Medicinal applications of Euphorbia umbellata, as an antitumor agent, antiulcerogenic and other applications: Review

Full text

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Journal of Pharmacognosy and Phytochemistry 2021; 10(2): 29-35
E-ISSN: 2278-4136
P-ISSN: 2349-8234
www.phytojournal.com
JPP 2021; 10(2): 29-35
Received: 04-01-2020
Accepted: 18-02-2020
Monique Gonçalves Alves
Faculty of Medicine, University
of São Paulo, FMUSP,
Laboratory of Development and
Innovation, Butantan Institute,
Sao Paulo, Brazil
Laertty Garcia de Sousa Cabral
Faculty of Medicine, University
of São Paulo, FMUSP,
Laboratory of Development and
Innovation, Butantan Institute,
Sao Paulo, Brazil
Thais de Oliveira Conceição
Faculty of Medicine, University
of São Paulo, FMUSP,
Laboratory of Development and
Innovation, Butantan Institute,
Sao Paulo, Brazil
Thalles Anthony Duarte Oliveira
Faculty of Veterinary Medicine,
University of São Paulo, FMVZ
USP, Laboratory of
Development and Innovation,
Butantan Institute, Sao Paulo,
Brazil
Mercedez Reyes Hernández
Development and Innovation,
Butantan Institute, Sao Paulo,
Brazil
José Artur Medina
Faculty of Medicine, University
of São Paulo, FMUSP,
Laboratory of Development and
Innovation, Butantan Institute,
Sao Paulo, Brazil
Rosa Andrea NogueiraLaiso
Laboratory of Development and
Innovation, Butantan Institute,
Sao Paulo, Brazil
Durvanei Augusto Maria
Professor, Laboratory of
Development and Innovation,
Butantan Institute, Sao Paulo,
Brazil
Corresponding Author:
Durvanei Augusto Maria
Professor, Laboratory of
Development and Innovation,
Butantan Institute, Sao Paulo,
Brazil
Medicinal applications of Euphorbia umbellata, as
an antitumor agent, antiulcerogenic and other
applications: Review
Monique Gonçalves Alves, Laertty Garcia de Sousa Cabral, Thais de
Oliveira Conceição, Thalles Anthony Duarte Oliveira, Mercedez Reyes
Hernández, José Artur Medina, Rosa Andrea NogueiraLaiso and
Durvanei Augusto Maria
DOI: https://doi.org/10.22271/phyto.2021.v10.i2a.13669
Abstract
The demand for herbal medicines is steadily increasing. Within this perspective, compounds derived
from the latex of the species Euphorbia umbellata have acquired a prominence presenting
antiulcerogenic, anti-inflammatory, homeostatic activities and mainly antitumor activity. Studies carried
out with tumor cells indicate that their fractions and subfractions act by modulating the apoptotic
pathway by decreasing the mitochondrial electrical potential, as well as activating caspases 3 and 7.
Concomitantly, its antiulcerogenic activity is related to the ability to capture radicals and species reactive
oxygen, in addition to its inhibitory action in a peroxidase model. Other studies regarding other
functionalities of this species are still in progress.
Keywords: Euphorbia umbellata, bio extracts, cancer
Introduction
Recently, the demand for herbal medicines and various natural products from a variety of plant
species is steadily increasing. This immense importance within medicine is due to the fact that
plants have been used for the treatment of various diseases for thousands of years, with
extracts from various medicinal plants being effective against microbial, parasitic infections,
inflammations, cancer, among several other applications [1, 2].
Of the total molecules approved for use in the pharmaceutical industry from 1981 to 2014,
52% are natural products or their derivatives [3]. Regarding cancer, for example, of all 131
molecules with antitumor potential released in the same period, 85 (49%) were derived from
natural products and their derivatives, such as drugs such as Paclitaxel (Taxol®), Docetaxel
(Taxotere®), Abraxane ® and Cabazitaxel (Jevtana®) [3, 4].
