recent report by Hardeland et al. [1]. The possible role of the pineal gland in the
growth of different types of tumors was hypothesized by numerous scientists during
the latter half of the last century, and different studies have been carried out to assess
the oncostatic properties of melatonin against different neoplasias including breast
cancer, leukemia, colorectal cancer, melanoma, prostate cancer, pancreatic cancer,
etc. [2]. Despite the promising outcomes of the experimental studies, the use of mel-
atonin in cancer treatment in humans is not frequent [3]. In our opinion, it is nec-
essary: i) to define which neoplasias are most susceptible of treatment with this
indolamine; ii) to describe the specific actions of melatonin in the treatment of
tumors sensitive to its actions; iii) to delimit the specific benefits achievable with
treatment with melatonin, alone or in combination with other drugs, not only in
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the treatment but in the prevention of several neoplasias.
These are the subjects that will be considered in this review.
2. Why hormone-dependent breast tumors
are susceptible to prevention or treatment
with melatonin?
One of melatonin’s actions more solidly established is the
control of reproduction in seasonal breeders, via the modu-
lation of the neuroendocrine-- reproductive axis [1].Whilea
negative effect of melatonin of the gonadal function in
humans remains questionable, there are data supporting
some effects. Thus, the onset of puberty has been related
to the decline in melatonin secretion at the age of sexual
maturation; children with precocious puberty have lower
serum melatonin than age-matched children; and melatonin
serum levels are related with amenorrhea [4,5].Furthermore,
the administration of large doses of melatonin decreases LH
and blocks ovulation [6]. Recently, a neuropeptide inhibitor
of gonadotropin secretion (GnIH) was described in an avian
species, and melatonin stimulates the release of this peptide
from hypothalamic GnIH neurons thus inhibiting gonadal
function in birds [7]. Interestingly, two GnIH homolog
(RFRP-1 and RFRP-3) have been found in human hypo-
thalamus [8], opening new insights on the possible melato-
nin regulation of the hypothalamic-- pituitary-- gonadal axis
in humans.
The former hypothesis on the possible role of the pineal
gland in breast cancer stated that, if the pineal gland, via the
secretion of melatonin, downregulates the gonadal activity,
then any reduction in melatonin synthesis, whatever its cause,
could lead to a relative increase in estrogen levels. This rise in
turn would increase the turnover of breast epithelial cells, and
aggravate the risk of malignant transformation as well as that
of the tumor promotion. Currently, the melatonin-- estradiol
interactions at cellular level, rather than changes in estradiol
levels, are considered the key to understanding the effects of
melatonin on breast cancer [2,9]. The review of the literature
on melatonin and cancer shows that, among the broad spec-
trum of tumors studied, more than 32% of the publications
are focused on mammary tumors. On the basis of the out-
comes of these studies, it is our opinion that estrogen-
dependent tumors, particularly breast cancer, are probably
the most specifically treatable with melatonin [9].
3. Properties of melatonin potentially useful
in the prevention and treatment of
hormone-dependent breast cancer
A summary of the mechanisms involved in melatonin’s onco-
static actions can be found in a recent review by Mediavilla
et al. [2]. In this section, the authors will analyze those melato-
nin properties which more directly relate to its ability to
prevent and treat breast cancer. Table 1 summarizes other
oncostatic properties of melatonin [2].
3.1 Antiestrogenic properties of melatonin
Treatment and chemoprevention of estrogen receptor posi-
tive (ER+) breast cancer is based on the use of drugs that
interact with the estrogen-signaling pathway, usually classi-
fied as selective estrogen receptor modulators (SERMs;
interfere with the action of endogenous estrogens at the level
of the ER) or selective estrogen enzyme modulators (SEEMs;
modulate the activity of enzymes involved in the synthesis or
transformation of steroids). Examples of SERMs are
tamoxifen and raloxifene. The SEEMs family include steroi-
dal (formestane, exemestane, etc.) as well as non-steroidal
(anastrozole, letrozole, etc.) compounds.
Melatonin shares properties of both SERM and SEEM mol-
ecules [9]. Melatonin, like a SERM, i) decreases the estrogen-
binding activity and the expression of ERawithout changing
its affinity, ii) reduces estradiol (E
2
)-induced ERatransactiva-
tion and iii) inhibits the binding of the complex E
2
-- ERato
the estrogen response element in DNA. Melatonin’s antiestro-
genic effects do not depend on its binding to the ER but to
high affinity MT
1
membrane melatonin receptors. MT
1
recep-
tors are expressed in human breast tumor cell lines as well as in
normal and malignant human breast tissue [9-11]. A variety of
in vivo and in vitro experiments have provided evidence for a
role of the MT
1
receptors in the antiestrogenic effects of
melatonin [10-12]. The antiestrogenic effects of melatonin also
depend on its binding to calmodulin (CaM) which regulates
ERadegradation and ERa-mediated transcriptional activa-
tion [13]. Melatonin acts as an endogenous CaM antagonist [14],
Article highlights.
.Melatonin shares properties of the selective estrogen
receptor modulators (SERM), selective estrogen enzyme
modulators (SEEM) and antioxidant compounds, without
most of their side effects.
.Melatonin, as a SEEM not only inhibits aromatase but
17b-hydroxysteroid dehydrogenase type 1 (17b-HSD1)
and estrogen sulfatase (STS) whereas increases the
activity of estrogen sulfotransferase (EST).
.Associated with antiaromatases, melatonin could reduce
osteoporosis induced by these drugs, potentiate the
effects of the antiaromatase and add its own
SEEM actions.
.Melatonin belongs to the antioxidant group of
radioprotectors and reduces the side effects
of radiotherapy.
.As an adjuvant therapy, melatonin protects against the
side effects of chemotherapeutic drugs and, in some
cases, potentiates their oncostatic effects.
.Light at night (LAN) disrupts the nocturnal secretion of
melatonin, a fact that is being considered as a risk
factor for breast cancer.
.Melatonin should be considered as an adjuvant therapy
for cancer prevention in women at risk for obesity,
hormonal treatments or circadian disruption by LAN.
This box summarizes key points contained in the article.
E. J. Sanchez-Barcelo et al.
2Expert Opin. Investig. Drugs [Early Online]
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blocking the E
2
-induced transactivation of ERabut not that of
ERbwhich does not bind CaM [15]. Retinoic acid-related
orphan receptor alpha (RORa) enhances ERatransactivation
induced by E
2
; melatonin indirectly inhibits these effects prob-
ably throughout its actions as CaM antagonist [16]. Differences
between melatonin’s affinities to MT
1
receptors and CaM
(20 -- 40 and 180 pM, respectively) could be relevant in the
selection of the therapeutic doses of this indoleamine.
Melatonin (Figure 1), as a SEEM, inhibits the expression
and activity of P450 aromatase, 17b-hydroxysteroid dehydro-
genase type 1 (17b-HSD1) and estrogen sulfatase (STS), three
enzymes involved in the synthesis or transformation of biolo-
gically active estrogens from androgens or estrogens with low
biological activity. By contrast, melatonin increases the exp-
ression and activity of estrogen sulfotransferase (EST), which
catalyzes the conversion of estrogens into inactive sulfate con-
jugates. In this way, melatonin could reverse the increased
expression of aromatase, 17b-HSD1 and STS characteristic
of mammary cancer tissue, responsible for the elevated con-
centrations of E
2
in the tumor [9,17-20]. These effects are addi-
tive to those obtained with other antiaromatase drugs such as
aminoglutethimide, and depends on the binding of melatonin
to its MT1 receptors [17]. Information about the doses of mel-
atonin used in basic experiments and clinical trials to obtain
antiestrogenic effects can be found in [2] and [3].
3.2 Antioxidant properties of melatonin
Oxidative stress, defined as an imbalance between the
production-- inactivation of reactive oxygen species (ROS) is
involved in the etiology of many diseases, including neo-
plasias [21]. The oxidative damage of nucleic acids, lipids and
proteins is the foundation of all three steps of carcinogenesis
(initiation, progression and metastasis). Consequently, anti-
oxidants may protect against cancer at all stages of develop-
ment [21]. Melatonin and most of its metabolites have the
capability of: i) scavenging ROS (superoxide anion, hydrogen
peroxide, hydroxyl radical) and reactive nitrogen species
(peroxynitrite anion and nitric oxide) [22], although the role
of melatonin in the detoxification of hydrogen peroxide is
debated, ii) stimulating the expression of antioxidative
enzymes (glutathione peroxidase and reductase, superoxide
dismutase and catalase) [23] and iii) reducing the expression
of pro-oxidative enzymes (nitric oxide synthase) [24]. The anti-
carcinogenic actions of melatonin based on its antioxidative
and free radical scavenging activity have been demonstrated
in different experimental models of carcinogenesis induced
by agents causing oxidative damage, in which melatonin
exerts protective effects [25].
