Biological Activities of Plant
IA-HERRERO, JOSEFA ESCRIBANO and
Departamento de Bioqu
ımica y Biolog
ıa Molecular A, Unidad Docente de Biolog
ıa, Facultad de Veterinaria,
Regional Campus of International Excellence “Campus Mare Nostrum,” Universidad de Murcia, Espinardo,
Betalains are a family of natural pigments present in most plants of the order Caryophyllales. They provide colors ranging
from yellow to violet to structures that in other plants are colored by anthocyanins. These include not only edible fruits and
roots but also ﬂowers, stems, and bracts. The recent characterization of different bioactivities in experiments with betalain
containing extracts and puriﬁed pigments has renewed the interest of the research community in these molecules used by
the food industry as natural colorants. Studies with multiple cancer cell lines have demonstrated a high chemopreventive
potential that ﬁnds in vitro support in a strong antiradical and antioxidant activity. Experiments in vivo with model animals
and bioavailability studies reinforce the possible role played by betalains in the diet. This work provides a critical review
of all the claimed biological activities of betalains, showing that the bioactivities described might be supported by the high
antiradical capacity of their structural unit, betalamic acid. Although more investigations with puriﬁed compounds are
needed, the current evidences suggest a strong health-promoting potential.
Keywords Antiradical, biological activity, cancer, diet, review
Betalains are water-soluble, nitrogen containing pigments
present in most plants of the order Caryophyllales. These are
divided into two groups: the violet betacyanins and the yellow
betaxanthins. Betacyanins present absorbance spectra centered
at wavelengths of around λ
D536 nm. Glycosylation and
acylglycosilation of one or two hydroxyl groups are possible
in betacyanins, and complex pigment structures can be
obtained (Heuer et al., 1994; Strack et al., 2003; Cai et al.,
2005). In contrast, betaxanthins are yellow and no glycosyla-
tion has ever been reported. The absorbance spectra of betax-
anthins are centered at wavelengths of around λ
Both groups share betalamic acid as the structural and chro-
mophoric unit. It is condensed with amines and amino acids in
betaxanthins and with cyclo-DOPA in betacyanins (Gand
Herrero et al., 2010a). Figure 1 shows the structures for beta-
lamic acid, the betacyanins aglyca (betanidin), and the general
structure for betaxanthins. The structure for the dopamine-
derived betaxanthin (miraxanthin V) is shown and compared
with other known bioactive metabolites such as resveratrol
and the anthocyanidin cyanidin.
Betalains are found not only in edible parts of plants but
also in leaves (Wang et al., 2007), ﬂowers (Gand
et al., 2009b), stems (Schliemann et al., 1996), and bracts
(Heuer et al., 1994). Anthocyanins and betalains are mutually
exclusive and have never been found together in the same
plant (Stafford, 1994; Brockington et al., 2011); in Caryophyl-
lales only the coloration of the Caryophylaceae and Mollugi-
naceae is due to anthocyanins. Among the Caryophyllales
plants, red beet roots (Beta vulgaris) (Hempel and B€
1997), the fruits of cacti belonging to the genus Opuntia
(mainly Opuntia ﬁcus indica) (Felker et al, 2008; Osorio-
Esquivel et al., 2011), the dragon fruits from Hylocereus cacti
(mainly Hylocereus polyrhizus) (Wybraniec and Mizrahi,
2002; Wybraniec et al., 2007), and the Swiss chard (Beta vul-
garis) (Kugler et al., 2004) are known edible sources of beta-
cyanins and betaxanthins. Less common sources are the ulluco
tubers (Ullucus tuberosus) (Svenson et al., 2008), fruits of
Eulychnia cacti (Masson et al., 2011), and the berries from
Address correspondence to Dr. Fernando Gand
ımica y Biolog
ıa Molecular A, Unidad Docente de Biolog
Facultad de Veterinaria, Universidad de Murcia, E-30100 Espinardo, Murcia,
Spain. E-mail: email@example.com
Color versions of one or more of the ﬁgures in the article can be found
online at www.tandfonline.com/bfsn
Critical Reviews in Food Science and Nutrition, 56:937–945, (2016)
OTaylor and Francis Group, LLC
ISSN: 1040-8398 / 1549-7852 online
Rivina humilis (Khan et al., 2012). Certain Amaranthus spe-
cies are also consumed as cooked or fresh (Amin et al., 2006;
Sang-Uk et al., 2009). Betalain containing beetroot extracts
are used as the additive 73.40 in the 21 CFR section of the
Food and Drug Administration (FDA) in the United States and
