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Current Angiogenesis, 2015, 4, 10-23

ISSN: 2211-5528

The State-of-Art in Angiogenic Properties of Latex

eISSN: 2211-5536

from Different Plant Species

Luciane M. de Almeida1*, Angélica D.L. do Prado2; Patrícia L. D’Abadia1,
Karine B. Machado3, Paulo R. Melo-Reis4, João C. Nabout1 and Pablo J. Gonçalves5

1
Universidade Estadual de Goiás - CCET, Anápolis, GO, Brazil; 2Universidade
Estadual de Goiás - Campus Ipameri, GO, Brazil; 3Universidade Federal de Goiás,
PPG em Ecologia e Evolução, UFG, Goiânia, GO, Brazil; 4Departamento de Medi-
cina, Pontifícia Universidade Católica de Goiás -PUCGo; 5Instituto de Física da
Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil

Abstract: Background: The development of drugs capable of enhance or inhibit

the cell proliferation is an area in expansion at modern biomedical sciences. Recent
researches have shown that latex has strong angiogenic potential.
Methods: We performed a bibliometric analysis on the global literature trying to identify: the main
scientometrics data, the botanical families and species, the angiogenic or antiangiogenic properties
and also discussed the results obtained on this topic up to now.
Results: The different bibliometric approaches, showed a continuous increase of both quantitative
and qualitative parameters in the studies of latex utilization in the angiogenesis process. From more
than 35,000 lactiferous species existing only 29 have been studied and showed angiogenic potential.
Then, the potential for finding new therapeutic compounds in latex is a new and promising field that
needs to be better explored. Regarding the biological activity, 59% of articles have reported the an-
giogenic activity and 41% the antiangiogenic property. The most articles identified in this research,
have been used in their experimental analysis the crude latex (73.41%). Only 26.52% of the articles
used biocompounds isolated from latex. Among the weaknesses in this field, it is necessary to point:
the molecular characterization of latex; the establishment of molecular mechanism of action; and
Current Angiogenesis

demonstration of latex biocompunds safety and effectiveness in clinical trials.

Conclusion: Those results are important to spread knowledge about the use of latex as a new bio-
material employed in medicine, indicate trends, point out the technical difficult on the development
of new drugs.
Keywords: Angiogenesis, cancer, Euphorbiaceae, natural rubber, scientometrics, wound healing.