4. Breast cancer risk factors
Cancer prevention is the more desirable objective in cancer
management. This goal depends on a previous knowledge of
the risk factors which enhance the possibility for the develop-
ment of the neoplasias. Risk factors were initially grouped
into four categories: family history/genetic; reproductive/hor-
monal; proliferative benign breast pathology; mammographic
density. Other classifications are based on whether the risk
factors are modifiable by hygienic measures (dietary habits,
alcohol and tobacco consumption, obesity, circadian disrup-
tion, hormonal therapies, etc.) or not (genetic factors, age of
menarche or menopause, ethnicity, mammographic breast
density, etc.). Of the numerous risk factors described, herein
Table 1. Melatonin actions that relate to cancer
treatment.
Modulation of cell cycle, differentiation and apoptosis
.Increases the duration of cycle in different cell lines
(MCF-7, HepG2, HL-60, etc.) expanding the G1 phase,
delaying the entrance into S phase and arresting cells in G2/M
.Decreases DNA synthesis (MCF-7 cells)
.Upregulates the expression of p53 and p21 in MCF-7 cells
.Downregulates the expression of cyclin D1
.Induces cell differentiation in different types of normal and
tumor cells
.Induces apoptosis by different mechanisms involving caspases
7 and 9 and TGFb-1
Inhibition of telomerase
.Inhibits the basal expression of hTERT in MCF-7 cells
.Inhibits hTERT expression induced by natural estrogens and
xenoestrogens (cadmium)
Antiangiogenesis
.Reduces serum levels of VEGF in advanced cancer patients
.At pharmacological doses, inhibits VEGF expression induced by
hypoxia
.At pharmacological doses, inhibits the expression of HIF-1a
Inhibition of metastasis
.Reduces the invasiveness of MCF-7 cells
.Increases the expression of E-cadherin and b
1
-integrin in
MCF-7 cells
Immunoenhancing effects
.Stimulates the production of NK cells, monocytes and
leukocytes
.Stimulates the production of cytokines including IL-2, IL-6,
IL-12, TNF-a
Fatty acid transport and metabolism
.Blocks tumor linoleic acid uptake and its conversion to
13-HODE, which normally activates EGFR/MAPK mitogenic
signaling
Epigenetic effects
.Inhibits p300 histone acetyl transferase in macrophages, thus
inhibiting p52 acetylation and binding to the DNA, and
silencing iNOS and COX-2 genes
.Increases histone H3 acetylation in C17.2 neural stem cells
Prevention of circadian disruption
.Modulates the expression of the clock genes: mPer1, mClock,
mBmal1 in neuronal cultures of mice striatum
.In different prostate cancer cell lines, upregulates clock and
Per2 proteins whereas it downregulates Bmal1 protein
Data from [2].
13-HODE: 13(S)-hydroxyoctadecadienoic acid; COX-2: Cyclooxygenase 2;
EGFR/MAPK: Epidermal growth factor receptor/mitogen activated protein
kinase; HIF-1a: Hypoxia inducible factor 1a; hTERT: Human telomerase
reverse transcriptase.
Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation
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the authors will consider those potentially modifiable by treat-
ment with melatonin, that is, obesity, hormonal factors and
circadian disruption.
4.1 Obesity and breast cancer risk
It is generally accepted that adult obese women have an
increased risk for postmenopausal but not premenopausal
breast cancer, although once a woman has developed breast
cancer, obesity predicts a bad prognosis for both pre- or post-
menopausal conditions [26]. Women carrying BRCA muta-
tions add an additional risk of breast cancer due to weight
gain [27].
A variety of hormonal mechanisms underlie the relation-
ship between obesity and breast cancer. One of the most
important is the elevated local concentration of E
2
which in
postmenopausal women depends on its local biosynthesis via
aromatization of androgens; aromatase activity in breast can-
cer tissue is higher than in non-malignant breast tissue and
the estrogens produced in breast tumors stimulate tumor
growth and metastasis [28].
A second hormonal factor-relating obesity and breast can-
cer is the insulin resistance developed by obese women, which
results in elevated circulating insulin levels, and decreased syn-
thesis of sex hormone-binding globulins, proteins which bind
to E
2
thereby decreasing its bioavailability. Insulin increases
proliferation of MCF-7 cells either directly or indirectly
by augmenting the levels of insulin-like growth factor
1 (IGF-1), which, in turn, regulates cell proliferation [26,29].
Several adipokines also contribute to the obesity-related
breast cancer [26]. Leptin is synthesized in preadipocytes, adi-
pocytes and mammary epithelial cells [30]. Serum leptin levels
positively correlate with the body mass index and are signifi-
cantly greater in breast cancer patients than in matched con-
trols; leptin concentration in breast cancer tissue is also
higher than in normal tissue [31]. The elevated leptin levels
in obese women may contribute to breast cancer development
via its stimulatory effects on cell proliferation and invasive-
ness, depending on the upregulation of VEGF, telomerase
activity and nuclear factor kappa B (NFkB) [32]. Another cyto-
kine, TNF-a, secreted by breast cancer cells, inhibit the dif-
ferentiation of the adipose fibroblasts surrounding the tumor
into mature adipocytes (desmoplastic reaction) [33]. Since aro-
matase expression in fibroblasts from adipose tissue surround-
ing tumor cells is higher than in malignant epithelial cells [34],
these cytokines by maintaining undifferentiated fibroblasts
with high levels of aromatase facilitate tumor growth
and metastasis.
4.2 Hormonal factors
Numerous lines of evidence, including the efficacy of
antiestrogenic therapies in reducing the incidence of breast
tumors, indicate that E
2
is a prime factor for breast cancer
Androstenedione DHEA
Androstenedione
Testosterone
5α-Dihydrotestosterone
Estrone
17b-Estradiol
5a-reductase
3a-hydroxysteroid
dehydrogenase
P450
Aromatase
Estrogen
sulfotransferase
Steroid
sulfatase
17b-hydroxysteroid
dehydrogenase
(type 1)
17b-hydroxysteroid
dehydrogenase
(type 2)
17b-hydroxysteroid
dehydrogenase
(type 1)
17b-hydroxysteroid
dehydrogenase
(type 2)
P450
Aromatase
MELATONIN
Stimulates
Inhibits
Estradiol sulfate
Figure 1. Effects of melatonin on the enzymes involved in the local production of steroids in human breast carcinoma tissue.
Adapted from [18-21].
E. J. Sanchez-Barcelo et al.
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development. Thus, E
2
is been classified as a carcinogen by
the International Agency for Research on Cancer (IARC).
The carcinogenic effects of E
2
depend not only on its stimu-
latory effects on cell proliferation of mammary epithelial cells
(increasing the probability of replication of mutated DNA),
but on oxidative stress induced by some of its metabolites [35].
Whether hormone replacement therapy (HRT) increases the
risk of breast cancer is always a controversial topic. The findings
of the three most relevant studies: the Collaborative Reanalysis,
the Women’s Health Initiative and the Million Women Study
claimed that HRT with estrogen + progestogen is an estab-
lished cause of breast cancer [36]. However, estrogen therapy
may not increase the risk of breast cancer. Interestingly, when
the HRT prescriptions decreased after the publication of its
negative effects, the incidence of breast cancer, also declined [37].
A higher risk of breast cancer has also been reported with the
use of oral contraceptives [38].
4.3 Circadian disruption and breast cancer risk
Epidemiologic and experimental evidence support the hypoth-
esis that disruption of nocturnal melatonin secretion is a risk
factor for breast cancer [39]. An association between increased
concentrations of urinary melatonin metabolites and a low
risk of breast cancer in postmenopausal women has been shown
in different trials [40] although, in premenopausal women, the
results are not as conclusive or even contrary [41]. A survey
including data from almost three million cases of breast cancer
revealed a seasonal pattern in cancer incidence, with peaks near
the equinoxes and nadirs near the solstices, clearly related to the
seasonal variations of melatonin synthesis [42]. Also interesting
is the relationship between shift work and breast cancer. The
IARC has classified shift work involving circadian disruption,
and suppression of the nocturnal melatonin secretion, as a
probable human carcinogen [39].