under the E-162 code in the European Union to give a pink or
violet color to foods and beverages (Mart
ınez et al., 2006; Pru-
dencio et al., 2008; Junqueira-Goncalves et al., 2011; Gand
Herrero et al., 2012b). Figure 2 shows pictures of edible prod-
ucts containing betalains. New colorants derived from Opuntia
fruit extracts (Mosshammer et al., 2006; Ob
on et al., 2009;
enz et al., 2009) or containing individual pigments (Gand
Herrero et al., 2010b) have been also proposed. The joint pres-
ence of betaxanthins and betacyanins in the same parts of
plants generates orange to red shades depending on the pig-
ment proportion (Schliemann et al., 2001; Kugler et al., 2004;
ıa-Herrero et al., 2005; Felker et al., 2008). Due to their
hydrophilic nature, betalains are accumulated in the vacuoles
of the cells that synthesize them, mainly in epidermal and sub-
epidermal tissues of plants (Wink, 1997). Interestingly, fungi
of the genera Amanita and Hygrocybe (von Ardenne et al.,
1974; Musso, 1979; Stintzing and Schliemann, 2007; Babos
et al., 2011) produce betalain-related pigments.
In recent years, betalains have shown promising bioactive
potential. Early investigations revealed a strong free radical
scavenging capacity of betalains puriﬁed from beetroot (Escri-
bano et al., 1998; Pedre~
no and Escribano, 2001). Subsequent
research revealed the existence of an intrinsic activity present
in all betalains that is modulated by structural factors (Cai
et al., 2003; Gand
ıa-Herrero et al., 2010a). Studies with
different cell lines have demonstrated the potential of betalains
in the chemoprevention of cancer (Wu et al., 2006; Sreekanth
et al., 2007), and experiments in vivo have shown that very
low concentrations of dietary pigments inhibit the formation
of tumors in mice (Kapadia et al. 2003; Lechner et al., 2010).
In humans, the plasma concentration of betalains after inges-
tion is sufﬁciently high to promote their incorporation into
low-density lipoprotein (LDL) and red blood cells, protecting
them from oxidative damage and hemolysis (Tesoriere et al.
2003, 2005). However, most of the biological activities
described have been reported according to studies with plant
extracts with limited or no pigment puriﬁcation. Although
these studies are useful in identifying potential activities, iso-
lated compounds are necessary to link the effects described
Figure 1 Structures for betalamic acid, the betacyanins aglyca (betanidin), and the general structure for betaxanthins. R
are side residues present in
amines or amino acids. For comparative purposes, the structure for the diphenolic betaxanthin Miraxanthin V is also shown together with resveratrol and
Figure 2 Pictures of the best known sources of betalains: (A) Opuntia ﬁcus-
indica fruit, and (B) Beta vulgaris root. (C) An encapsulated commercial col-
orant based on B. vulgaris root extracts, and (D) a dairy product containing B.
938 F. GAND
IA-HERRERO ET AL.
with the structures responsible. In this work, the biological
activities of betalains are exhaustively reviewed, considering
in vitro and in vivo experiments developed since the early
description of its free radical scavenging activity more than a
ACTIVITIES IN VITRO
Free Radical Scavenging and Antioxidant Activities
Since the introduction of a feasible technology to determine
the free radical scavenging potential of molecules and extracts
by the Rice-Evans group (Re et al., 1999), the ABTS (2,2’-azi-
nobis-(3-ethylbenzothiazoline-6-sulfonic acid)) radical assay
has become a standard technique in the evaluation of this
activity. In betalains, the ABTS radical assay has gained rele-
vance with respect to other similar methodologies such as the
DPPH (2,2-diphenyl-1-picrylhydrazyl) radical assay (Brand-
Williams et al., 1995) and the Oxygen Radical Absorbance
Capacity (ORAC) assay (Ou et al., 2001), or the direct reduc-
tion of Fe(III) to Fe(II) through the Ferric Reducing Antioxi-
dant Power (FRAP) assay (Benzie and Strain, 1996). This is
due to the use of a fully aqueous medium, the possibility of pH
variation, and the lack of signal interferences with ﬂuorescent
probes. Antioxidant and antiradical concepts are frequently
not differentiated in the literature. It can be considered that
antiradicals or radical scavengers are antioxidant molecules
measured experimentally in the reduction of a radical. In this
section the term antiradical will be used when the activity has
been assessed through a radical-based assay (ABTS, DPPH, or
ORAC) independent of the original terms used by the authors.
