Melatonin: New applications in clinical and veterinary medicine, plant physiology and industry

Abstract

Novel functions of melatonin continue to be uncovered. Those summarized in this report include actions at the level of the peripheral reproductive organs and include functions as an antioxidant to protect the maturing oocyte in the vesicular follicle and during ovulation, melatonin actions on the developing fetus particularly in relation to organizing the circadian system, its potential utility in combating the consequences of pre-eclampsia, reducing intrauterine growth restriction, suppressing endometriotic growths and improving the outcomes of in vitro fertilization/embryo transfer. The inhibitory effects of melatonin on many cancer types have been known for decades. Until recently, however, melatonin had not been tested as a protective agent against exocrine pancreatic tumors. This cancer type is highly aggressive and 5 year survival rate in individuals with pancreatic cancer is very low. Recent studies with melatonin indicate it may have utility in the treatment of these otherwise almost untreatable pancreatic cancers. The discovery of melatonin in plants has also opened a vast new field of research which is rapidly being exploited although the specific functions(s) of melatonin in plant organs remains enigmatic. Finally, the described application of melatonin's use as a chemical reductant in industry could well serve as a stimulus to further define the utility of this versatile molecule in new industrial applications.

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To cite this article:
Neuroendocrinol Lett 2011; 32(5):575–587
REVIEW ARTICLE
Neuroendocrinology Letters Volume 32 No. 5 2011
Melatonin: new applications in clinical and
veterinary medicine, plant physiology and industry
Russel J. R, Ana C-M, Jose Antonio B, Lorena F-B,
Sergio R-C, Dun-Xian T
Department of Cellular & Structural Biology, UT Health Science Center, San Antonio, Texas, USA
Correspondence to: Prof. Russel J. Reiter,
Department of Cellular and Structural Biology,
University of Texas Health Science Center,
7703 Floyd Curl Drive, San Antonio, Texas, USA 78229.
-: reiter@uthscsa.edu
Submitted: 2011-07-28 Accepted: 2011-08-17 Published online: 2011-11-12
Key words: melatonin; placenta; fetus; in vitro fertilization; auxin-like actions; plants;
industrial use; bio-compatible reductant
Neuroendocrinol Lett 2011; 32(5):575–587 PMID: 22167140 NEL320511R01 © 2011 Neuroendocrinology Letters • www.nel.edu
Abstract
Novel functions of melatonin continue to be uncovered. Those summarized
in this report include actions at the level of the peripheral reproductive organs
and include functions as an antioxidant to protect the maturing oocyte in the
vesicular follicle and during ovulation, melatonin actions on the developing fetus
particularly in relation to organizing the circadian system, its potential utility
in combating the consequences of pre-eclampsia, reducing intrauterine growth
restriction, suppressing endometriotic growths and improving the outcomes of in
vitro fertilization/embryo transfer. The inhibitory effects of melatonin on many
cancer types have been known for decades. Until recently, however, melatonin
had not been tested as a protective agent against exocrine pancreatic tumors.
This cancer type is highly aggressive and 5 year survival rate in individuals with
pancreatic cancer is very low. Recent studies with melatonin indicate it may have
utility in the treatment of these otherwise almost untreatable pancreatic cancers.
The discovery of melatonin in plants has also opened a vast new field of research
which is rapidly being exploited although the specific functions(s) of melatonin in
plant organs remains enigmatic. Finally, the described application of melatonin’s
use as a chemical reductant in industry could well serve as a stimulus to further
define the utility of this versatile molecule in new industrial applications.
INTRODUCTION
Subsequent to its discovery and characterization
more than 50 years ago (Lerner et al. 1958; 1959),
melatonin has been linked to a wide variety of
functions in organisms from plants (Paredes et
al. 2009; Iriti et al. 2010) to humans (Dominguez-
Rodriguez et al. 2010; Paradies et al. 2010). Indeed,
the functional versatility of this indoleamine has
surprised even the most ardent scientists working
in this dynamic field. While its actions are often
characterized as being hormonal in nature, it also
functions as a paracoid, an autocoid, a tissue factor
and as an amine antioxidant (Tan et al. 2003). These
multiple actions involve both receptor-mediated
mechanisms (Stankov & Reiter 1990; Dubocovich
& Markowska 2005) as well as processes that are
receptor-independent (Reiter et al. 2007b; Jou et al.
2010). The receptor-dependent processes of mela-
tonin involve classical membrane receptors (Pozo
et al. 2010; Hardeland et al. 2011), nuclear binding
sites (Acuna-Castroviejo et al. 1994; Carrillo-Vico

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Russel J. Reiter, Ana Coto-Montes, Jose Antonio Boga, Lorena Fuentes-Broto, Sergio Rosales-Corral, Dun-Xian Tan
et al. 2005) as well as its ability to interact with cytosolic
proteins (Hardeland 2009; Sharkey et al. 2010). Mela-
tonin’s multi-faceted actions make it one of the most
ubiquitously acting molecules in nature (Reiter 1991).
While melatonin was initially thought to be synthesized
exclusively in the pineal gland of vertebrates (Axelrod
1970; Klein & Weller 1970), its production has now
been documented in an uncommonly large number of
vertebrate tissues (Hamm & Menaker 1980; Huether
1994) as well as in non-vertebrates which lack a pineal
gland (Finnocchiaro et al. 1988; Hardeland & Poeggeler
2003) and also likely in plants (Murch & Saxena 2006).