The relationship between LAN and breast cancer in
humans is supported by both epidemiologic and experimental
studies. An inverse relationship between blindness and risk of
breast cancer, has been explained by a lower nocturnal melato-
nin suppression by light in totally blind people [39,43]. On the
contrary, shift work, including nocturnal rotations, increases
the risk of breast cancer by reducing nocturnal melatonin
secretion [43]. Experimental results in rats indicate that LAN
disrupts the nocturnal secretion of melatonin enhancing the
growth of chemically induced mammary adenocarcinomas
in comparison with the control animals [44]. Thus, melatonin
is clearly the link between circadian disruption and cancer
development [39,43]. In support of this hypothesis is an inter-
esting experiment carried out by Blask et al. They perfuse
human breast cancer xenografts growing in nude rats with
blood obtained from premenopausal women either at
nighttime (in darkness, containing elevated endogenously
produced melatonin levels) or after exposure to LAN (with
reduced levels of melatonin). Blood collected at night inhibi-
ted cellular metabolism associated with tumor growth,
whereas perfusion with blood from the same women but
obtained after exposure to LAN, lacked the inhibitory effects
in tumor growth [45]. Moreover, the addition of melatonin
receptor antagonist to the blood perfusate collected in dark-
ness completely blocked the tumor-suppressive effects of this
melatonin-rich blood [45].
The circadian clock controls cell cycle in healthy and malig-
nant mammalian tissues regulating cell proliferation. The evi-
dence for the importance of the dysfunction in the circadian
oscillator system in the mammary carcinogenesis derives
from the observed effects of polymorphisms and alterations in
clock gene expression (Per1, Per2, Per3, Cry1 and NPAS2)in
humans [46].
5. Breast cancer preventive therapy
The application of prophylactic therapies depends on the
levelofriskofthepatient.Carriers of the BRCA mutation
with a familial history of cancer represent the highest level
of risk, and the necessity of more aggressive therapies (mas-
tectomy and oophorectomy) is considered [47]. On the other
hand is risk in women without a family history but simply
overweight; for these cases elemental hygienic practices are
usually sufficient. Women with a moderately increased risk
are the population considered for chemopreventive thera-
pies [47]. Recently, the term ‘preventive therapy’ has been
proposed in lieu of ‘chemoprevention’, more associated
with cancer treatment (chemotherapy) rather than with pro-
phylaxis. The estrogen signaling pathway is a common link
among most of the risk factors for breast cancer. Conse-
quently, antiestrogens and antiaromatases are the usual
chemopreventive treatments.
Tamoxifen is currently the preventive agent of choice for
high-risk women. The results of four trials show a 43% reduc-
tion in ER+ breast cancer but no effects on ER- diseases when
this drug is used [47]. However, tamoxifen treatment is not
exempt of side effects which limit its use. These include hot
flashes (64%), vaginal dryness (35%), sleep problems
(36%), weight gain (6%), depression and mood swings
(6%) [48]. Furthermore, increased rates of endometrial cancer
and venous thromboembolic events have been reported in all
tamoxifen trials published [47]. The cancer preventive effects
of raloxifene, studied in three randomized trials [49-51], seem
to be greater than those of tamoxifen in the MORE and
RUTH trials whereas no differences were found in START.
However, the absence of effects on the endometrium and a
reduced incidence of thromboembolism compensate for its
possible lower effectiveness in terms of percentage of risk
reduction compared with tamoxifen [47]. Other SERMs (laso-
foxifene and arzoxifene) seem to be efficient in reducing risk
of breast cancer although venous thromboembolic effects are
major adverse effects [52,53].
The efficacy of the third generation of aromatase inhibitors
(anastrozole, letrozole and exemestrane) in preventing breast
cancer development in healthy women has been assessed both
from studies in women with early breast cancer, by evaluating
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the development of contralateral tumors (ATAC trial), and also
in multicenter, randomized, placebo-controlled trials in
postmenopausal women who are at increased risk of breast
cancer (IBIS-II trial). From these trials, a consistent reduction
in the rates of contralateral breast cancer has been observed
after treatment with antiaromatase [47]. Although the aroma-
tase inhibitors have a lower incidence of endometrial cancer
and tromboembolic side effects than SERMs, they reduce
bone mineralization, increasing the risk of fracture and
musculoskeletal disorders [47].
6. Melatonin and breast cancer preventive
therapy
Experimental studies suggest that melatonin, via different
mechanisms [2], reduces the incidence and increases the
latency of mammary tumor development in rodents exposed
to chemical carcinogens [54]. Thus, melatonin administered
to female rats for 15 days before the administration of a
chemical carcinogen, partially prevented the development of
mammary adenocarcinomas [55]. Using the hamster kidney
model of E
2
-induced carcinogenesis, Karbownik et al. [56]
demonstrated that melatonin prevented the enhanced oxida-
tion of guanine bases caused by the E
2
, thereby preventing
the DNA damage and leading to a potential suppression of
estrogen-mediated cancer.
6.1 Melatonin and prevention of risk factor
associated with obesity
Melatonin may also be useful in preventing breast cancer asso-
ciated with obesity. This is a consequence of its SEEM and
SERM properties mentioned above, but also for its important
role in body weight regulation and as a tool for therapy of
obesity-associated effects [57,58]. Whereas circulating melato-
nin levels are decreased in obese animals, melatonin adminis-
tration in different models of obese rats, reduces body weight
and visceral fat, decreases plasmatic levels of glucose, leptin,
triglyceride, total cholesterol and low-density lipoprotein
(LDL) cholesterol, and increases glutathione peroxidase and
high-density lipoprotein (HDL) cholesterol [57,58]. Although
obese individuals at pubertal age seem to have elevated levels
of melatonin, in patients with metabolic syndrome, a
1-month administration of melatonin (5 mg/day) reduced
their body mass index, improved their antioxidative status,
decreased serum LDL and increased HDL [59]. Based on the
outcomes of numerous experimental studies showing that
melatonin attenuates or reverses insulin resistance in obe-
sity [57], the recommendation of melatonin for breast cancer
preventive therapy in obese women, associated or not with
other drugs, would add to its SERM and SEEM properties,
its positive effects against the obesity-related metabolic prob-
lems as well as against the root of the problem, that is, the
obesity. It is possible that the protective effect of exercise
with respect to breast cancer in obese women may operate
in part through an increase in melatonin synthesis [60].
6.2 Melatonin and prevention of hormonal risk
factors in breast cancer
The possible control by melatonin of the GnRH (gonadotro-
pin-releasing hormone) pulse generator in humans has been
considered for the development of contraceptives. Thus, mel-
atonin, combined with a progestin, has been proposed as an
oral contraceptive combination which might prevent breast
cancer in long-term users [61] and the idea was already pat-
ented by Cohen and Wassehaar (US 19894855305) and
Cohen et al. (US 19935272141) several years ago. Similarly,
the association of melatonin with HRT has been recently pat-
ented by Witt-Enderby and Davis (USPTO 20110028439) as
a way to reduce breast cancer incidence associated with this
hormonal treatment.
6.3 Melatonin prevention of osteoporosis associated
with antiaromatase treatment
Osteoporosis resulting from decreased bone mineralization is
a negative side effect of aromatase inhibitors [49]. Interestingly,
melatonin regulates bone physiology [62]. The three principal
mechanisms of melatonin effects on bone function are:
i) the promotion of the osteoblast differentiation and
activity; ii) an increase in the osteoprotegerin expression by
osteoblasts, thereby preventing the differentiation of osteo-
clasts; iii) scavenging of free radicals generated by osteoclast
activity and responsible for bone resorption [62]. In summary,
melatonin seems to promote bone formation and prevent
bone resorption via the above-listed mechanisms. Conse-
quently, melatonin, together with antiaromatases: i) could
reduce osteoporosis induced by these drugs, ii) potentiate
the effects of antiaromatases and iii) add its own antiaroma-
tase actions. Osteoporosis induced by antiaromatases has
been treated with bisphosphonates, which induces oxidative
gastric damage and causes serious adverse gastrointestinal
effects. Melatonin, like omeprazol, has been proven to have
protective effects against this damage due to their antioxidant
properties [63].