The antioxidant term will be restricted to experiments not
involving stable radicals.
The ﬁrst investigations that demonstrated a radical scaveng-
ing capacity in betalains were carried out separately with beta-
cyanins and betaxanthins, extracted from Beta vulgaris
(Escribano et al., 1998). Other works demonstrated activities
in betalains puriﬁed from different sources: Opuntia ﬁcus-ind-
ica (Butera et al., 2002), B. vulgaris roots grown under axenic
conditions (Pavlov et al., 2002), and plants from Amarantha-
ceae (Cai et al., 2003). In all cases the radical scavenging
activity determined was higher than that detected for other
well-known compounds such as ascorbic acid, catechin, and
Trolox. Glucosylation from betacyanins was demonstrated to
reduce the activity of pigments (Cai et al., 2003) due to the
blockage of one of the hydroxyl groups. However, the pres-
ence of these groups is not necessary to express activity, in
contrast to the results obtained for ﬂavonoids, where the
absence of activity has been described in dehydroxylated com-
pounds trans-chalcone, ﬂavone, ﬂavanone, and isoﬂavone
(Cai et al., 2006). Thus, an “intrinsic activity” exists in all
betalains studied, which can be enhanced by the presence of
hydroxyl groups, with an increase in terms of Trolox Equiva-
lent Antioxidant Capacity (TEAC) from 2.5 units to 4.0 units
for one hydroxyl group and to 5.8 units for two hydroxyl
ıa-Herrero et al., 2009a). The last value is higher
than those found for other well-known antioxidants such as
epigallocatechin gallate (EGCG) present in green tea (Rice-
Evans et al., 1996; Stewart et al., 2005). Betalamic acid is the
simplest structure with betalain properties and it also possesses
antiradical and antioxidant activities, with a TEAC value of
2.7 units (Gand
ıa-Herrero et al., 2012a). Thus, betalamic acid
can be considered as the bioactive unit of these pigments
(Fig. 1). Structure–activity relationships in betalains show that
the antiradical activity for the simplest pigments is enhanced
by the connection of the betalain characteristic electron reso-
nance system with an aromatic ring, thus increasing the TEAC
value by 0.4 units. If this is done to form indoline-like sub-
structures, similar to those present in betacyanins, the
enhancement is higher, increasing the TEAC value by
1.6 units (Gand
ıa-Herrero et al., 2010a).
Although the actual contribution of individual pigments is
difﬁcult to be established, the free radical scavenging activity
of betalain containing extracts has been determined in several
cases. The fruits of cactus Hylocereus polyrhizus have
revealed a strong free radical scavenging activity that was
higher in peel extracts than in those obtained from ﬂesh, con-
sistent with a higher content of betalains and ﬂavonoids in the
peel (Wu et al., 2006). Multiple clones of Opuntia plants
showed that the TEAC values for cactus juices were close to
those of red wine and green tea infusions (Stintzing et al.,
2005). In addition to O. ﬁcus-indica, recent attention has been
focused on the fruits of other edible species like O. joconostle
and O. macrorhiza (Moussa-Ayoub et al., 2011; Osorio-Esqui-
vel et al., 2011; Morales et al., 2012). A complex proﬁle of
bioactive substances, including betalains, has been described
in these species, with extracts showing high antiradical and
antioxidant activities. When puriﬁed betalain fractions were
obtained, these exhibited higher activity than the ﬂavonoid
and phenolic containing fractions obtained from the same
fruits (Osorio-Esquivel et al., 2011). Betalains from Rivina
humilis were also partially puriﬁed and the activity of betacya-
nin- and betaxanthin-rich fractions were assayed (Khan et al.,
2012). This conﬁrmed both antiradical and antioxidant activi-
ties of the pigments and explained the antiradical effect
detected in fruit extracts. In the case of B. vulgaris, extracts
from hairy root cultures have revealed a higher radical scav-
enging potential than intact plants. It has been proposed that
this is due to an increased concentration of phenolic com-
pounds, which may have a synergistic effect with betalains
(Georgiev et al., 2010).