This brief survey highlights some of the emerging
fields of melatonin research. Of particular note is the
large number of scientists from widely diverse disci-
plines whose investigative efforts now involve melato-
nin. The rapid expansion of research activities on this
indoleamine has opened new vistas that will surely be
exploited within the next decade.
NEW ASPECTS OF MELATONIN AND
REPRODUCTIVE PHYSIOLOGY
Even before melatonin was extracted from the bovine
pineal gland (Lerner et al. 1958, 1959), morphological
changes in the appearance of cells in this gland sug-
gested it was regulated/influenced by the light:dark
environment (Quay 1956). Thus, after its discovery, the
metabolic activity of the pineal gland throughout the
light:dark cycle was examined and it quickly became
obvious that the gland, judging from the level of pre-
cursors and the activities of the enzymes involved in
tryptophan metabolism, was more active at night than
during the day (Quay 1963; Axelrod & Wurtman 1968).
Moreover, since it had long been suspected that some
factor of pineal origin was capable of altering repro-
ductive physiology (Kitay & Altschule 1954), it was
surmised very early that annual changes in photope-
riod likely impelled seasonal changes in reproductive
capability (Reiter & Fraschini 1969). This was also sup-
ported by the observations that either surgical removal
of the pineal gland (Hoffman & Reiter 1965, 1966) or
its sympathetic denervation (Reiter & Hester 1966)
prevented perturbations of the light:dark cycle from
influencing the annual reproductive fluctuations in the
photoperiodic rodent, the Syrian hamster (Reiter 1973).
While the activity of the pineal gland was clearly
linked to fluctuations in sexual physiology induced by
changes in the photoperiod, tests to document the role
of melatonin in these responses initially failed (Reiter
et al. 1974). Using a more appropriate experimental
paradigm, however, it eventually became apparent that
melatonin was the pineal factor responsible for the reg-
ulatory actions of the pineal on reproductive atrophy
and recrudescence (Reiter et al. 1976; Tamarkin et al.
1976; Carter & Goldman 1983).
It is currently well accepted that seasonal reproduc-
tive changes in photoperiod-sensitive mammals are
inextricably linked to the changing duration of noc-
turnal melatonin levels (Reiter 1974; Malpaux et al.
2002; Focada et al. 2006). This is true for both long day
and short day breeding mammals with the molecular
mechanisms of these interactions having been at least
partially clarified (Vidal et al. 2009; Scherbarth & Stein-
lechner 2010).
The ability of melatonin to synchronize the annual
cycle of reproduction in photoperiodic species generally
involves its ability to modulate the activities of hypo-
thalamic neurons and pars tuberalis cells which subse-
quently control gonadotropin secretion from the cells
of the pars distalis (Malpaux et al. 2002; Focada et al.
2006; Vidal et al. 2009; Clarke et al. 2009; Schenbarth &
Steinlechner 2010). At the level of the peripheral repro-
ductive organs, however, melatonin also has important
actions that are essential for optimal sexual physiology
(Reiter et al. 2009c; Tamura et al. 2009). In the follicu-
lar fluid of the human vesicular ovarian follicle, the
measured melatonin concentrations exceed those of
simultaneously collected blood samples (Brzezinski et
al. 1987; Nakamura et al. 2003). These differential levels
of melatonin in follicular fluid and blood indicate an
important point, namely, that melatonin concentrations
in the body are not in equilibrium but vary from one
fluid (or cell?) to another. This is also consistent with
observations that other fluids, e.g., bile (Tan et al. 1999;
Koppisetti et al. 2008) and cerebrospinal fluid (Skinner
& Malpaux 1999; Tan et al. 2010), also have melatonin
levels that exceed those measured in the peripheral cir-
culation. Thus, as a general rule, it seems that the con-
centrations of melatonin are lower in the blood than
they are in other bodily fluids. One seemingly impor-
tant implication of this is that at least the cell membrane
receptors, which exist in many cells throughout the
organism, may be exposed to vastly different melato-
nin concentrations. Whether this has relevance to an
influence on the signal transduction processes of these
receptors or whether different melatonin membrane
receptors respond to different concentrations of mela-
tonin remains a subject for later research. The possi-
bility also exists that elevated melatonin levels in some
bodily fluids may be unrelated to the receptor actions
of this indoleamine but rather may be essential for its
functions as a direct free radical scavenger (Reiter et al.
2002c, 2008b; Tan et al. 2008; Romero et al. 2010).
Melatonin and ovarian function
In the ovarian follicular fluid, melatonin has ready
access to the granulosa and luteal cells. In the human
and in the rat ovary these cells have been found to pos-
sess the classic membrane melatonin receptors, i.e., the
MT1 and MT2 receptor (Niles et al. 1999; Woo et al.