6.4 Melatonin and prevention of breast cancer
associated with circadian disruption
If melatonin suppression (as noted above) has any role in
breast cancer risk either avoiding the nocturnal melatonin
inhibition induced by LAN or administering exogenous mel-
atonin, should achieve a certain degree of breast cancer pre-
vention. Obviously, it is unrealistic to propose the abolition
of nocturnal work or the reduction of nocturnal lighting in
order to prevent melatonin suppression. However, there is
an important issue concerning melatonin suppression by
light. Although green-absorbing cones contribute to the light
signals transmitted to the SCN, defined wavelengths of the
visible spectrum, that is, wavelengths in the blue/green range
(460 -- 480 nm), are those which strongly suppresses noctur-
nal melatonin production [64]. This relates to the fact that
melanopsin, the photopigment that mediates the actions of
light in the circadian system, is exclusively sensitive to those
E. J. Sanchez-Barcelo et al.
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wavelengths. Melanopsin is located in the retinal ganglion
cells the axon of which project to the biological clock (the
suprachiasmatic nuclei in the basal hypothalamus) [65]. Conse-
quently, any optical device capable of filtering the blue light
spectrum, or lighting systems lacking the 460 -- 480 nm wave-
lengths could avoid the risk of light-induced suppression of
nocturnal melatonin [66]. Not surprisingly, some patents based
on these ideas have already been registered.
6.5 Melatonin as an adjuvant of other drugs used in
breast cancer prevention
As previously mentioned, melatonin has SERM and SEEM
properties which could be additive to those of the currently
used antiestrogenic or antiaromatase drugs. Since the actions
of melatonin and tamoxifen are similar, although via different
mechanisms, it enhances the likelihood that their effects could
be additive [17]. Thus, a pilot Phase II study carried out by
Lissoni et al. [67] suggests that the concomitant administration
of melatonin may induce objective tumor regressions in
metastatic breast cancer patients refractory to tamoxifen alone.
Drugs other than SERM and SEEMs, originally designed
for different purposes, are now being evaluated for their pos-
sible usefulness in chemopreventive therapies. This is the case
for metformin (an antidiabetic drug), biphosphonates (inhib-
itors of osteoclastic activity), aspirin (a cyclooxygenase
(COX)-2 inhibitor), statins (anti-lipidic), inhibitors of poly
(ADP-ribose)polymerase, retinoids, calcium-- vitamin D com-
plex, IGF-1R inhibitors, leptin receptor antagonists, etc. In
some cases, their association with melatonin has been studied.
Aspirin and non-steroidal anti-inflammatory drugs inhibit
COX-2 as does melatonin. COX inhibitors decrease aroma-
tase expression and enzymatic activity in human breast can-
cer cells, suggesting that these agents may be useful in
suppressing local estrogen biosynthesis in the treatment of
hormone-dependent breast cancer [68].
Both, melatonin and metformin inhibit mammary carci-
noma development in transgenic HER-2/neu mice. Com-
bined treatment with melatonin may have an additional
impact on the effects of metformin in the prevention as well
as treatment of breast cancer [69].
Melatonin and vitamin D3 inhibit breast cancer cell
growth and induce apoptosis. In MCF-7 cells, melatonin
together with vitamin D3, caused a synergistic proliferative
inhibition, with an almost complete cell growth arrest, associ-
ated with an elevated TGFb-1, a significant reduction in
Akt phosphorylation and MDM2 values, and an increase of
p53/MDM2 ratio [70].
7. Melatonin treatment of the side effects of
radio and chemotherapy
7.1 Radiotherapy
In breast cancer treatment, radiotherapy to the conserved
breast is used after breast-conserving surgery. This treatment
reduces disease recurrences and breast cancer death rate [71].
Radiotherapy is also used intraoperatively, for early breast
cancer treatment, and as adjuvant therapy for women over
the age of 65 [72]. In the early intermediate stages of breast
cancer, neoadjuvant radiochemotherapy is an alternative to
chemotherapy alone, and might further impact the surgical
treatment by downsizing the tumor [73]. While total breast
radiation after tumor resection is used to reduce recurrence
rates, it may cause poor cosmetic results as well as breast
pain, cardiac and lung toxicity and dermatitis [71].
Radiotherapy induces the formation of ROS including free
radicals, which, in many cases, are sources of the negative side
effects of these therapies. This is the rationale for using antioxi-
dant adjuvants to reduce radiotherapy toxicity [74]. Not all
oncologists consider antioxidants to be beneficial in radiother-
apy; rather, they believe that the production of free radicals is
part of the tumor-killing effects or radiation [75]. However,
most studies draw positive conclusions about the interaction
of radiotherapy and antioxidants [74]. Ideally, radiotherapy
protocols look for a high tumor control with the minimal
damage of normal tissue. The increase of the therapeutic
index is assisted by the administration of cytoprotective com-
pounds capable of protecting vulnerable tissues from the toxic
effects of radiotherapy. Melatonin belongs to the antioxidant
group of radioprotectors [76]. Melatonin may delay the satura-
tion of the repair enzymes, thus allowing the repair of induced
damage and the use of higher doses of radiation may provide
better therapeutic value [76]. Experimental data document the
protective effect of melatonin against the genetic damage in
blood and bone marrow and lethal effect of whole-
body radiation in mice [76]. Melatonin administration to rats
before radiation, protects against molecular damage by upre-
gulating endogenous antioxidant enzymes, scavenging the
free radicals generated by the radiation, and by increasing
lymphocyte count [77]. A meta-analysis of 21 randomized
clinical trials carried out in patients with solid tumors treated
with chemotherapy or radiotherapy, showed that melatonin
improved the frequency of complete responses, partial
responses and stable disease while significantly reducing asthe-
nia, leucopenia, thrombocytopenia, hypotension, nausea and
vomiting [78].
Acute radiation dermatitis occurs in up to 90% of patients
undergoing radiotherapy following lumpectomy and partic-
ularly among women with genotypes encoding lower protec-
tion from oxidative stress [79]. Management of skin toxicity
during radiotherapy includes topical corticosteroids, hialur-
onic acid gel, petrolatum gel, sucralfate, calendula, silver
leafdressing,etc.Emulsionscontaining melatonin could,
because of the antioxidant properties of the indole, reduce
the development of radiation dermatitis after adjuvant breast
radiotherapy. Topical application of melatonin to prevent
local radiation injuries in rats showed low efficacy [80].
However, in this experiment, the concentration of melatonin
in the emulsion was probably too low (2 -- 5%) to be effec-
tive. New formulations of melatonin-loaded polymeric
nanoparticles allow melatonin concentrations ranging from
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29 to 50% (depending on the nanocarriers) providing an
important increase in the antioxidant effect of melatonin [81].
These formulations should be evaluated for radioprotection.
7.2 Chemotherapy
Chemotherapy is the treatment of choice for patients with
disease unresponsive to endocrine agents or with rapidly
progressive visceral disease. Chemotherapeutic agents
include anthracyclines (epirubicin, doxorubicin), taxanes
(paclitaxel, docetaxel), capecitabine, vinorelbine, platinum
drugs (cisplatin, carboplatin), gemcitabine, trastuzumab
(herceptin) and angiogenesis inhibitors. These therapies
prolonged survival of the patients, but they produce impor-
tant side effects such as cardiotoxicity, neuropathy, hemato-
logical toxicity, skin necrosis, gastric effects (nausea and
vomiting), etc. [82-85]. The detrimental effect of these thera-
pies depends, at least in part, on the generation of free oxy-
gen radicals. Melatonin as an adjuvant therapy, protects
against the side effects of different chemotherapeutic drugs
and, in some cases, potentiates their oncostatic effects.
Numerous experimental studies as well as isolated clinical
trials have confirmed this supposition:
I) Anthracyclines are a group of antineoplastic agents widely
used in the treatment of breast cancer. They increase the pro-
duction of free radicals, thus altering antioxidant enzyme lev-
els of cells and causing molecular damage. Numerous
experimental studies have evidenced the protective effects of
melatonin against cardiac, renal and hematologic toxic effects
of anthracyclines (mainly doxorubicin). Also, a Phase II clini-
cal trial [86] carried out on 14 consecutive women with meta-
static breast cancer treated with oral melatonin (20 mg/day,
in the evening), and epirubicin (25 mg/m
2
, i.v., at weekly
intervals) described that melatonin treatment prevented the
chemotherapy-induced platelet decline and achieved an
objective tumor regression in 41% of the patients.
II) In reference to taxanes, melatonin (1 nM) enhances the
antitumor effects of paclitaxel in the ER+ endometrial can-
cer cell line (Ishikawa), which express MT
1
melatonin
receptors [87]. A pilot clinical trial to assess the neuropro-
tective effects of melatonin during taxane chemotherapy
for breast cancer was carried out in 22 consecutive patients
receiving either paclitaxel (750 mg/m
2
, i.v., weekly, for
2-- 3 doses) or docetaxel (75 mg/m
2
, i.v., every
2-- 3 weeks, for 6 doses). The conclusion was that patients
receiving melatonin (21 mg/day, at bedtime) during taxane
chemotherapy had a reduced incidence of neuropathy and
no reported daytime sedation [88].