The redox properties of betalains have been studied by
cyclic and differential pulse voltammetry. Reduction poten-
tials were determined for puriﬁed indicaxanthin and betanin,
and were higher in the case of the betacyanin (Butera et al.,
2002). Strong antioxidant and antiradical betanin activities
have been properly explained in terms of its electron donor
capacity, calculating the bond dissociation energy and the ioni-
zation potential of the molecule (Gliszczy
Swiglo et al.,
BIOLOGICAL ACTIVITIES OF PLANT PIGMENTS BETALAINS 939
2006). This explains the marked pH dependence found in free
radical scavenging experiments. Increased pH values imply
higher activity and higher TEAC values not only in the case of
betanin. A comparative study with 15 natural and synthetic
betalains showed a common trend in the pH dependence of the
free radical scavenging activity (Gand
ıa-Herrero et al.,
2010a). This indicates the existence of a relevant deprotona-
tion equilibrium in the expression of the activity and common
to all betalains. The same tendency was found for free betala-
mic acid, and it has been linked to its nucleophilic capacity,
determining a pK
value of 6.8 (Gand
ıa-Herrero et al., 2012a).
A similar pH dependence of the free radical scavenging activ-
ity has been described for ﬂavonoids. Deprotonation generates
a phenolate anion in these molecules, which is a better electron
donor and, thus, a more effective scavenger (Madsen et al.,
2000; Muzolf et al., 2008).
Relatedtotheirspectroscopic properties and to their
redox capacity to transfer electrons, betalains have been
used as natural dyes in dye-sensitized solar cells (Zhang
et al., 2008). These are one of the most promising devices
for solar energy conversion due to their reduced production
cost and low environmental impact (Narayan, 2012). The
technology has been assayed with betalain containing
extracts of Beta vulgaris roots (Zhang et al., 2008; Calo-
gero et al., 2010), Hylocereus fruits (Ali and Nayan, 2010),
Opuntia fruits (Calogero et al., 2010; Calogero et al.,
2012), and Bouganvillea bracts (Calogero et al., 2010; Her-
nandez-Martinez et al., 2011). While dye-sensitized solar
cells containing anthocyanins and carotenoids as dyes have
shown overall solar energy conversion efﬁciencies below
1%, betalain containing cells obtain conversion efﬁciencies
of up to 1.7% under simulated sunlight conditions, which
is comparable to that of natural photosynthesis (Calogero
et al., 2009; Calogero et al., 2010; Zhou et al., 2011). On
optimizing the performance of solar cell and using puriﬁed
betanin instead of raw extracts, the energy conversion efﬁ-
ciencies of the cells have recently been raised to 2.7%
(Sandquist and McHale, 2011; Calogero et al., 2012).
Other Activities In vitro
In addition to their potent antioxidant and free radical scav-
enging activities, and probably in relation with them, the beta-
cyanins betanin and betanidin isolated from B. vulgaris were
able to inhibit the peroxidation of linoleic acid and the oxida-
tion of LDL. The effect was higher than that detected for other
known antioxidants such as a-tocopherol and catechin (Kanner
et al., 2001). These activities were assessed considering differ-
ent oxidizers on linoleic acid emulsions and the oxidative sus-
ceptibility of human LDL obtained from healthy volunteers
and microsomes obtained from turkey muscle tissue. Puriﬁed
betalains have been also reported to be scavengers of hypo-
chlorous acid, which is the most powerful oxidant produced
by human neutrophils in inﬂammatory processes and to
interfere with the activity of myeloperoxidase enzyme respon-
sible for its formation (Allegra et al., 2005).
Although the molecules responsible for plant pigmentation
seem to be erroneously identiﬁed (Kugler et al., 2004), aque-
ous extracts of Swiss chard (B. vulgaris) containing betalains
were demonstrated to possess inhibitory activity on the
enzyme acetylcholinesterase (Sacan and Yanardag, 2010).
This enzyme is involved in the processes of neurotransmission
by cleaving the neurotransmitter acetylcholine and its inhibi-
tion has been demonstrated to have therapeutic potential in the
treatment of neurological disorders, including Alzheimer’s
disease (Orhan, 2012).