2001). After ovulation, the developing corpus luteum
also contains these receptors (Soares et al. 2003). Mela-
tonin has been shown to influence steroidogenesis by
the ovarian granulosa cells (Yie et al. 1995). Receptor-
independent functions of melatonin in the follicle may

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Melatonin: Diverse uses
be to protect especially the maturing oocyte from oxi-
dative damage particularly at the time of ovulation,
a process that is believed to involve an inflammatory
response (Espey et al. 2003) and, as a consequence, the
generation of large numbers of free radicals. The mature
oocyte, which when fertilized will develop into the next
generation, is a precious commodity that must be pro-
tected from damage of any type including mutilation by
free radicals. Follicular fluid melatonin levels seem to
reach their maximal concentrations just prior to ovula-
tion (Tamura et al. 2009). Exogenously-applied melato-
nin may be helpful in reducing free radical-mediated
damage to the maturing oocyte since the concentra-
tions of melatonin in the follicular fluid of infertile
women given 3 mg melatonin daily increased 3–4 fold
(Tamura et al. 2008b). Whereas these findings are con-
sistent with melatonin being taken into the ovarian fol-
licular fluid from the blood, whether this is the case in
women not supplemented with melatonin, where the
concentration of the indoleamine also is greater than
the level in the blood, remains to be proven. Melatonin
produced in the ovaries themselves may contribute to
the elevated melatonin concentrations in the follicular
fluid. Recall, the activities of the two melatonin syn-
thesizing enzymes, i.e., alkylamine N-acetyltransferase
(AANAT) and acetylserotonin N-methyltransferase
(ASMT) (formerly called hydroxyindole-O-methyl-
transferase or HIOMT) are detectable in human ovar-
ian homogenates (Itoh et al. 1999).
Melatonin and the fetus
Pregnancy is a hazardous time for both the mother and
the fetus. For optimal fetal development and normal
fetal delivery, a healthy placenta is required. The devel-
oping fetus produces no melatonin but melatonin in
the maternal blood is quickly transferred through the
placenta to the fetus (Okatani et al. 1998). Thus, the
fetal circulation exhibits a melatonin rhythm like that
of the mother. Also, anything that perturbs the mater-
nal melatonin rhythm, e.g., light at night, likewise alters
the concentrations of melatonin in the fetal blood.
Moreover, a faulty association between the maternal
and fetal placental components could also jeopardize
the amount of melatonin entering the fetal circulation.
The importance of the fetal melatonin rhythm, derived
from the maternal pineal gland, relates to the role of
this indoleamine in synchronizing the fetal biological
clock, i.e., the suprachiasmatic nuclei (SCN). Also, in
the event that the fetus is rendered hypoxic (a condi-
tion that generates excessive free radicals) as a result
of some abnormality, Wakatsuki and colleagues (1999)
have shown that supplementing pregnant rats with
melatonin results in reduced oxidative damage in the
fetus. Thus, physiological levels of melatonin in the
fetal circulation can be supplemented by administer-
ing pharmacological amounts of this antioxidant to
the mother (Tamura et al. 2009). These findings could
have implications for the prevention of periventricular
leukomalacia and the subsequent cerebral palsy (Lee &
Davis 2011).
In addition to protecting the fetus from free radi-
cal damage, the melatonin rhythm due to its actions on
the fetal SCN impacts its circadian maturation. This in
turn, has affects on postnatal behavior (Kennaway 2002;
Torres-Farfan et al. 2006). In view of this, it would seem
judicious that pregnant women, particularly during
the third trimester of pregnancy, avoid light at night
so as to preserve a normal circadian melatonin signal
thereby allowing it to influence the normal maturation
and development of the fetal circadian system.
Melatonin and pre-eclampsia
The placenta is a highly complex organ that, under
conditions of abnormal development, can jeopardize
the health of both the fetus and the mother. Interest-
ingly, the placenta, i.e., the cytotrophoblasts as well as
the syncytiotrophoblasts, have the enzymatic machin-
ery to produce melatonin (Lanoix et al. 2008). The
production of melatonin in this organ could be highly
advantageous considering that a major disease of preg-
nancy, i.e., pre-eclampsia, is a high free radical-related
condition (Siddiqui et al. 2010; Benedetto et al. 2011).
Typically women with pre-eclampsia possess many fea-
tures which are indicative of high oxidative stress, e.g.,
elevated placental superoxide anion radicals, reduced
placental superoxide dismutase and glutathione per-
oxidase activities, reduced placental and whole blood
glutathione and depressed levels of circulating vitamins
C and E and melatonin. Additionally, there is often an
elevation in maternal blood pressure and pre-eclampsia
can proceed to eclampsia in which seizures occur (Saft-
las et al. 1990). The use of melatonin has been suggested
as a potential treatment for pre-eclampsia (Tamura et
al. 2008a). Such studies seem justified considering the
potent free radical scavenging activities of melatonin
and its metabolites (Tan et al. 1993, 2008; Reiter et al.
2008a; Das et al. 2010; Milczarek et al. 2010; Stasiak
et al. 2010), melatonin’s ability to stimulate antioxida-
tive enzymes (Rodriguez et al. 2004), and its beneficial
synergistic actions with other antioxidants (Gitto et al.
2001; Milczarek et al. 2010). Additionally, melatonin
has antihypertensive actions (Scheer 2005; Simko &
Pechanova 2009; Reiter et al. 2010b) which may reduce
the mean blood pressure of pre-eclamptic women and
it has anti-seizure actions (Molina-Carballo et al. 1997)
which could aid in preventing the progression of pre-
eclampsia to eclampsia. Finally, melatonin has not been
shown to exhibit toxicity either in the fetus or in the
mother when given to pregnant rats (Jahnke et al. 1999).
Melatonin and intrauterine growth restriction
Intrauterine growth restriction (IUGR) of the fetus is
also not an uncommon feature of abnormal placenta-
tion and other factors which reduce the blood supply
and/or the availability of oxygen to the fetus (Salafia et
al. 1992). To simulate compromised blood flow to the

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Russel J. Reiter, Ana Coto-Montes, Jose Antonio Boga, Lorena Fuentes-Broto, Sergio Rosales-Corral, Dun-Xian Tan
placenta and fetus with the intent of limiting intrauterine
growth, it is common to transiently occlude the utero-
ovarian arteries in late pregnancy in rats (Tanaka et al.