III) Despite the effectiveness of cisplatinum, the dose of
the drug that can be administered is limited by its toxicity.
Treatment of human peripheral blood mononuclear cells
with cisplatinum depletes intracellular glutathione (GSH)
and leads to apoptotic changes. Melatonin treatment
counteracts the antiproliferative and apoptotic effect of
cisplatinum and protects these cells against GSH
depletion [89]. Experimental studies concluded that the
antioxidant effects of melatonin reduce the renal damage
induced by cisplatin [90]. One group of authors claimed
that melatonin did not interfere with oxidative stress and
kidney injury induced by cisplatin in rats [91].
IV) In a model of chemically induced hamster pancreatic
tumor, the combined administration of capecitabine and
melatonin improved the antitumor effects of the cytostatic.
Thus, after receiving the carcinogen, only 10% of the ani-
mals treated with melatonin + capecitabine developed
moderately differentiated pancreatic adenocarcinomas,
whereas 66% of the hamsters treated with capecitabine
alone and 33% of those treated with melatonin alone,
developed pancreatic cancer [92].
V) Melatonin has also been tested for its ability to reduce
the toxicity of combined chemotherapies. One clinical trial
analyzed 370 patients with different types of solid tumors,
randomized to receive chemotherapy alone or plus melato-
nin (a daily oral dose of 20 mg/day, in the evening, by
starting 7 days prior to the onset of chemotherapy). Chemo-
therapy treatments consisted of different combinations of
cisplatin, etoposide, gemcitabine, oxaliplatin, 5-fluorouracil,
epirubicin and folates. The conclusion was that the admini-
stration of melatonin, in comparison with chemotherapy
alone, increased 2-year survival rate, caused objective
tumor regression rate and reduced the incidence of throm-
bocytopenia, neurotoxicity, cardiotoxicity, stomatitis and
asthenia [93].
8. Beneficial effects of melatonin for
symptoms associated with breast cancer or
its treatment
Many woman suffering with breast cancer experience depres-
sion, anxiety, sleep disturbances and cognitive dysfunction
which represent a severe impairment in their quality of life and
which also contributes to a worsen prognosis of the illness.
Depression is more frequent in breast cancer patients than
in other neoplasias. Treatment of these patients is sometimes
problematic because of the interaction between antiestrogenic
and antidepressive drugs. Tamoxifen is metabolized in the liver
by CYP2D6 enzymes to endoxifen, the active metabolite,
100 times more potent than tamoxifen and responsible for
its pharmacological actions [94]. Some serotonin reuptake
inhibitors (SRIs) used as antidepressants (fluoxetine, paroxe-
tine, venlafaxine and sertraline) inhibit the activity of
CYP2D6, reducing the effectiveness of tamoxifen [95].
Melatonin and melatonin receptor agonists represent new anti-
depressants with the circadian system as a target. Agomelatine,
a melatonin-receptor agonist and selective 5-HT(2C) seroto-
nergic receptor antagonist has chronobiotic, antidepressant
and anxiolytic effects similar to SRIs, and improves sleep qual-
ity. Neither melatonin nor agomelatine, however, induce the
gastrointestinal, sexual or metabolic side effects characteristic
of many other antidepressant compounds nor do they inhibit
E. J. Sanchez-Barcelo et al.
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tamoxifen metabolism [96]. Thus, melatonin and melatoniner-
gic drugs used as adjuvant with conventional antiestrogens
could provide a double benefit in terms of their antiestrogenic
and antidepressive properties.
Insomnia is a prevalent problem in breast cancer patients,
usually associated with depression [97]. Difficulties in falling
asleep, sleep continuity, slow-wave sleep and REM sleep pat-
terns occur and may be a cause or the consequence of the
depression. Fatigue is another frequent complaint of cancer
patients. Fatigue, sleep disturbances and depression could
have a common link in circadian rhythm disruption, and
they are especially prevalent in patients with breast cancer [98].
In this context, treatment with melatonin offers the advan-
tages of its chronobiotic properties [1]. Agomelatine (designed
for the treatment of major depressive disorders, particularly
sleep disorders and circadian disturbances) and ramelteon
(recommended for long-term treatment of sleep disturbances
with difficult sleep onset), are two melatonin receptor agonist
recently patented and have proven useful for sleep disturban-
ces in breast cancer patients; these properties are similar to
those of the natural melatonin. [99].
Many women with breast cancer complain of poor concen-
tration and memory, and muddled, inefficient and effortful
thought processes even though they may not have received che-
motherapy, radiotherapy or hormonal treatment [100].The
studies being carried out to characterize the role of melatonin
and clock genes in mediating sleep-wakefulness and circadian
processes modulating cognition should provide information
about new therapies for these cancer-related problems. In rela-
tion to this, MELODY is a double-blind randomized, placebo-
controlled trial designed to investigate whether daily treatment
with melatonin (6 mg oral) has ameliorating effect on depres-
sion, fatigue, anxiety, sleep disturbances and cognitive dysfunc-
tion in women with breast cancer [101]. The results of this trial
should provide information regarding these issues in the next
several years.
9. Conclusion
This review of the literature focused on melatonin and breast
cancer leads to the conclusion that most experimental studies
carried out in vitro (using MCF-7 estrogen-sensitive human
breast cancer cells) or in vivo (chemically induced mammary
tumors in rats) showed positive results in terms of anticancer
effects of melatonin. The few clinical trials designed to exam-
ine the role of melatonin as an adjuvant therapy for cancer
showed melatonin caused substantial improvements in tumor
remission, 1-year survival as well as a significant reduction of
the side effects related to radio- or chemotherapy. The data
summarized in the present review encourages the implemen-
tation of additional clinical trials on the possible usefulness
of melatonin as a therapeutic agent for hormone-dependent
breast cancer. Moreover, melatonin used in association with
other conventional treatments could enhance their therapeutic
effects and reduce their side effects.
10. Expert opinion
The functions of melatonin are extensive [1] and their mecha-
nism of action, both receptor-dependent and receptor-inde-
pendent, support its wide spectrum of effects [3]. These
observations, together with its low toxicity, stimulated numer-
ous studies on melatonin in the field of cancer treatment. The
studies focused on melatonin- and estrogen-dependent mam-
mary adenocarcinomas have contributed highly interesting
results. However, clinical studies have practically been
reduced to those of Lissoni et al, who obtained positive results
by using melatonin as an adjuvant therapy for different kinds
of tumors, including breast cancer. Why, despite the promis-
ing experimental results, clinical trials to verify the therapeutic
usefulness of melatonin in humans are scarce, is a difficult
question to answer; perhaps there are a number of reasons.
Whit regard to this, there are several ideas that should be con-
sidered. The first idea is that, without ruling out the future
findings that may change this opinion, at present no one suf-
fering from breast cancer would accept a treatment with mel-
atonin alone as an alternative to current therapies. As a result,
the conclusion is that melatonin should be basically consid-
ered as an adjuvant therapy. Once this idea is accepted, and
considering melatonin’s antiestrogenic, antiaromatase and
antioxidant properties, all of which are well founded in strong
experimental data, the clinical applications of the indoleamine
should include the following: i) use in combination with
tamoxifen, raloxifene or other SERM drugs. Predictably, the
SERM actions of melatonin, which depend on different
mechanisms than those of the conventional SERMs, could
be additive. Furthermore, melatonin could prevent some of
the side effects of SERMs, for example, sleep problems,
weight gain or depression, ii) use in combination with antiar-
omatases and other SEEM drugs (anastrozole, letrozole, etc.).
In this case, melatonin would bring not only its own SEEM
properties (not limited to inhibition of aromatase) but it
may also reduce osteoporosis and other side effects of the cur-
rent SEEM drugs, iii) melatonin use in combination with
chemo- or radiotherapies. In this context, melatonin could
enhance the antitumor effects of chemo- or radiotherapeutic
agents, as has been suggested by several experiments and clini-
cal trials. Moreover, there is evidence that melatonin would
reduce some of the side effects of chemo- and radiotherapy
including leucopenia, thrombocytopenia, nauseas, dermatitis,
etc. In authors’ opinion, the indications of adjuvant therapy
with melatonin are twofold, that is, breast cancer prevention
of women at risk for obesity, hormonal treatments (or
exposure to xenoestrogens), and breast cancer treatment with
cytostatic drugs or radiotherapy.