In turn, the species Euphorbia umbellata (Pax) Bruyns, of African origin and belonging to the
order Geraniales, family Euphorbiaceae5. Popularly known as "Janaúba'' and "cola-nota" in
Brazil, it has already registered that its latex has been used in popular medicine as an anti-
ulcer, anti-inflammatory, homeostatic, antiangiogenic, and mainly as an antitumor agent [6-8].
In southern Brazil, as well as common sense, it is used as a treatment for all types of cancer
and has recently even shown molluscicidal activity to control schistosomiasis [9].
Family Euphorbiaceae
The Euphorbiaceae family corresponds to a botanical family distributed in 317 genera [10] with
a total of 8,000 species present in the most diverse habitats, from humid tropics to arid regions,
taken among the most economically important families in the Angiosperms group [11].
With the genera Euphorbia, Croton, and Phyllanthus being the most representative with
respectively 1,500, 1,300, and 400 species, these plants have the most varied forms of life,
such as herbs, shrubs, succulents, and trees with alternating leaves [12, 13]. Being the only family
to present some species with a combination of glands and latex, generally recognized for
exhibiting ciatio type inflorescence, unisexual flowers, and capsule type fruits [14-21].
In terms of industrial economic importance, Ricinus communis L., popularly known as castor,
stands out, being a source of castor, an important product for the production of plastic,
synthetic fibers, alternative fuel, among other applications. In addition to Hevea brasiliensis,
which has its latex used for a natural rubber manufacturer [22].

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Other species of this family are used for folk medicine, for
their property in the treatment of hepatitis-B (antiviral
activity), elimination of kidney stones (diuretic), and cancer,
probably because they have several types of chemical
compounds, such as flavonoids, saponins, terpenes, esters,
cyanogenic glycosides, tannins, lectins, alkaloids, and
glycoproteins [23, 24].
Species of the genera Croton and Mahinot were studied due to
mineral absorption properties [25, 26]. The genus Croton is one
of the largest genera of Euphorbiaceae most used in
traditional medicine with several products derived from their
species and commercialized on an international scale. Others
of the genus Euphorbia L. and Cnidosculus Pohl have
antidiarrheal effects [27]. The species Euphorbia tirucalli L.
popularly known as "pau-pelado" or "avelós" for example, is
traditionally used in Brazil as an analgesic, antitumoral, and
antiviral [28].
In Brazil, in turn, is considered one of the most important
research centers related to this family, more than 1,100
species [29], all of them native or acclimatized, with many of
these species becoming objects of multidisciplinary studies
from their characteristics, ethnobotanical and taxonomic
importance, even biological properties, the majority medicinal
potential [30].
Therefore, this work was developed through an integrative
literary review, seeking to highlight the anti-tumor effects that
E. Umbellata substances are capable of developing, as well as
their applications and studies developed for other diseases.
Materials and Methods
The present work is characterized as an integrative literary
review, seeking to study the aspects of Euphorbia umbellata
as a phytotherapeutic agent, discussing its efficiency. For this,
the Google Scholar, Scientific Electronic Library Online
(SCIELO), and Pubmed platforms were used as a research
base.
Development
Phytochemical studies
Several chemical metabolites have been detected in E.
Umbellata latex since 1984 [31]. Premaratna et al., isolated and
purified lectins with antitumor properties [31]. Kinghorn
(1980) discovered and isolated the 4-deoxy-starred ester, a
product that causes skin irritability [32]. Other researchers, in
turn, discovered the presence of diterpenes, protease enzymes,
glycoproteins, and triterpenes [33, 36].
Likewise, its crude extract, as well as its diluted latex, shows
antiulcerogenic activity in rats treated with this plant material,
preventing the formation of peptic ulcers, in which such
gastroprotective action was related to the presence of phenolic
and non-saponifiable substances detected in its latex [37].