1994). Nagai and colleagues (2008) used this method
and gave supplemental melatonin to determine whether
the damage inflicted in the placenta and fetus as a result
of the transitory period of hypoxia and reoxygenation
could be prevented. In this study, the utero-ovarian
arteries of pregnant rats were occluded for 30 min-
utes on the 16th day of pregnancy (gestation length is
20 or 21 days). At day 20, the non-melatonin treated
rats exhibited reduced placental and fetal weights and a
lower respiratory control index, a marker of mitochon-
drial respiratory chain activity, as well as elevated levels
of a damaged DNA product (8-hydroxy-2-deoxyguano-
sine) and redox factor-1 (which promotes the repair of
damaged DNA) in the placenta. In addition to prevent-
ing the molecular damage at the level of the placenta,
melatonin limited the reduction in fetal weight and fetal
death resulting from the ischemia/reperfusion episode.
Clearly, melatonin had limited the IUGR that resulted
from a compromised blood supply. That melatonin also
restored the mitochondrial respiratory control index
is in line with the actions of melatonin at the level of
the mitochondria (Acuna-Castroviejo et al. 2001, 2011;
Rodriguez et al. 2007; Garcia-Macia et al. 2011) includ-
ing in the human placental mitochondria (Milczarek et
al. 2010).
A diminished blood supply to the fetus also reduces
fetal nutrient delivery which negatively impacts the
placento-fetal unit (Fowden et al. 2006) and leads to
elevated oxidative/nitrosative stress in these tissues
(Franco et al. 2007). Richter and co-workers (2009)
examined the ability of melatonin to counteract the
effects of malnourishment or placental efficiency, fetal
weight and markers of oxidative stress in rats. Nutri-
ent restriction was achieved by a 35% reduction in food
intake during the last 5 days of pregnancy in rats while
melatonin was given via the drinking fluid. Maternal
undernutrition limited placental function and caused
fetal growth retardation, changes prevented when mela-
tonin was available to the undernourished rats. The pro-
tective effects of melatonin in this study were believed
to relate to the direct free radical scavenging actions of
melatonin and its metabolites (Hardeland et al. 2009;
Bonnefont-Rousselot et al. 2011) and to its indirect
antioxidant actions via stimulation of the enzymes,
superoxide dismutase and catalase, which metabolize
potentially toxic oxygen derivatives to innocuous prod-
ucts (Fowden et al. 2006).
Melatonin and endometriosis
Endometriosis is a severe chronic inflammatory condi-
tion in which implantation and growth of endometrial
tissue occurs outside the uterine cavity (Garai et al.
2006). Although this condition is not life threatening, it
poses a major risk factor for infertility and predisposes
to ovarian cancer. Since it is an inflammatory condition,
massive free radical generation occurs during endome-
triosis (Zeller et al. 1987). Data suggesting a beneficial
action of melatonin in endometriosis is still fragmen-
tary and limited but the preliminary findings suggest
the indoleamine may have therapeutic value in this
condition. Findings published by Güney et al (2008)
confirmed, in a rat model of endometriosis, that mela-
tonin induced regression and atrophy of endometriotic
lesions and reduced the number of cyclooxyenase-2
(COX-2) positive cells and the levels of lipid hydroper-
oxides in the diseased tissues. In mice as well, melato-
nin caused the regression of an endometriosis model
and arrested lipid peroxidation and protein damage in
the lesions (Paul et al. 2008). This group also reported
on a new diagnostic marker for judging the progression
and severity of the disease, i.e., the expression ratio of
matrix metalloproteinases (MMP-9)/tissue inhibitors
of metalloproteinases (TIMP). Melatonin down regu-
lated the activity and expression of pro-MMP-9 and
elevated TIMP expression further supporting a role for
melatonin in suppressing endometriosis. The regula-
tion of MMP and TIMP by melatonin has far reaching
implications considering these enzymes are involved in
a number of pathophysiological conditions (Swarnakar
et al. 2011).
Melatonin and IVF-ET
A highly important application of melatonin was
recently reported when it was found that the indole-
amine improved the pregnancy outcome of in vitro
fertilization/embryo transfer (IVT-ET) (Tamura et
al. 2008b). Poor oocyte quality is a major factor that
reduces successful implantation in assisted reproduc-
tive technologies. The less than optimal oocyte qual-
ity is often considered to be a result of damage by free
radicals, which have a major impact on reproductive
physiology generally (Sugino 2005, 2007). Given that
melatonin and its metabolites are versatile antioxidants
(Rodriguez et al. 2004; Tan et al. 2008; Korkmaz et al.
2008; Reiter et al. 2009a; Wiktorska et al. 2010), Tamura
and co-workers (2008b) tested whether melatonin
would protect the oocyte from free radical damage and
thereby improve the outcome of IVF-ET. Human ovar-
ian follicular fluid was sampled at the time of oocyte
retrieval and the level of 8-hydroxy-2-deoxyguanosine
(8-OHdG), a damaged DNA product, was estimated in
the fluid. The quantity of damaged DNA was found to
be inversely related to degenerate state of the oocytes,
i.e., the follicular fluid associated with the most dete-
riorated oocytes had the highest levels of 8-OHdG
and there was also a negative correlation between the
melatonin concentration of the fluid and intrafollicu-
lar 8-OHdG levels. When women who were undergo-
ing IVF-ET were treated with melatonin prior to the
procedure, the fertilization and pregnancy rates were
improved and were correlated with a reduction in
8-OHdG and a damaged lipid product, hexanoyl-lysine
adduct, in the follicular fluid. Considering the improve-

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Melatonin: Diverse uses
ment of both the fertilization and pregnancy rates in
the women treated with melatonin, the indoleamine,
presumably because of its antioxidant activities, may
prove to be highly beneficial in reducing the necessity
for repeated attempts at IVF-ET.