1. INTRODUCTION species of flowering plants in over 40 families ex-

Latex is a stable emulsion containing proteins,
alkaloids, starches, carbohydrate, oils, tannins, res-
ins and rubbers [1]. This emulsion is usually ex-
uded from plants after tissue injury. There are
more than 35,000 species of vascular plants that
exude latex, resin and others, and over 20,000
*Address correspondence to this author at the Universidade
Estadual de Goiás, Rodovia BR 153, nº 3105, Fazenda Barreiro do
Meio - Campus Henrique Santillo-Anápolis, Caixa Postal 459;
CEP: 75.132-400, Brasil. Tel: 55 62 3328115; Fax: 55 62
33281177; E-mail: luciane.almeida@ueg.br
2211-5536/15 $58.00+.00
ude latex [2]. Despite the wide distribution into
different botanical families, latex is most com-
monly found in Euphorbiaceae and Apocynaceae
plants. Concerning latex’s role, there are several
hypotheses, such as excretion of waste metabo-
lites, coverage of damaged tissue, defense against
herbivores, and defense against pathogens [2].
The main commercial interest in latex is due to
the production of natural rubber. Natural rubber
obtained from Hevea brasiliensis is a valuable
commodity and holds a strong position in the
world economy. Natural rubber is used in over
© 2015 Bentham Science Publishers
Angiogenic Properties Of Latex
40,000 products in different medical and techno-
logical applications, including more than 400
medical devices, surgical gloves, toys, waterproof
clothing, elastic products, insulation for electrical
wiring, and countless engineering and consumer
products [3]. However, the main use of rubber is in
automotive industry and in particular the manufac-
ture of pneumatic tires which consumes 60% to
70% of the total world production and its demand
has grown remarkably each year [4].
Current evidence indicates that a huge number
of people rely on medicinal plant products to
maintain their health or treat illnesses [5]. Think-
ing that, many pharmaceutical companies are in-
vestigating the industrial applications of a range of
medicinal plant species. This occurs because
plants have large chemical diversity which is effi-
cient in the treatment of diseases and also could be
used to develop new drugs or therapies. In the last
years, there are several studies showing the me-
dicinal potential of the latex, such as: antifungal
[6]; antiviral [7]; antioxidant [8]; antimicrobial [9];
angiogenic [10]; antigenotoxic [11]; anticancer
[12]; anti-inflammatory [13]; antiulcer [14]; insec-
ticidal [15]; antinociceptive [16]; and analgesic
[17]. Then, the potential for finding new therapeu-
tic compounds in latex is enormous, according to
the initial survey realized in this article, less than
1% of lactiferous plant species have been studied
for their pharmacological potential, and only 29
species have been evaluated in relation to the an-
giogenic or antiangiogenic potential.
Particularly this study is interested in reporting
the angiogenic and antiangiogenic properties from
latex. Angiogenesis is a complex biological proc-
ess that favors the formation of new blood vessels
from preexisting vascular tissue by the prolifera-
tion, migration, regulation and differentiation of
vascular cells [18]. From the point of view of
medical applications, materials that induce angio-
genesis are important for tissue engineering, to
enhance cell proliferation or to promote wound
healing [19, 20]. An interesting example of latex
used to promote angiogenesis is latex obtained
from Hevea brasiliensis. It has been shown that
the natural rubber latex not only is biocompatible
but also stimulates tissue regeneration, cellular ad-
hesion and extracellular matrix formation [21].
On the other hand, tumor angiogenesis, that is,
the development of new blood vessels from pre-
Current Angiogenesis, 2015, Vol. 4, No. 1 11
existing ones, plays an essential role in tumor
growth, invasiveness, and metastasis [22]. It is es-
timated that angiogenesis in tumors contributes to
more than 90% of all cancer deaths. A compound
with anti-angiogenesis potential is a promising
therapeutic target for the treatment of cancer.
There are some reports that have been showing the
antiproliferative potential from latex of different
species, such as Calotropis procera [23] and Ficus
carica [24].
Aiming to broaden our knowledge about the
therapeutic potential of latex species on the angio-
genic process we performed a bibliometric analy-
sis on the scientific literature trying to evaluate: 1)
the global publication trends, 2) the quality of the
scientific production estimated by number of cita-
tions and impact factor of the journals, 3) countries
of publication, average authorship and collabora-
tion network, 4) mapping from the countries inter-
ested in the theme and the international research
network, 5) identification of families and species
which produce latex with angiogenic or antiangio-
genic properties, 6) evaluation of the latex used in
traditional or allopathic medicine, 7) identification
of the assay methodologies employed to infer the
angiogenic activity, and 8) analyses of biocom-
pounds responsible for angiogenic activity of latex.
2. MATERIAL AND METHODS
2.1. Data Source
Data were retrieved from the Thomson Reuters