Later it was also verified through phytochemical studies the
existence of lipophilic and phenolic compounds, starch, and
mucilage. In addition to the isolation of two triterpenes
identified using nuclear magnetic resonance (NMR)
techniques, one being a pentacyclic called germanicol acetate
and the other a tetracyclic called Euphol. In addition, other
research has allowed the isolation of fractions and
subfractions from the latex of this plant, such as fractions
hexane, chloroform, ethyl acetate, and methanol and
subfractions such as methanol, dichloride, ether, and ethanol
[38].
In turn, the identification of the chemical composition of this
plant is necessary because it is through it that it can be
understood and attributed to the reason for its various
therapeutic actions, through the action of primary and
secondary metabolites that are present.
The class of secondary metabolites such as terpenes,
alkaloids, and flavonoids has a promising anticancer activity
[39-41]. Some terpenes and phenolic compounds are as
promising, either because of an action directly linked or
indirectly, such as that of phenolics that have proven
antioxidant activity and may act to inhibit the development of
the formation of free radicals, related to the progression of
cancer [42, 43]. Some alkaloids in turn, such as those identified
from Catharanthus roseus (L.) already present their active
principles in drugs taken on the market such as vincristine and
vinblastine [44].
Plant lectins also reveal themselves with heterogeneities
appear mainly in their carbohydrate-binding sites, thus
conferring multiple biological activities, among them
potential as carcinogenic agents and recently in the discovery
of tumor biomarkers, due to their ability to recognize a large
number of glycans and mediate several biological processes,
such as cell migration and immune defense [45].
It is also worth mentioning that the identification of bioactive
compounds euphol, friedelin, and 3-friedelinol from the crude
E. umbellata extract reinforced the idea that this plant is a
source of antioxidant compounds, due to the marked action of
the extract in chemical and enzymatic systems. (MPO) in
vitro, as for the ex vivo system through hemolysis induced by
free radicals, indicate a potential not only to neutralize but
also to reduce the formation of free radicals, as well as to
protect cells from its harmful action [46].
Antitumor potential
The crude ethanolic extract (EESU), its fractions chloroform,
hexane, methanol, and its residual fractions chloroform (CF),
hexane (HF) and methanolic (ME) had its antitumor activity
tested in Ehrlich ascitic cells (EAT), decrease in cell viability
in vitro by 50%, and inhibition around 75, 68 and 60%,
respectively for the compounds CEE, CF and HF. In turn, in
vivo, it was possible to observe better results for the crude
ethanolic extract, where the dissipated mice had longer
survival, 36.7% reduction in the intraperitoneal tumor cell
load, and a 42% reduction in VEGF levels when compared to
the control [47].
During the development of a tumor, it has been expanded that
VEGF (vascular endothelial growth factor) is present in high
definitions and plays a necessary role in increasing the
permeability of specific vascularization in a variety of human
animals and tumors [48, 49]. Therefore, it is important to
determine the progression of the tumor and the induction of
Angiogenesis [50]. Therefore, bioactive compounds that come
to act in its demonstration reduction as a potent antitumor
agent. In turn, in the same study, such compounds in vitro
also demonstrated antitumor effects for k-562 [47] leukemic
cells.
Another study also carried out with this cell line, Jukart cells
(leukemic cell), HL-60 (Leukemic cell), HRT-18 (human
ileocecal colorectal adenocarcinoma), and B16-F10 (murine
melanoma cells), sought to evaluate in vitro the cytotoxic
action of the compound euphol, a tetracyclic triterpene
alcohol present in E. umbellata, showing that euphol has a
cytotoxic effect mainly against leukemia potentially related to
the apoptosis mechanism. However, the evaluation of the
stability, distribution, and metabolism properties showed that
euphol was unstable in gastric and intestinal fluids with an
elimination half-life of two hours and possible phase II [51]
hepatic metabolism, showing that in vivo such isolated

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terpene has low cytotoxicity, which indicates that probably as
anti-cancer properties of the extract may be caused by other
substances present in the hexane fraction.