On the basis of the studies summarized here as well
as those surveyed in other reviews (Malpaux et al. 2002;
Tamura et al. 2008a, 2009; Revel et al. 2009; Casao et al.
2010), it is obvious that melatonin has multiple actions
on the hypothalamo-hypophyseal axis as well as at the
level of the peripheral reproductive organs. Whereas the
bulk of the studies summarized above were performed
in females, similar protective effects have been shown
for the reproductive system of males, in both humans
and domestic animals (Casao et al. 2010; Ortiz et al.
2011; Succu et al. 2011). These diverse roles of melato-
nin probably involve actions via membrane receptors,
i.e., MTI and MT2 (Dubocovich & Markowska 2005;
Hardeland 2009), and also via receptor-independent
effects when melatonin and its metabolites function in
the scavenging of free radicals and related derivatives
(Reiter et al. 2009a; Paradies et al. 2010; Galano et al.
2011).
NEW ASPECTS OF MELATONIN AND
CANCER
As with melatonin and reproductive physiology, the
established association between melatonin and cancer
has a rather long investigative history with the earli-
est studies claiming that surgical removal of the pineal
gland, and therefore removal of a major source of mela-
tonin, enhanced tumor growth (Rodin 1963; Das Gupta
& Terez 1967). That the loss of melatonin was likely the
cause of accelerated cancer cell proliferation after pineal
removal became apparent about a decade later when it
was shown that daily melatonin administration slowed
tumor growth in rats (Lapin & Ebels 1976); in addition
to melatonin, this group also argued that low molecular
weight peptides from the ovine pineal gland contribute
to the oncostatic actions (Lapin & Ebels 1976). Prior
to melatonin being established as the major secretory
product of the pineal gland, it was commonly asserted
that in fact peptides, rather than the indoleamine mela-
tonin, accounted for the endocrine effects of the pineal
(Benson 1980; Pevet et al. 1980). This notion has been
dispelled in recent decades by the failure of these inves-
tigators to identify any peptide that is synthesized and
released from the pineal.
That melatonin has oncostatic actions is no longer
debated (Mediavilla et al. 2010) and interest in the use
of this endogenous non-toxic molecule as a cancer
treatment is high. Despite this interest, clinical trials
have been agonizingly slow to be executed. The reason
for this is that melatonin per se has garnered little sup-
port from the pharmaceutical industry because it is a
non-patentable molecule. Thus, drug companies are
unwilling to support extensive clinical trials of an anti-
cancer drug if they will not be the exclusive purveyor
of the agent once its efficacy is established. Similarly,
the granting agencies, whose budgets are being strained
by numerous grant applications, have yet to support an
expensive human trial related to the oncostatic proper-
ties of melatonin. From the pharmaceutical company
perspective, however, it would seem that they should be
interested in combining their toxic cancer chemothera-
pies with melatonin since it has repeatedly been shown
to reduce the toxicity of many of the chemotherapies in
common use (Reiter et al. 2002a, 2002b). By reducing
their side effects, the dose of the chemotherapy could
possibly also be increased thereby elevating its tumor-
killing potential. Finally, melatonin, which itself has
obvious anti-cancer actions, could further elevate the
oncostatic effects of the combined therapies.
Within the last two decades, there has been a major
emphasis on the ability of melatonin to inhibit especially
breast (Blask et al. 1992, 2005; Coleman & Reiter 1992;
Cos & Sanchez-Barcelo 1994; Stevens & Davis 1996;
Leon-Blanco et al. 2003) and prostate cancer (Philo &
Berkowitz 1988; Lupowitz & Zisapel 1999; Marelli et al.
2000; Sainz et al. 2005; Shiu et al. 2003; Shiu 2007), a
trend that continues to the current time (Korkmaz et al.
2009; Jung-Hynes et al. 2010a, 2010b; Shiu et al. 2010).
Many of these investigations have been elegant and
have unequivocally established a role for melatonin as
an effective experimental oncostatic agent. What is per-
plexing, however, is the very wide range of mechanisms
proposed to explain the processes by which melatonin
suppresses the growth of breast and prostate cancer cells
(Cos & Sanchez-Barcelo 1994; Yuan et al. 2002; Leon-
Blanco et al. 2003; Blask et al. 2005; Sainz et al. 2005;
Korkmaz et al. 2009; Jung-Hynes et al. 2010a, 2010b;
Shiu 2007; Shiu et al. 2010; Park et al. 2010; Proietti et
al. 2011). How these multiple potential mechanisms by
which melatonin modulates tumor cell proliferation
will be reconciled awaits further investigations.
Breast and prostate cancers are by no means the only
tumor types that are reportedly inhibited by melatonin.
This indoleamine has been effective in restraining the
growth of virtually every tumor against which it has
been tested. Recently, melatonin was examined for its
efficacy in diminishing the growth of pancreatic cancer
(Leja-Szpak et al. 2010; Padillo et al. 2010; Gonzalez et
al. 2011). These findings are particularly noteworthy
since cancer of the pancreas is especially difficult to
treat and even when all available measures are used, the
5-year survival is still less than 5% (Han et al. 2006).