STUDIES WITH CELLS
Recent research with different cancer cell lines has demon-
strated a high chemopreventive potential of betalain contain-
ing extracts. The use of puriﬁed pigments in some of the
studies justiﬁes the activities assessed and reinforces the bio-
logical potential of betalains. Extracts of Beta vulgaris have
shown high chemopreventive effect in the induced Epstein–
Barr early antigen activation assay in vitro using a cell line
from lymphoma (Kapadia et al., 1996). Extracts signiﬁcantly
reduced cells’ viability, with the effect being ascribed to beta-
lains. The activity was compared with other plant extracts,
including an anthocyanin-rich cranberry extract, exhibiting
maximum activity. A limited cytotoxicity of B. vulgaris
extracts has also been demonstrated for human prostate and
breast cancer cell lines (Kapadia et al., 2011).
Extracts obtained from Opuntia ﬁcus-indica proved to be
an effective growth inhibitor and apoptosis inductor in sev-
eral cell lines of immortalized ovarian and cervical epithelial
cells and ovarian, cervical, and bladder cancer cells (Zou
et al., 2005). The effect of the cactus pear solution was dose-
and time-dependent. Cactus extracts were able to inhibit
growth of cancer cells and affect their morphology with con-
centrations of 5% of fruit extract in cell culture. A higher
concentration was necessary (10–25%) for apoptotic effect.
However, the use of raw extracts avoided the identiﬁcation of
active compounds. Betalains from the berries of Rivina
humilis were tested regarding their effect on hepatocellular
carcinoma cells (Khan et al., 2012). In this case, the betalains
were partially puriﬁed and betaxanthins and betacyanins sep-
arately showed dose-dependent cytotoxicity after 24 and
48 hours respectively.
Extracts from the fruit of the cactus Hylocereus polyrhizus
revealed an inhibitory activity of growth of melanoma cancer
cells (Wu et al., 2006). The inhibition was dose-dependent
and higher in peel than in ﬂesh extracts, in relation with a
higher content of ﬂavonoids and betalains. Remarkably, in the
same experiment pure betanin was assayed, revealing a strong
inhibition of the proliferation of melanoma cancer cells. Pure
betanin was also used against a human chronic myeloid leuke-
mia cell line in a different study (Sreekanth et al., 2007). The
940 F. GAND
IA-HERRERO ET AL.
addition of betanin implied the inhibition of cell growth in a
dose-dependent manner with an IC
of 40 mM after 24 hours
of incubation. Betanin enters the cells and alters the mitochon-
drial membrane integrity. This ultimately leads to the activa-
tion of caspases and nuclear disintegration. The biochemical
alterations were reﬂected in morphological changes in cells,
which were followed by scanning and transmission electron
microscopy and ﬂow cytometry. Cells entered apoptosis, in a
clear in vitro demonstration of anti-cancer potential of
betalains. Table 1 summarizes all the studies developed with
betalains, which involved cancer cells, identifying the corre-
sponding cell lines.
In addition to the effect on cancer cell lines, B. vulgaris
extracts have been found to dose-dependently suppress the
degradation of tryptophan and the production of neopterin in
human peripheral blood mononuclear cells involved in the
inﬂammatory response (Winkler et al., 2005). Cells were
obtained from healthy donors and stimulated in the presence
of the betalain containing extracts. The cell response was
reduced by the presence of extracts, suggesting that the B. vul-
garis juice possesses compounds with immunosuppressive and
anti-inﬂammatory activities. Human red blood cells also
showed increased resistance to hemolysis when they were
incubated with growing concentrations of puriﬁed indicaxan-
thin and betanin in vitro (Tesoriere et al., 2005). Furthermore,
LDLs isolated from healthy humans have been demonstrated
to incorporate puriﬁed indicaxanthin and betanin after ex vivo
incubation (Tesoriere et al., 2003). LDLs enriched with the
pigments were more resistant than native LDLs to copper-
induced oxidation, with indicaxanthin being more effective
than betanin in the protection from oxidative damage.
STUDIES WITH ANIMALS
In vivo anti-tumor formation activity in mouse skin has
been demonstrated for Beta vulgaris extracts. The extracts
were orally administered to the animals in drinking water after
topical tumor induction (Kapadia et al., 1996). Results showed
a signiﬁcant decrease in the incidence and number of papillo-
mas found in the mice skin. In the same study, lung tumor for-
mation was induced to mice, and inhibited by the oral
administration of B. vulgaris extracts. A 60% reduction in the
number of mice with adenomas was observed, with an addi-
tional 30% reduction in the number of tumors for the affected
animals. Skin tumor formation induced chemically and pro-
moted by ultraviolet (UV)-based light was also inhibited after
the oral administration of B. vulgaris extracts in mice (Kapadia
et al., 2003). In addition, animals that followed the treatment
also showed a reduced splenomegaly. In the case of induced
tumors in the liver, oral administration of beet extract reduced
the tumor incidence to 40%, showing a potent cancer chemo-
preventive activity in the model animals.