One special issue relates to the problem of melatonin dis-
ruption by LAN. It is now more than a century ago that
man has used artificial light sources with sufficient intensity
as to inhibit melatonin secretion. Experimental and epi-
demiological evidence have revealed a possible relationship
between exposure to LAN and risk of breast cancer. Although
Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation
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it is evident that LAN may disrupt the expression of clock
genes, with repercussions for cell cycle control and carcino-
genesis, the role of melatonin as the link between LAN and
cancer has now been documented in two key publica-
tions [44,45]. The discovery of melanopsin (a photopigment
with an absorption peak in the blue/green range of the visible
spectrum) in the retinal ganglion cells, and the consequential
relevance of these wavelengths in LAN-induced inhibition of
melatonin secretion, has triggered new strategies for breast
cancer prevention in women with occupational exposure to
LAN. Prevention could be based on the development of
glasses that filter or lighting systems which avoid the blue
spectrum of manufactured light.
Declaration of interest
The authors state no conflict of interest and have received no
payment in preparation of this manuscript.
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with human blood to compare the
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Affiliation
Emilio J Sanchez-Barcelo
1
, Maria D Mediavilla
1
,
Carolina Alonso-Gonzalez
1
& Russel J Reiter
2
Author for correspondence
1
University of Cantabria, Department of
Physiology & Pharmacology, 39011 Santander,
Spain;
E-mail: barcelo@unican.es
2
The University of Texas Health Science Center,
Department of Cellular & Structural Biology,
San Antonio, TX 78229-3900, USA
Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation
Expert Opin. Investig. Drugs [Early Online] 13
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... Therefore, circadian preference may influence the prevalence and clustering of these symptoms in breast cancer survivors. Insights into the underlying pathophysiological mechanisms of the depression, fatigue, and insomnia symptom cluster may provide directions for research to determine whether these circadian preferences can be potentially modified using psycho-oncological or pharmaceutical interventions such as timed bright light exposure [16] or melatonin supplements [17]. Therefore, in this study, we aimed to (1) identify groups of breast cancer survivors based on symptoms of fatigue, depression, and insomnia, and 2) assess whether circadian parameters (i.e., chronotype, amplitude, and stability) at baseline are associated with symptom burden at follow-up. ...
... While associations with languidness remained inconclusive, eveningness was identified as a potential risk factor for long-term, co-occurring symptoms of fatigue, depression, and sleep problems in breast cancer survivors. Innate chronotype is largely influenced by non-modifiable factors including genetics and age; however, if the associations seen in our study are due to disruption of circadian rhythm in evening type women, it may be worth investigating interventions such as bright light exposure [16] and melatonin supplements [17] during or after breast cancer treatment which have shown promising effects on circadian re-alignment. Therefore, psycho-oncological or pharmaceutical therapies to re-align survivors' chronotype and circadian amplitude could provide important directions to targeted interventions in evening types and may subsequently reduce long-term symptom burden. ...
Article
Full-text available
Purpose Circadian rhythms control a wide range of physiological processes and may be associated with fatigue, depression, and sleep problems. We aimed to identify subgroups of breast cancer survivors based on symptoms of fatigue, insomnia, and depression; and assess whether circadian parameters (i.e., chronotype, amplitude, and stability) were associated with these subgroups over time. Methods Among breast cancer survivors, usual circadian parameters were assessed at 3–4 months after diagnosis (T0), and symptoms of fatigue, depression, and insomnia were assessed after 2–3 years (T1, N = 265) and 6–8 years (T2, N = 169). We applied latent class analysis to classify survivors in unobserved groups (“classes”) based on symptoms at T1. The impact of each of the circadian parameters on class allocation was assessed using multinomial logistic regression analysis, and changes in class allocation from T1 to T2 using latent transition models. Results We identified 3 latent classes of symptom burden: low (38%), moderate (41%), and high (21%). Survivors with a late chronotype (“evening types”) or low circadian amplitude (“languid types”) were more likely to have moderate or high symptom burden compared to “morning types” and “vigorous types,” respectively. The majority of survivors with moderate (59%) or high (64%) symptom burden at T1 had persistent symptom burden at T2. Implications for Cancer Survivors A late chronotype and lower circadian amplitude after breast cancer diagnosis were associated with greater symptoms of fatigue, depression, and insomnia at follow-up. These circadian parameters may potentially be novel targets in interventions aimed at alleviating symptom burden among breast cancer survivors.
... Moreover, as an adjuvant therapy, reduces the side effects of chemotherapeutic drugs (18) . Melatonin acts in different pathways related antioxidant properties (19) . Experimental evidences indicate the radio protective effect of melatonin against radiation induced genetic damage in blood, bone marrow and mortality of mice (20) . ...
... [ DOI: 10.52547/ijrr.19.2.26 ] [ Downloaded from ijrr.com on 2021-12-14 ] Int. J. Radiat. ...
... Chemotherapeutic drugs are also known to have side-effects in the hematopoietic and gastrointestinal systems. Melatonin has potential to alleviate side-effects of chemotherapeutic drugs (93)(94)(95)(96). In fact, clinical studies using melatonin in breast cancer treated with radiotherapy and chemotherapy consistently demonstrated the possible adjuvant role of melatonin, and extensively reviewed by Reiter (97). ...
Article
Full-text available
Background/aim: Melatonin (N-acetyl-5-methoxytryptamine), a chief secretory molecule of the pineal gland, has multiple properties, and numerous clinical investigations regarding its actions are in progress. This study investigated the radiomitigative role of melatonin in C57BL/6 mice. Materials and methods: Melatonin (100 mg/kg) was orally administered once daily starting at 1 h on day 1 and subsequently every 24 h until day 7 after whole-body irradiation (WBI) and survival was monitored for 30 days. The bone marrow, spleen, and intestine were studied to evaluate the mitigative potential of melatonin after radiation-induced damage. Results: Melatonin significantly improved the survival upto 60% and 90% after 9 Gy (lethal) and 7.5 Gy (sub-lethal) WBI, respectively. Melatonin alleviated WBI-induced myelosuppression and pancytopenia, and increased white blood cell, red blood cell, platelet, and lymphocyte (CD4+ and CD8+) counts in peripheral blood. Bone marrow and spleen cellularity were restored through enhanced haematopoiesis. Melatonin ameliorated the damage in the small intestine, and promoted recovery of villi length, crypts number, and goblet cell count. Conclusion: Melatonin mitigates the radiation-induced injury in the gastrointestinal and haematopoietic systems. The observed radiomitigative properties of melatonin can also be useful in the context of adjuvant therapy for cancer and radiotherapy.
... Its presence in foods has attracted much interest for its recognized bioactive properties (antioxidant, neuroprotective, antinflammatory and cardiovascular properties) (R. J. Reiter et al., 2000;Russel J. Reiter et al., 2010;, Sanchez-Barcelo et al., 2012) and has been analysed in different foods and beverages. Indeed, it has been detected in several foodstuffs including, among others, tomatoes, strawberries (Stürtz et al., 2011), cherry , apple , walnuts (Russel Reiter et al., 2005) and pistachios (Oladi et al., 2014) as well as fermented foods such as wine (Rodriguez-Naranjo et al., 2011), fermented orange beverages (Fernández-Pachõn et al., 2014) and beer (Edwin Fernández-Cruz et al., 2020). ...
Article
Full-text available
Yeasts can synthetise bioactive compounds such as Melatonin (MEL), Serotonin (SER) and Hydroxytyrosol (HT). Deciphering the mechanisms involved in their formation can lead to exploit this fact to increase the bioactive potential of fermented beverages. Quantitative analysis using labelled compounds, 15-N2 L-tryptophan and 13-C tyrosine, allowed tracking the formation of the above-mentioned bioactive compounds during the alcoholic fermentation of synthetic must by two different Saccharomyces cerevisiae strains. Labelled and unlabelled MEL, SER and HT were undoubtedly identified and quantified by High Resolution Mass Spectrometry (HRMS). Our results prove that there are at least two pathways involved in MEL biosynthesis by yeast. One starts with tryptophan as precursor being known for the vertebrates’ pathway. Additionally, MEL is produced from SER which in turn is consistent with the plants’ biosynthesis pathway. Concerning HT, it can be formed both from labelled tyrosine and from intermediates of the Erlich pathway.
... Hardeland et al. (16) have published a review of the physiology and function of melatonin. Different studies have been performed to determine the oncostatic properties of melatonin against various tumours, including BC (17)(18)(19). Melatonin and its metabolites were found to be a direct free radical scavenger agent (20)(21)(22) that had the capability to stimulate the production of anti-oxidative enzymes and reduce the expression of pro-oxidative enzymes. Therefore, its use as a radioprotector and anti-cancer agent has been proposed (23). ...