(ISI-Web of Knowledge). This databank was cho-
sen because it has long been recognized as the
most authoritative scientific and technical litera-
ture indexing tool providing data on the most im-
portant areas in science and technology research,
especially about medicine. Data analysis was re-
stricted to articles published from 1991 to 2014;
data entries from 2015 were excluded from the
analysis, because acquisition for this year was not
yet complete and data before 1991 were not consid-
ered because the electronic summaries are not
available in the ISI data base before this period. The
impact factor for each journal was obtained on the
Journal Citations Reports (JCR) for the year 2014.
2.2. Search Strategies
In order to arrive as closely as possible at cap-
turing all of the available scientometric data the
12 Current Angiogenesis, 2015, Vol. 4, No. 1
combination of the termini "latex" AND "angio-
genesis" OR "latex" AND "angiogenic*" OR "la-
tex" AND "wound healing" OR "latex" AND
"wound" OR "latex" AND "healing" OR "latex"
AND "burn" OR "latex" AND "skin" OR "latex"
AND "cicatrization*" OR "latex" AND "regenera-
tion*" OR "natural rubber" AND "angiogenesis"
OR "natural rubber" AND "angiogenic*" OR
"natural rubber" AND "wound healing" OR "natu-
ral rubber" AND "wound" OR "natural rubber"
AND "healing" OR "natural rubber" AND "burn"
OR "natural rubber" AND "skin" OR "natural rub-
ber" AND "cicatrization*" OR "natural rubber"
AND "regeneration*" OR "latex" AND "cancer"
OR "natural rubber" AND "cancer” were used in
the search field. The asterisk (*) was used as a
wildcard and enabled the search of any letters in
its place. We searched for papers that contain
those words in the title, abstract or list of key-
words. All types of publications were retrieved.
2.3. Analysis of Articles
For each paper we identified: 1) number of cita-
tions, 2) impact factor of the journal, 3) the journal
of publication, 4) the year of publication, 5) the
article type (review, research article, proceedings,
meeting abstract and others), 6) number of authors,
7) geographical origin of the corresponding author,
8) geographical origin of the all authors, 9) name
of the latex species and the family, 10) latex activ-
ity (angiogenesis or antiangiogenesis), 11) the
methodology employed to describe the latex bio-
logical function, and 12) use in folk or allopathic
medicine, and 13) use of crude latex or isolated
biocompounds.
2.4. Data Analysis
For evaluating the publication tendency we per-
formed a Pearson correlation between the number
of articles and years. A positive r value indicates
an increase in the number of articles associated
with the angiogenic potential of latex over the
years, while a negative r value indicates a decrease
in the number of publications on this theme. The
significant value was obtained through the Monte
Carlo test with 999 randomizations. We consid-
ered significant P values <0.05. This analysis was
conducted using the R 3.2.2 program [25]. The
impact factor and the number of citations were
evaluated using descriptive statistics (e.g. mean
and variation coefficient).
de Almeida et al.
For collaboration network we obtained, for
each paper, the nationality of the all authors. The
binary matrix containing the countries involved in
each article was used to calculate the Jaccard in-
dex (distance matrix) and estimate the collabora-
tion network among the countries. We used the
igraph [26] packages in R program to view the col-
laboration network.
3. RESULTS AND DISCUSSION
3.1. Document Types
In the initial screening of Thomson Reuters da-
tabase (ISI-Web of Knowledge), there were 2,166
total latex related papers. These articles were dis-
tributed over 10 different document types: 1,707
research article; 176 reviews; 109 article proceed-
ing papers; 73 proceedings; 45 meeting abstracts;
21 editorial materials; 19 letters; 13 notes; 1 news
item; 1 correction and 1 book chapter. For analysis
in this presented paper we used only research arti-
cles (i.e. 1,707 papers). The other document types
can promote biases in bibliometrics analysis, for
example, number of citation, impact factors and
others (see 27, 28; for using the same strategy).
A second screening was conducted based on the
subject of interest, namely the angiogenic property
of latex. At this step, 1,628 articles were removed
from our analysis, leaving only 79 articles which
describe the angiogenic properties from latex.
Specifically 702 articles about allergy, hypersensi-
bility, occupational exposure, or anaphylaxis
caused by latex; 313 articles about method of di-
agnosis; 191 articles about agronomy or plant sci-
ence, 85 articles about nanoscience and polymer
science and 337 other subjects in fewer amount
were removed from this analysis.
3.2. Bibliometric Data
The bibliometric data, such as: publications
tendency, number of citations per year, journal
impact factor and the journals interested in the
theme are shown in Fig. (1). The temporal publica-
tion trends about angiogenic potential of latex
from 1991 to 2014 are shown in Fig. (1A). This
analysis showed that after 2007, the annual num-
ber of publications has grown, indicating that re-
search has recently garnered more attention. In a
general analysis, the number of articles on this