Melatonin is well known to be a pro-apoptotic stim-
ulus for a large number of cancer cell types (Sainz et
al. 2003). This proved also to be the case for human
pancreatic cancer cells (PANC-1) in culture. After 24
or 48 hours of incubation with melatonin (10–8–10–12),
PANC-1 cells exhibited elevated Bcl-2/Bax and caspase
9 levels with the strongest signal of these pro-apoptotic
factors being achieved with melatonin at a concentra-
tion of 10–12 M (Leja-Szpak et al. 2010). When pan-

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Russel J. Reiter, Ana Coto-Montes, Jose Antonio Boga, Lorena Fuentes-Broto, Sergio Rosales-Corral, Dun-Xian Tan
creatic cancer cells were incubated with a combination
of melatonin and luzindole (10–12), a MT1 and MT2
melatonin receptor blocker, the pro-apoptotic actions
of the indoleamine were completely abolished. While
these findings are consistent with melatonin promoting
apoptosis of pancreatic carcinoma cells via a membrane
receptor-mediated pathway, considering the wide vari-
ety of mechanisms by which the indoleamine inhibits
cancer cells of other types (Reiter et al. 2009b; Media-
villa et al. 2010), the processes described in this report
may not be the only mechanisms by which melatonin
suppressed pancreatic cancer cell growth.
Pancreatic cancer was induced in Syrian hamsters
by the administration of N-nitrosobis (2-oxopropyl)
amine (BOP). This agent was used to establish pan-
creatic lesions since it causes a similar pancreatic
tumor pattern to that type seen in humans. Following
the administration of BOP, melatonin or celecoxib, a
COX-2 inhibitor, were given alone or in combination
during the initiation phase, the post-initiation phase or
during both phases of tumor development (Padillo et al.
2010). Melatonin proved more effective than celecoxib
in reducing the development of pancreatic tumor nod-
ules and improving survival of the hamsters. There was
also some evidence that the combined treatment, espe-
cially during the post-initiation phase, reduced pancre-
atic tumor incidence but, in general, celecoxib had a
very minor effect in improving the beneficial effects of
melatonin (Padillo et al. 2010).
In the third report of this series, AR42J pancre-
atic tumor cells (derived from rat exocrine pancreas)
were used; AR42J is the only cell line that maintains
many of the characteristics of normal pancreatic acinar
cells including the synthesis and secretion of digestive
enzymes. When incubated in the presence of mela-
tonin, the indoleamine caused transitory changes in
cytosolic-free Ca2+ levels [Ca2+] and mitochondrial
free Ca2+ concentrations [Ca2+]m and induced mito-
chondrial membrane depolarization which led to a
reduction in oxidized flavin adenine dinucleotide
(FAD). Also, melatonin reduced AR42J cell viability
and activated Ca2+-dependent caspase-3. In view of the
cellular changes observed, Gonzalez et al (2011) theo-
rized that melatonin curtailed pancreatic cell viability
via mechanisms that involved mitochondrial function
impairment.
These three reports, all of which appeared within the
last year, convincingly show that, at least under experi-
mental conditions, melatonin inhibits the growth and
reduces the viability of pancreatic exocrine tumors.
These findings could prove to be of major importance
since there are currently few adequate treatments for
these very aggressive tumors in humans.
A number of the scientific publications have noted
that the nighttime physiological melatonin concentra-
tion is capable of inhibiting tumor growth and that
even partial suppression of nocturnal melatonin levels
may promote excessive tumor metabolic activity and
growth (Blask et al. 2005). Indeed, the nighttime inhibi-
tion of melatonin by artificial light has been frequently
invoked as an explanation for the elevated incidence of
breast cancer in women who work at night (Schern-
hammer et al. 2006; Erren et al. 2010; Kloog et al. 2010;
Reed 2011). It is also noteworthy that since as animals
(Reiter et al. 1980; 1981) and humans (Sack et al. 1986;
Pang et al. 1998) age, their ability to produce melatonin
(judging from the drop in pineal and serum melatonin
concentrations) wanes and a natural consequence may
be an elevated risk of developing cancer. Of course,
many cancer types are, in fact, age-related; however,
whether the rise in cancer incidence in the elderly has
anything to do with the attenuated melatonin levels
remains unproven at this point but would be worth
examining. If an association is shown to exist it may be
possible to reverse the trend of elevated cancer risk in
an aging population by encouraging the regular use of
melatonin.
The amplitude of the nocturnal rise in endogenous
melatonin in humans is genetically determined. As a
result, the amplitude of the nighttime increase varies
widely, i.e., some individuals have a robust melatonin
increase nightly while in other individuals the rise is
significantly attenuated. Thus, it appears some indi-
viduals are relatively melatonin deficient even during
early and middle age. If such attenuated nocturnal
levels of melatonin promote tumor growth as suggested
by at least one study (Blask et al. 2005), then people
with a relative deficiency of melatonin may be prone
to developing cancer at an earlier age than normal. If
so, measuring the nighttime serum melatonin rise early
in life may have prognostic value as a predictor of the
likelihood of an individual to develop cancer.
NEW ASPECTS OF MELATONIN IN PLANTS
In reality, everything that is known about melatonin in
plants must be considered as new. In the early 1990s
it had been established that melatonin was very wide-
spread in the animal kingdom, existing in organisms
as diverse of humans (Vaughan et al. 1976) and uni-
cellular algae (Poeggeler et al. 1991). This prompted
scientists to search for melatonin in plants and in 1995
two publications appeared that measured melatonin
in various plant organs (Dubbels et al. 1995; Hattori et
al. 1995). Although initially viewed with skepticism,
these findings have been repeatedly confirmed using
all currently available techniques for the measurement
of this indoleamine. This field of research is currently
in an exponential growth phase and the findings have
attracted the attention of botanists, plant physiologists,
nutritionists, etc. (Paredes et al. 2009; Iriti et al. 2010;
Huang et al. 2011; Sharman et al. 2011).