Analogously, chemoprevention against induced esophageal
carcinogenesis was also demonstrated in rats for B. vulgaris
extracts administered orally (Lechner et al., 2010). Results
showed a reduction of 45% in the number of papillomas, limit-
ing cell proliferation, angiogenesis, and inﬂammation. It was
hypothesized that betalains antioxidant activity reduced the
level of reactive oxygen species to levels that were too low to
stimulate the anomalous proliferation.
In addition, dose-dependent protection of the adverse
effects of g-ray irradiation in rats has been demonstrated in
vivo for Beta vulgaris extracts, and the effect has been
ascribed to betalains (Lu et al., 2009). Orally administered
extracts partially restored the normal biochemical levels of the
altered parameters caused by irradiation, including catalase,
superoxide dismutase, and lipid oxidation activities in liver,
spleen, and kidney. Furthermore, the prevention of decline in
the spleen and thymus index in irradiated mice led the authors
to suggest that betalains could partially restore the immuno-
logical function and improve the pathological status in vivo.
Although the effect of betalains cannot be identiﬁed, aque-
ous extracts of Opuntia ﬁcus-indica were able to inhibit tumor
Table 1 Studies with betalain containing extracts involving cancer cells. The cell line identiﬁcation, the source of betalains, the use of puriﬁed pigments, and the
corresponding references are shown in each case
Cell line Betalains source Effect Pigment puriﬁcation References
Raji (lymphoma, human) Beta vulgaris Reduced cell viability No Kapadia et al., 1996
IOSE (ovarian epithelium, human) Opuntia ﬁcus-indica Growth inhibition No Zou et al., 2005
OVCA420 (ovarian cancer, human) Opuntia ﬁcus-indica Growth inhibition, apoptosis induction No Zou et al., 2005
SKOV3 (ovarian cancer, human) Opuntia ﬁcus-indica Growth inhibition, apoptosis induction No Zou et al., 2005
TCL-1 (cervical epithelium, human) Opuntia ﬁcus-indica Growth inhibition, apoptosis induction No Zou et al., 2005
HeLa (cervical cancer, human) Opuntia ﬁcus-indica Growth inhibition, apoptosis induction No Zou et al., 2005
Me180 (cervical cancer, human) Opuntia ﬁcus-indica Growth inhibition, apoptosis induction No Zou et al., 2005
UM-UC-6 (bladder cancer, human) Opuntia ﬁcus-indica Growth inhibition No Zou et al., 2005
T24 (bladder cancer, human) Opuntia ﬁcus-indica Growth inhibition, apoptosis induction No Zou et al., 2005
B16F10 (melanoma, mouse) Hylocereus polyrhizus Growth inhibition No Wu et al., 2006
B16F10 (melanoma, mouse) Unspeciﬁed (commercial) Growth inhibition Puriﬁed betanin Wu et al., 2006
K562 (leukemia, human) Opuntia ﬁcus-indica Growth inhibition, apoptosis induction Puriﬁed betanin Sreekanth et al., 2007
PC-3 (prostate cancer, human) Beta vulgaris Growth inhibition No Kapadia et al., 2011
MCF-7 (breast cancer, human) Beta vulgaris Growth inhibition No Kapadia et al., 2011
HepG2 (liver cancer, human) Rivina humilis Reduced cell viability Partial Khan et al., 2012
BIOLOGICAL ACTIVITIES OF PLANT PIGMENTS BETALAINS 941
growth in a nude mouse of ovarian cancer model compared
with untreated animals (Zou et al., 2005). The extract was
administered by injection and compared with the chemo-
preventive agent N-(4-hydroxyphernyl) retinamide (4-HPR),
used in ovarian cancer clinical trials. Both cactus pear extracts
and chemopreventive agent reduced the tumor size in a com-
parable manner. Opuntia fruits’ extracts have also demon-
strated their potential in the protection and recovery of the
liver after damage has been induced. Hepatotoxicity by carbon
) in rats was limited in animals fed with the
betalain containing extracts both after and before the damag-
ing treatment (Galati et al., 2005). The oral administration of
the extract promoted liver recovery at histochemical and bio-
chemical levels. The same effect was described for betalain
containing extracts of whole plants of Amaranthus spinosus,
and it has been proposed that the mechanism of hepatoprotec-
tion was due to its antioxidant activity (Zeashan et al., 2008,
Interestingly, other activities have been also described for
betalains. Puriﬁed pigments extracted from Portulaca olera-
cea have demonstrated their capacity to reverse induced learn-
ing and memory impairments produced by D-galactose in