Article
Full-text available
Objective: The aim of this study was to evaluate the effects of individual or combined use of two antioxidants, melatonin and famotidine on radiation induced apoptosis in leukocytes from breast cancer (BC) patients. Materials and methods: In this experimental study, the DPPH assay was used to determine the appropriate doses of melatonin and famotidine for treatment of BC and control leukocytes. The leukocytes were cultured in complete RPMI1640 medium and treated with either agent for two hours. Cells were exposed to 4 Gy gamma rays generated from a Co-60 source at a dose rate of 0.85 Gy for 48 hours before harvesting. The cells were placed on slides and the neutral comet assay was performed. A total of 500 cells were stained with ethidium bromide and assessed for the amount of apoptosis under a fluorescent microscope x400 magnification. Results: We observed significantly more apoptosis following radiation alone in the leukocytes from BC patients compared with normal individuals (P<0.01). Individual use of famotidine and melatonin induced very low frequencies of apoptosis that was not significantly different from the control (P>0.05). However, when combined with radiation, there was a decreased frequency of apoptosis in leukocytes of both normal and BC patients (P<0.05). The effect of famotidine was more pronounced than melatonin. Conclusion: Melatonin, despite its potent antioxidant property, does not significantly affect radiation induced apoptosis in leukocytes derived from normal individuals; however, it has a moderately significant protective effect on in leukocytes derived from BC patients. Therefore, when used with radiation it might not intervene with the radiotherapy (RT) regimen of BC cancer patients. Famotidine is a good radioprotector for normal tissue. However, the efficacy of RT might be reduced with an accumulation of famotidine in tumour tissues.
... [21][22][23] Several studies demonstrated that MLT has an important role in the regulation of intermediary metabolism and breast cancer. [24][25][26] Zharinov et al have reported that MLT has a significant positive effect on long-term survival in PCa patients with poor prognosis. Wang et al have reported that melatonin reduced PCa metastasis by inhibiting the expression of MMP13. ...
Article
Full-text available
Background Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration-resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. Methods We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. Results We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta-analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1-knockout (Ces−/−) mice verified the important role of endogenous Ces1 in PCa. Conclusions Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa.
... Moreover, as an adjuvant therapy, reduces the side effects of chemotherapeutic drugs (18) . Melatonin acts in different pathways related antioxidant properties (19) . Experimental evidences indicate the radio protective effect of melatonin against radiation induced genetic damage in blood, bone marrow and mortality of mice (20) . ...
Article
Full-text available
Background: Radioprotective effects of melatonin and famotidine were reported in previous studies. In this study, modulating effects of these agents alone or in combination were tested on high dose radiation induced cell lethality in MRC5 and Hela cells. Materials and Methods: DPPH (2,2-Diphenyl- 1-picrylhydrazyl) was used to measure antioxidant property of famotidine and melatonin at different concentrations. Famotidine at a concentration of 80 μg/ml and melatonin at a concentration of 80 μg/ml was added to culture flasks containing MRC5 and Hela cells two hr prior to gamma-irradiation. Treated and untreated cells were irradiated with doses of 4 and 8 Gy gammarays. MTT assay was used to measure cell viability 48 and 72 hours after irradiation. Data were analyzed using nonparametric one way analysis of variance (ANOVA). Results: DPPH assay showed high antioxidant potential for melatonin. Presence of melatonin led to significant elevation of cell viability of both MRC5 and Hela cell lines after 4 and 8 Gy gamma-irradiation at both sampling times (p<0.01). However, for Hela cells exposed to 4 Gy, melatonin led to reduced cell viability (p<0.05). Famotidine, did not improve radiation induced cell lethality for both MRC5 and Hela cells exposed to 4 and 8 Gy. Conclusion: Except for 4 Gy irradiated Hela cells, presence of melatonin led to a significant radioprotection against radiation induced cell lethality of cells, Famotidine failed to improve cell viability in both cell lines. The mechanism of radioprotection of melatonin might be attributed to its radical scavenging potential. Keywords: Radioprotection, melatonin, famotidine, MRC5 and Hela cells, cell viability.
... Melatonin has long been known as an anti-cancer agent [1][2][3][4][5][6][7][8][9] as well as a molecule that overcomes chemoresistance [10][11][12][13] and protects non-cancer tissues from toxic oncostatic treatments [14][15][16][17][18]. Melatonin's mechanisms as an anti-cancer agent seem to be multiple [19][20][21][22][23] with no clear definition of the most essential process for its anti-tumor actions. ...
Article
This brief review describes the association of the endogenous pineal melatonin rhythm with the metabolic flux of solid tumors, particularly breast cancer. It also summarizes new information on the potential mechanisms by which endogenously-produced or exogenously-administered melatonin impacts the metabolic phenotype of cancer cells. The evidence indicates that solid tumors may redirect their metabolic phenotype from the pathological Warburg-type metabolism during the day to the healthier mitochondrial oxidative phosphorylation on a nightly basis. Thus, they function as cancer cells only during the day and as healthier cells at night, that is, they are only part-time cancerous. This switch to oxidative phosphorylation at night causes cancer cells to exhibit a reduced tumor phenotype and less likely to rapidly proliferate or to become invasive or metastatic. Also discussed is the likelihood that some solid tumors are especially aggressive during the day and much less so at night due to the nocturnal rise in melatonin which determines their metabolic state. We further propose that when melatonin is used/tested in clinical trials, a specific treatment paradigm be used that is consistent with the temporal metabolic changes in tumor metabolism. Finally, it seems likely that the concurrent use of melatonin in combination with conventional chemotherapies also would improve cancer treatment outcomes.
Article
Non-Saccharomyces yeasts represent a very attractive alternative for the production of beers with superior sensory quality since they are able to enhance the flavour of beer. Furthermore, they can produce beers with low ethanol content due to the weak fermentative capacity of a large percentage of non-Saccharomyces species. The objective of this study was to evaluate the ability of 34 non-Saccharomyces yeast strains isolated from Madrilenian agriculture to produce a novel ale beer. The non-Saccharomyces yeast strains were screened at two scales in the laboratory. In the first screening, those with undesirable aromas were discarded and the selected strains were analysed. Thirty-three volatile compounds were analysed by GC, as well as melatonin production by HPLC, for the selected strains. Thirteen strains were then fermented at a higher scale in the laboratory for sensory evaluation. Only yeast strains of the species Schizosaccharomyces pombe and Lachancea thermotolerans were able to complete fermentation. Species such as Torulaspora delbrueckii, Metschnikowia pulcherrima, Wickerhamomyces anomalus, Hanseniaspora vineae, and Hanseniaspora guilliermondii could be used both for production of low ethanol beers and co-fermentation with a Saccharomyces yeast to improve the organoleptic characteristics of the beer. In addition, for these strains, the levels of melatonin obtained were higher than the concentrations found for Saccharomyces strains subjected to the same study conditions. The selected strains can be used in future trials to further determine their viability under different conditions and for different purposes.
Article
Full-text available
Background: It is unclear which psychological factors (stressors, emotional correlates, and psychophysiological markers) induce cancer risk. This currently limits the potential for prevention strategies. Purpose: The aim of this review is to bring forth evidence of stress as a determinant of cancer risk from a public health perspective, written for a broad public of practitioners and scientists. Methods: Based on a semisystematic literature search, the impact of different aspects/types of stress and the potential physiological and behavioral pathways are summarized, while highlighting further research, public health and clinical implications. Results: Between 2007 and 2020, 65 case-control or cohort studies have been identified. Apart from overall cancer (N = 24), 12 cancer types have been associated with psychological stress with most for breast (N = 21), colorectal (N = 11) and lung/prostate/pancreas cancer (N = 8 each). Although the evidence regarding the mechanisms is still scarce, cancer development in relation to stress might be due to interacting and combined effects of different stress(or) types, but such interaction has not really been tested yet. The path from stress towards cancer incidence consists of a biological pathway with endocrinology and immunology as well as stress-induced behavioral pathways, including smoking, alcoholism, sleep disruption, an unhealthy diet, and low physical activity together with the related phenomenon of obesity. Conclusion: Not only the stress but also the stress-induced lifestyle should be targeted for cancer prevention and treatment. Future research should include a more diverse spectrum of cancer types (not only hormonal related like breast cancer) and of stress measures while also considering behavioral covariates.