The concentration of melatonin in different plants
and different plant organs varies widely (Reiter et al.
2007a). Interestingly, the highest melatonin levels mea-
sured in any plants have been in Chinese herbal medi-

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Melatonin: Diverse uses
cines (Chen et al. 2003). It is also common that plant
seeds contain high melatonin concentrations, although
again the levels vary widely among different seeds
(Manchester et al. 2000). It is speculated that the high
melatonin concentrations, because of the antioxidant
activity of the indoleamine, aids in the germination of
the seed. Seeds are rich in easily oxidized fats and high
concentrations of a potent antioxidant such as melato-
nin would be highly beneficial in preventing molecular
damage and maintaining the ability of a seed to suc-
cessfully germinate.
In at least one plant, the water hyacinth, melatonin
levels as well as its metabolite N1-acetyl-N2-formyl-5-
methoxykynuramine (AFMK) varies throughout the
light:dark cycle (Tan et al. 2007a). The peak melatonin
levels, however, are not linked to darkness as in most
vertebrates, but rather occur near the end of the light
phase. Tan and colleagues (2007a) surmised that mela-
tonin increases during the day to scavenge free radicals
produced as a consequence of the process of photosyn-
thesis. That this may be the function of melatonin in this
situation is consistent with peak AFMK concentrations,
which followed shortly after the melatonin peak in the
hyacinth. AFMK is known to be formed when melato-
nin scavenges free radicals in animal tissues (Tan et al.
2002). The free radical scavenging activity of melatonin
may also explain how plants, enriched with melato-
nin, resist damage when exposed to heavy metals (Tan
et al. 2007b). The distribution of melatonin in plants
includes its presence in flowers and fruits (Burkhardt et
al. 2001; Iriti 2009; Murch et al. 2009, 2010). Consump-
tion of plant products that contain melatonin cause a
rise in blood melatonin concentrations (Hattori et al.
1995; Reiter et al. 2005) which correlate with the total
antioxidant status of the blood (Benot et al. 1999; Reiter
et al. 2005).
Okazaki and co-workers (2009) have cloned and
characterized the cDNA for arylalkylamine N-acetyl-
transferase (AA-NAT) of Chlamydomonas reinhardtii
(green alga). The cDNA was used to produce trans-
genic Micro-Tom tomato plants which then synthe-
sized elevated amounts of melatonin. This showed that
it is possible to genetically engineer plants to gener-
ate more than normal amounts of melatonin. Kang et
al (2010) also overexpressed human AA-NAT in rice
(Oryza sativa cv Dongjin) calli. The rice seedlings that
grew from the calli expressed high levels of AA-NAT
and melatonin. The transgenic rice plants also exhib-
ited elevated chlorophyll synthesis during cold stress.
The findings published in these two reports suggest
AA-NAT, as in animals, is an essential enzyme for
melatonin production in plants; moreover, the findings
of these two studies have implications for nutrition,
phytoremediation, resistance from harsh environmen-
tal conditions, etc. More recently, this latter group also
cloned plant N-acetylserotonin methyltransferase (for-
merly known as hydroxyindole-O-methyltransferase)
from rice (Kang et al. 2011). Considering the impor-
tance of rice as a dietary commodity throughout the
world, engineering rice to produce increased amounts
of the antioxidant melatonin could have enormous
benefits.
With the idea of clarifying the functional role of
endogenously produced melatonin, Okazaki et al
(2010) genetically engineered tomato plants to overex-
press the melatonin metabolizing enzyme indoleamine
2, 3-dioxygenase (IDO). The transgenic Micro-Tom
plants expressing IDO at high levels exhibited depressed
endogenous melatonin levels. Compared to leaf devel-
opment in wild type plants, the T1 progeny of tomato
plants with high IDO activity (and low melatonin)
formed odd-pinnately compound leaves and exhibited
a general leaf maldevelopment implying a metabolic
role for plant melatonin in leaf maturation. Clearly,
plants genetically engineered to produce reduced or
exaggerated levels of melatonin could be valuable tools
in defining the functional relevance of this indoleamine
in plants organs.
There are a number of studies documenting a role
for melatonin in enhancing the germination of seeds
and functioning as a growth promoter in plants (Pare-
des et al. 2009). One of the initial studies that led to the
assumption that melatonin promoted growth in plants
was published by Murch et al (2001) who found that
manipulating melatonin levels inhibited auxin-induced
root and cytokinin-induced root organogenesis in
explants of St. John’s wort. Hernandez and Arnao (2005)
and Arnao and Hernandez (2007) followed this with
observations that melatonin in equimolar concentra-
tions to the auxin, indole-3 acetic acid, promoted root
growth in the lupin, Lupinus albus. Similarly, Afreen
et al (2006) reported that melatonin dose-dependently
promoted vegetative growth and development of the
medicinal plant Glycyrrhiza uralensis. They also pro-
vided evidence that as the plant grew, the melatonin
levels increased. Melatonin also improves the survival
of the calli of Rhodiola crenulata after their cryopreser-
vation (Zhao et al. 2011).