mice (Wang and Yang, 2010). In comparison with ascorbic
acid, orally administered betalains showed a more pronounced
effect in ameliorating cognition deﬁcits in mice and restored
the normal biochemical levels of relevant enzymes, being
proposed a neuroprotective effect. Extracts of Amaranthus spi-
nosus and Boerhaavia erecta containing betalains have dem-
onstrated antimalarial activity in an in vivo model assay in
mice (Hilou et al., 2006). The aqueous extracts were able to
inhibit the growth of inoculated parasites in a dose-dependent
manner. These plants are used in the traditional medicine
against Plasmodium falciparum infections (malaria) in
humans. The authors pointed to betacyanins betanin and amar-
anthin as possible molecules responsible for the assessed activ-
ity at the same time that they acknowledged the need to
perform experiments with puriﬁed compounds. Opuntia ﬁcus-
indica extracts and its main pigment, indicaxanthin, in a pure
form were demonstrated to reduce the contractility of the ileal
longitudinal muscle obtained from mice (Baldassano et al.,
2010, 2011). The authors propose the usefulness of the ﬁnding
in the regulation of intestinal motility in related disorders and
describe the mechanism of action. It implies the inhibition of
phosphodiesterase enzymes and the increase in cAMP levels,
which lead to a decrease in intracellular Ca
which ultimately promotes the smooth muscle relaxation.
Bioavailability studies of betalains after oral administration
in humans indicate that model betalains, betanin, and indicax-
anthin remain in the body and are able to play a health-promot-
ing function, thereby improving the body redox status
(Tesoriere et al., 2004; Frank et al., 2005). Maximum plasma
concentrations are reached three hours after consumption,
with a decline corresponding to ﬁrst-order kinetics. After this
time period, betalains can be incorporated into the red cells in
vivo (Tesoriere et al., 2005). They are completely eliminated
after 12 hours of ingestion, with a urinary excretion of 76% in
the case of betaxanthin, but highly limited in the case of beta-
nin. This indicates metabolization of the pigment and its trans-
formation to other compounds, including betalamic acid, as
demonstrated in simulated digestion studies (Pavlov et al.,
2005; Tesoriere et al., 2008). However, the inability of part of
the population to metabolize betanin has also been described,
excreting it to a high level in urine. This is known as beeturia,
and although its mechanism is not well understood, its inci-
dence is high in iron-deﬁcient subjects (Watson et al., 1963;
Sotos, 1999; Mitchell, 2001).
The description of the betalains free radical scavenging
activity implied the renaissance of interest in these molecules
by the research community. Since then, multiple articles with
claims regarding the biological activity of betalains have been
published, including studies on the chemoprevention of tumor
formation. Considering their demonstrated safety (Schwartz
et al., 1983; Khan et al., 2011), the recent bibliography indi-
cates the potential of betalains for food, pharmaceutical, and
Promising results have been reported for tumor prevention
in vivo and the possible role played by betalains in the diet.
However, the use of extracts limits the conclusions drawn, the
hypothesis on the mechanisms involved, and the therapeutic
potential of the assays. Currently, studies with puriﬁed pig-
ments are scarce but they provide exciting conclusions.
Increasing of these studies would help to establish the actual
role played by betalains alone or in cooperation with other
compounds. Caution must be taken regarding the possible
application of biological activities described in natural mole-
cules, but the results for betalains are promising in terms of
their health-promoting potential.
The authors acknowledge the ﬁnancial support of Ministerio
de Ciencia e Innovaci
on (MICINN, FEDER, Spain, project
AGL2011-25023 and AGL2014-57431) and Fundaci
oneca, Agencia de Ciencia y Tecnologia de la Regi
Murcia (Plan Regional de Ciencia y Tecnologia 2007/2010,
Programa de Ayudas a Grupos de Excelencia de la Regi
Murcia). F. Gand
ıa-Herrero has a contract with the “Programa
on y Cajal” (MICINN, FEDER, Spain).
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