Hela cells (human cervical adenocarcinoma cells) and HRT-
18 were also evaluated from tests with E. umbellata latex,
where the latex cytotoxic application in HRT-18 cells after
48h and cytotoxic sensitization as Hela cells in all dose-
dependent moments [52]. In turn, in subsequent studies, the
cells and cells of Jukart cells undefined that the hexane
fraction has a greater cytotoxic action, such action being
associated with a possible trigger of cellular apoptosis [53].
In a biomonitored study to identify a more active fraction
present in E. umbellta latex, methanol (MeOH), iso-propanol
(iso-prop), ethyl acetate (EtOAc), chloroform (CHCl 3) en-
hexane (Hex) were also evaluated. The results showed that all
cytotoxicity fractions depend on concentration and time. It
can also be assumed that for the three application methods,
the hexane fraction has the greatest cytotoxic effect when
compared to the chloroform (CHCl3), ethyl acetate (EtOAc),
and methanol (MeOH) fractions, with a marked reduction in
cell viability over time incubation of 24, 48 and 72 h for the
hexane fraction for Hela, HRT-18 and Jukart cells, and the
cytotoxicity of the hexane fraction for Jukart cells is related to
the increased fragmentation of genetic material, cell death
(apoptosis) and stopping the cell cycle in the g0/G1 phase
with a reduction in the S and G2/M phases [54].
Such results of which mechanism of action E. umbellata acts
can also be corroborated, through two other in vitro studies
with the same cell line, in which for one of them Jukart cells
through the cytotoxic action of the chloroform fraction
(CHCl3) from the crude extract of the plant's bark, the cell
cycle stopped and apoptosis, with the compounds present in
CHCl3 presenting a greater amount of steroids and
triterpenes55. And another showed that the dichloromethane
subfraction from the hexane fraction indicated a promising
result possibly due to the synergistic action of the terpenes
present in it [56].
The action of steroids and terpenes has been previously
described as promising, either directly or indirectly due to
their antioxidant actions [42, 43], responsible for the reduction
of free radicals that are normally present in a tumor
microenvironment, showing them in large quantities and in
excess related to several cellular dysfunctions [57]. In turn,
recent studies show that the use of antioxidant compounds as
part of the nutritional therapy of cancer patients has positive
results in mitigating adverse effects generated by chemo and
radiotherapy [58].
Another study also showed that fractions of terpenes enriched
in E. umbellata latex promoted apoptosis in HL-60 leukemic
cells, causing morphological changes compatible with the
induction of apoptosis, altered cell cycle, depolarized cells,
and the activation of caspase 3 and caspase 7 [59].
In general, caspase 3 mediates apoptosis by acting via the
mitochondrial pathway [60] and terpenes activate caspase 3
activity as seen in tumor cells k-562, Hela, MCF-7 (breast
cancer) and MDA-MB 231 (Breast cancer negative triple) [61].
And, likewise, caspase 7 is also an executor in which its
enzymatic activity is necessary to complete cell death by
apoptosis [62].
In turn, other studies carried out with tumor cells of murine
melanoma B16-F10 showed that the hexane fraction, the
petroleum ether subfraction, and dichloromethane showed
potential in vitro but without significant results in vivo [63].
However, the chloroform and acetate fractions in vitro
exhibited selective cytotoxicity when compared to normal
human fibroblast (FN1) cells, reducing the mitochondrial
electrical potential, modifying the cell morphology, and
affecting the actin filaments, probably promoting the
modulation of the apoptotic pathway [64].
The chloroform fraction and especially the acetate fraction
also acted in reducing the mitochondrial electrical potential,
as well as in stopping the cell cycle in the G2/M phase and
reduced cell reduction in the G0/G1 phase. It also exhibits the
same effect on MDA MB-231, 4T1 breast cancer cells, and
Hepa1c1c7 [64-66] Hepatocarcinoma cells. The sub-fraction
methanol (MeOH), derived from the hexane fraction, also
responsible for reducing the mitochondrial electrical potential
rm Hepa1c1c7 [67].