The most extensive studies related to the impact
of melatonin and seed germination come from the
research of Posmyk and co-workers (Janas et al. 2009;
Posmyk & Janas 2009; Posmyk et al. 2009). They incu-
bated either cucumber or corn seeds in a melatonin-
containing solution before planting them. Melatonin
generally improved seed germination in both plants,
especially when the studies were carried out at reduced
environmental temperature, i.e., 15 °C or 10 °C. This
group also reported that plants grown from melatonin-
treated seeds grew larger and produced more edible
product.
Clarification of the function of melatonin in plants
is a major area of research. In some cases, melatonin,
an indole similar to indole-3-acetic acid, has actions
like the auxin. It would seem likely that melatonin also
functions as an antioxidant in plants and scavenges free
radicals generated during photosynthesis.

582
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Russel J. Reiter, Ana Coto-Montes, Jose Antonio Boga, Lorena Fuentes-Broto, Sergio Rosales-Corral, Dun-Xian Tan
MELATONIN: AN INDUSTRIAL
APPLICATION
A publication that appeared in mid-2011 stands to
revolutionize the production of graphene. Graphene,
identified as the next “big thing”, is a monolayer of
sp2-bonded carbon atoms that form a hexagonal two-
dimensional lattice. This lattice of carbon atoms is one
of the strongest metals discovered to date. Moreover,
graphene is foldable, crushable and stretchable and
is very light weight. The potential applications of this
material are predicted to be extremely far reaching.
A common method for the preparation of graphene
is the chemical exfoliation of graphite which is accom-
plished using powerful oxidizing agents (Stankovich et
al. 2007; Kudin et al. 2008). The product produced by
this process is graphene oxide nanosheets. These are
subsequently chemically reduced to generate graphene
nanosheets, which exhibit high electrical conductivity.
A number of methods have been used to reduce gra-
phene oxide nanosheets to graphene including the use
of strong chemical reductants such as hydrazine (Kim et
al. 2009; Akharen & Ghaderi 2010). The use of chemi-
cal reductants, especially hydrazine, results in serious
environmental contamination with negative health
consequences. Thus, in addition to being corrosive and
highly explosive (Schmidt 2001), hydrazine is extremely
toxic to DNA, to neural tissue and to blood cells (Mo
et al. 2001; Prabakar & Narayanan 2008) in addition to
being carcinogenic and inducing hepatic and renal tox-
icity (Reilly & Aust 1997).
In view of the short comings of the chemical reduc-
tant, hydrazine, Esfandiar et al (in press) considered the
use of other powerful reductants that are more environ-
mentally friendly for the reduction of graphene oxide
to graphene. For this purpose, they selected melatonin
as a powerful bio-antioxidant. The use of melatonin as
a substitute for hydrazine proved an excellent choice.
Melatonin as a reductant resulted in an increased
amount of absorbed nitrogen on the reduced graphene
oxide nanosheets. The oxidized melatonin absorbed
onto the surface of the reduced sheets acted as a sta-
bilizer which prevented aggregation of the reduced
sheets in suspension for three months. In comparison,
hydrazine-reduced graphene oxide sheets are stable for
only a few days. Raman spectroscopy confirmed the
role of oxidized melatonin as a capping stabilizer of
the reduced sheets. The authors of this seminal report
predict that the use of melatonin, in lieu of hydrazine,
will be a major step forward with the promise of high
efficiency of deoxygenation of graphene oxide suspen-
sions, which will be especially important in the large-
scale production of graphene.
CONCLUDING REMARKS
At the time of its discovery, surely no one predicted that
melatonin would turn out to be one of nature’s most
biologically-diverse molecules. It is indeed a “regula-
tor of regulators” (Reiter 1980) and a multitasking
agent (Reiter et al. 2010a). It has been described as a
molecule that improves cellular physiology. This may in
fact define what melatonin does on a day-to-day basis.
After arriving at the cellular level, melatonin seems to
function as a “molecular handyman”, thereby doing
what is necessary to improve the function of cells and
thereby organs. These actions can be accomplished via
its receptor-mediated functions or a result of the non-
receptor actions of the indoleamine and its metabolites.
It may be that the precise function of melatonin
remains unknown. What we are observing as the
actions of melatonin are possibly the epiphenomena
of more basic functions that have yet to be de-coded.
There are certainly many questions related to the very
complex and diverse functions of melatonin.
The discovery of melatonin throughout the animal
kingdom and more recently in plants has already
attracted many investigators to research melatonin.
Thus, in the foreseeable future, there is every reason to
believe that the general field of melatonin research will
continue to mushroom. This is also emphasized by the
most recent paper that illustrates the use of melatonin
in industry. Once confirmed, this could lead to the use
of melatonin for other industrial applications.
By necessity, this brief review had to be selective in
terms of the subjects covered. There are many other
burgeoning fields of melatonin research that deserved
to be mentioned (Pacini & Borzani 2009; Srinivasan et
al. 2010; Casao et al. 2010; Huang et al. 2010; Rodella et
al. 2010; Calvo-Guirado et al. 2010; Yoo & Jeung 2010;
Rosenstein et al. 2010; Hong et al. 2010) but were not
because of space constraints. In reference to endog-
enous melatonin production in vertebrates, the contin-
ued misuse of artificial light, which lowers endogenous
melatonin synthesis and perturbs circadian rhythms
(Erren & Reiter 2008; Claustrat et al. 2010; Figueiro and
Rea 2010), must be taken seriously as a potential caus-
ative factor of some disease states that are related to a
relative melatonin deficiency or an abnormal melatonin
rhythm.
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