Article
The large-scale Women's Health Initiative has confirmed that, in postmenopausal women, combined estrogen/ progestin therapy entails an increased risk of invasive breast cancer. The investigators have now explored this relationship in detail, characterizing the cancers that developed and seeking to learn whether hormonal effects on the mammogram can influence diagnosis. A total of 16,608 postmenopausal women 50 to 79 years of age, all with an intact uterus, were randomly assigned to receive active treatment (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate daily in a single tablet) or placebo. The participants, seen at 40 clinical centers, were to be followed from 1993 to 1998 by annual clinical breast examinations and mammograms, but the trial was ended after a mean interval of 5.2 years. Intent-to-treat analyses demonstrated a hazard ratio of 1.24 for both total cancers and invasive cancers in women given hormone therapy compared with the placebo group. There was some suggestion of an increased risk for in situ breast cancer in hormone-treated women. An increased risk of breast cancer in treated women emerged after 3 years in those not receiving hormones previously and after 2 years in previously treated women. The findings were similar when women in specific risk categories were analyzed, and race and ethnicity were not significant factors. Invasive cancers associated with combined hormone therapy were larger than those in placebo recipients, more likely to be node-positive, and diagnosed when more advanced. There was, however, no difference in tumor grade or in the distribution of histologic types of breast cancer. After the first year, hormone-treated women more often had abnormal or highly suspicious mammograms than did those given placebo. In this prospective, randomized trial, combined estrogen/progestin treatment of postmenopausal women increased both breast cancer risk and the frequency of abnormal mammograms requiring medical assessment. In addition, cancers in treated women were more advanced when diagnosed than was the case for placebo recipients.
Article
Previous studies have demonstrated that lasofoxifene, a nonsteroidal selective estrogen-receptor modulator, decreases bone resorption, bone loss, and low-density lipoprotein cholesterol in postmenopausal women. Its effects of the risk of fractures, breast cancer, and cardiovascular disease are unclear. The postmenopausal evaluation and risk-reduction with lasofoxifene trial was an international, randomized, placebo-controlled trial that investigated the effects of lasofoxifene on the risk of fractures, estrogen receptor (ER)-positive breast cancer, and cardiovascular disease in a population of postmenopausal women with osteoporosis. The study subjects were a population of women between the ages of 59 and 80 years who had a bone mineral density T score of -2.5 or less at the femoral neck or spine. Participants were randomized to receive once-daily lasofoxifene at a dose of either 0.25 mg (low-dose, n = 2852) or 0.5 mg (high-dose, n = 2852) or placebo (n = 2852, control group) for 5 years. The trial was conducted at 113 sites in 32 countries. Vertebral and nonvertebral fractures and ER-positive breast cancer were the primary study end points. Major coronary heart disease events and stroke were the secondary endpoints. Compared with placebo, treatment with the high-dose lasofoxifene was associated with a reduction in the risk of vertebral fractures (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.47-0.70), nonvertebral fractures (18.7 vs. 24.5 cases per 1000 person-years; HR, 0.76; 95% CI, 0.64-0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; HR, 0.19; 95% CI, 0.07-0.56), major coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; HR, 0.68; 95% CI, 0.50―0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; HR, 0.64; 95% CI, 0.41-0.99). At 5 years compared to the placebo group, postmenopausal women receiving low-dose lasofoxifene showed reduced rates of vertebral fractures (16.0 vs. 22.4 per 1000 person-years; HR, 0.69; 95% CI, 0.57-0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; HR, 0.61; 95% CI, 0.39-0.96). Both drug doses were associated with increased risk of a venous thromboembolic event: Compared to the placebo which had 1.4 venous thromboembolic events per 1000 person-years, the low-dose group had 3.8 events per 1000 person-years (HR, 2.67; 95% CI, 1.55-4.58) and the high-dose group had 2.9 events per 1000 person-years (HR, 2.06; 95% CI, 1.17- 3.61). No increased risk of endometrial hyperplasia or endometrial cancer was observed at 5 years with either dose. Deaths per 1000 person-years were 7.0 and 5.7 for low dose and high dose, respectively, compared to 5.1 for the placebo (P = ns for both comparisons). These findings show that treatment of postmenopausal women with osteoporosis using a daily dose of lasofoxifene of 0.5 mg is associated with reduced risks of vertebral and nonvertebral fractures, ER-positive breast cancer, major coronary heart disease, and stroke, and an increased risk of thromboembolic events.
Article
In an attempt to define the role of the pineal secretory melatonin and an analogue, 6-hydroxymelatonin (6-OHM), in limiting oxidative stress, the present study investigated the cisplatin (CP)-induced alteration in the renal antioxidant system and nephroprotection with the two indolamines. Melatonin (5 mg/kg), 6-OHM (5 mg/kg), or an equal volume of saline were administered intraperitoneally (i.p.) to male Sprague–Dawley rats 30 min prior to an i.p. injection of CP (7 mg/kg). After CP treatment, the animals each received indolamine or saline every day and were sacrificed 3 or 5 days later and plasma as well as kidney were collected. Both plasma creatinine and blood urea nitrogen increased significantly following CP administration alone; these values decreased significantly with melatonin co-treatment of CP-treated rats. In the kidney, CP decreased the levels of GSH (reduced glutathione)/GSSG (oxidized glutathione) ratio, an index directly related to oxidative stress. When animals were treated with melatonin, the reduction in the GSH/GSSG ratio was prevented. Treatment of CP-enhanced lipid peroxidation in the kidney was again prevented in animals treated with melatonin. The activity of the antioxidant enzyme, glutathione peroxidase (GSH-Px), decreased as a result of CP administration, which was restored to control levels with melatonin co-treatment. Upon histological analysis, damage to the proximal tubular cells was seen in the kidneys of CP-treated rats; these changes were prevented by melatonin treatment. 6-OHM has been shown to have some antioxidative capacity, however, the protective effects of 6-OHM against CP-induced nephrotoxicity were less than those of melatonin. The residual platinum concentration in the kidney of melatonin co-treated rats was significantly lower than that of rats treated with CP alone. It is concluded that administration of CP imposes a severe oxidative stress to renal tissue and melatonin confers protection against the oxidative damage associated with CP. This mechanism may be reasonably attributed to its radical scavenging activity, to its GSH-Px activating property, and/or to its regulatory activity for renal function.
Article
The use of the conventional combination oral contraceptives (containing ethinyl-estradiol and a progestin) is associated with reduced risk of ovarian and endometrial cancer. However, prolonged use of these pills before first term pregnancy apparently increases the risk of pre menopausal breast cancer. We propose that the pineal gland hormone melatonin, combined with a progestin, as a new and novel oral contraceptive combination might prevent breast cancer in long term users. This hypothesis is based on the assumption that women have a propensity to develop breast cancer which correlates with number of ovulatory cycles over their lifetime. In evolution, the phylogenetic point at which women became sensitive to breast cancer evolved at a transfer point of the mechanism of ovulation from seasonal ovulation, which is still common in many mammalian species, to the current human pattern of continuous ovulatory cycles. We suggest that melatonin/ovariansteroid contraceptive will restore the lost mechanism of endogenous anovulation, and thus, by preventing continuous epithelial breast cell proliferation, will reduce the risk of breast cancer in long-term users.
Article
Estradiol stimulates the growth of breast tumor cells in both pre- and post menopausal women. Following the menopause, the levels of estradiol in breast tumor tissues are similar to those from tumors obtained prior to cessation of ovarian function, even though plasma estrogen levels are 10–50 fold lower in post- than in premenopausal women. These observations suggested the possibility of enhanced estradiol uptake from plasma or in situ synthesis in post-menopausal women. We systematically studied these possibilities in a series of model systems. Initially we demonstrated a very high affinity estradiol binding site in tissues from castrated rats. Enhanced uptake occurred under conditions of low plasma estrogen levels when compared to animals with higher estradiol levels. In situ synthesis also occurred both through the sulfatase and aromatase pathways. In further studies, we compared uptake from plasma with in situ synthesis via aromatase in a nude mouse model. Under the conditions utilized, in situ synthesis resulted in much higher tissue estradiol levels and tumor growth rates than did uptake from plasma. During these studies we demonstrated that tumors deprived of estradiol developed mechanisms rendering them more sensitive to estrogen. This involved the ability of cells to adapt to estradiol deprivation to allow them to be responsive to four log lower amounts of estrogen than when studied under wild type conditions. In addition, cells adapted by increasing their level of aromatase and thus developing the capability to become more sensitive to estrogen precursors. Taken together, these studies demonstrate that breast cancer tissue is highly plastic and can adapt to conditions of estrogen deprivation via a variety of mechanisms.