Such results indicate that there is an action of these fractions
and subfractions with respect to a stop of the cell cycle, which
is related to the control point (checkpoints) that guarantees the
safety of the molecular structure of DNA, avoiding changes
that cause harmful changes, genomic instability, and
mutations that would be transmitted to the next cells [67-22]. As
well as the decrease in mitochondrial electrical potential, it
further supports the idea of a possible activation of apoptotic
modulation of tumor cells through depolarization of the
mitochondrial membrane. (Figure 1).

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Fig 1: The action of compounds extracted from E. umbellata latex on tumor cells
Antiulcerogenic potential and other applications
To date, few studies have evaluated the pharmacological
action of Euphorbia umbellata for the treatment of ulcers of
the gastrointestinal tract. However, the few existing, existing
that such a species has a promising potential.
The methanolic fraction (FM) from the E. umbellata peel had
its antioxidant action tested against DPPH •, ABTS • +, O2 • -
, HOCl, TauCl and HRP, where the responses in the
antioxidant testicles are subject to the ability to capture
radicals and reactive oxygen species by FM, in addition to its
inhibitory action in a peroxidase model. In addition,
histologically an FM provided gastroprotection and an
enzymatic block presentation from the anti-urease test,
allowing to suggest that the gastroprotective effect of FM may
be related to the presence of polyphenols, as well as to its
potential scavenger on reactive species, activation of the path
nitric oxide/cyclic guanosine monophosphate and
cyclooxygenases and anti-H actions. pylori and anti-urease [73].
Previously, Costa et al. also indicated that its crude and
diluted latex promotes antiulcerogenic activity, preventing the
formation of peptic ulcers in the food of rats treated by the
action of phenolic and non-saponifiable substances [37].

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Polyphenols, an example of flavonoids, are an important
factor for gastroprotective activity and are substances that
have been showing good activity against urease [74], acting in
an antioxidant way and consequently contributing to anti-
ulcer activity since urease, H. pylori and arginase are
inhibitors of macrophage phagocytic function and are related
to stimulating the activity of lymphocytes and neutrophils
with a high production of ROS, which affects the transduction
of signals from the gastric mucosal epithelium and allows the
formation of neoplastic mass [75-78].
With regard to other applications, E. umbellata latex has the
potential for obtaining molluscicidal agents that can be used
to control schistosomiasis mansoni due to the presence of
triterpenes [9]. In addition, chitosan membranes containing the
E. umbellata methanolic fraction for topical application were
developed, characterized, and evaluated for their antioxidant
and antimicrobial potential, being considered promising for
topical application for anti-inflammatory action [79].
In vitro experiments also induced that deoxy-phorbol esters
present in the alcoholic extract of E. umbellta latex are able to
increase HIV transcription and reactivate it from latency
models and induce the production of pro-inflammatory
cytokines together with interleukin-21, thus being promising
candidates for future clinical trials aiming at the shock and
deadly therapies that refer to HIV [80].
Conclusion
Like other species of the Euphorbiaceae family, a type
Euphorbia umbellata has enormous pharmaceutical potential
and can act in a beneficial way to fight various diseases. Other
studies still need to be carried out so that it is possible to
discover, in fact, which compounds are related to the most
diverse pathogens, as well as their components of actions and
consequences in the organism.
However, it is possible to notice an advance in studies with
cancer cells when compared to other areas on the action of E.
umbellata latex. It is possible to state that the various
compounds from plant latex that have antitumor activity
through the depolarization of the mitochondrial membrane,
modulating the apoptotic pathway probably from the
activation of caspases 3-7, operational for the cell cycle in the
G2/M phase. Further studies are needed to specifically
characterize the action of fractions and subfractions from
latex.
With regard to its antiulcerogenic activity, it is related to the
ability to capture radicals and reactive oxygen species, in
addition to its inhibitory action in a peroxidase model.
Regarding the other characteristics of this species, the studies
are still chosen at an early stage.
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