subject is relatively low (only 79 articles), but has
Angiogenic Properties Of Latex
increased significantly along the period of the
study (r=0.84 and P<0.001).
According to Vitzthum et al. [29], “whereas the
number of published items was currently consid-
ered as a quantitative measure of research produc-
tivity, citation analysis and impact factor of the
journal may be used as an indicator for research
quality”. These parameters are quantitative and
objective indicators directly related to published
science. The citation data are obtained from a da-
tabase produced by the Institute for Scientific In-
formation (ISI), the Journal Citations Reports,
which continuously records scientific citations as
represented by the reference lists of articles from a
large number of the world's scientific journals. The
references are rearranged in the database to show
how many times each publication has been cited
within a certain period. Similarly, the journal im-
pact factor can be calculated as the mean citation
rate of all the articles contained in the journal. The
analysis of these parameters showed that the arti-
cles about the angiogenic potential of latex are not
cited often. The number of citations ranged from 0
to 61, but most of the articles presented no more
than ten citations (Fig. 1B). This skewness of cita-
Fig. (1). Article related bibliometric data: A) shows the publish items; B) shows the citations; C) shows the impact
factor of the journals and D) shows the number of articles per journal.
Current Angiogenesis, 2015, Vol. 4, No. 1 13
tion is a very common pattern in bibliometric
analysis [e.g 27, 30], moreover, the number of ci-
tation depends on the year of publication, where,
older papers tend to have more citations [31].
Thus, the fewer citations, the more recent is the
research area. After the establishment of new re-
search groups (intra and international) and stan-
dardization of techniques, the number of articles
and citations tends to increase. In relation to the
impact factor, the journals analyzed ranged from
0.01 to 5.0 (Fig. 1C), with the highest frequency
between 2.5 to 3.0. These data indicate that the
research is published in good science communica-
tion journals.
We identified 59 journals interested in publish-
ing articles about angiogenesis properties from
latex. Fig. (1D) shows the journals with more than
one published article. These data showed the wide
diversity of journals interested in the theme. The
journal with the highest number of publications
was the Journal of Ethnopharmacology, with 11
published articles, followed by Journal Material
Science: Material in Medicine and Pakistan Jour-
nal of Pharmaceutical Sciences which published
three articles related to the topic. All bibliometrics
14 Current Angiogenesis, 2015, Vol. 4, No. 1
approaches used in this work, showed a continu-
ous increase in both quantitative and qualitative
parameters in the studies of latex utilization in the
angiogenesis process.
3.3. Countries of Publication, Average Author-
ship and Collaboration Network
Fig. (2A) shows that the average authorship has
been increasing, indicating that researchers have
recently given more attention to this theme. Fig.
(2B) shows the country of the corresponding
author. The largest number of scientific works
about angiogenic potential from latex is published
in Brazil (or by Brazilians) with 41 articles
(51.9%). The nation with the second most pub-
lished works is India with 8 articles (10.12%). Ma-
laysia and USA have 4 articles, and 16 other coun-
tries have less than 3 articles (Fig. 2A). The re-
search cooperation was evaluated by the average
authorship and collaboration network. Figure 2C
shows the international collaboration network be-
tween authors from different countries. USA has
achieved the highest amount of overall interna-
tional cooperation, as it collaborates with 4 differ-
Fig. (2). Analysis of author geographic distributions and collaboration network: A) shows the average authorship
per year; B) shows the number of publish items per country (using data from corresponding author); and C) shows
the international collaboration network.
de Almeida et al.
ent countries. The amount of international collabo-
ration is very small and confirms that this subject
is mainly of national interest. This result is also
associated with the fact that it is a recent area of
research. International collaborations tend to in-
crease when there is a convergence of issues and
common interest, such as the Human Genome Pro-
ject stimulated that cooperation between several
countries [32]. In addition, international collabora-
tions promote the need for standardization of labo-
ratory techniques as well as reduce costs. There-
fore, considering that study of angiogenic potential
from latex is recent and yet already there are inter-
national collaborations, there is an expectation that
international collaboration will increase (number
of countries and connections between countries).
3.4. Identification of Botanical Families and
Species, Biological Activity, Ethno Botanical or
Scientific Study, Biological Assay Model
All lactiferous with angiogenic or antiangio-
genic properties identified in this research were
presented in Table 1. As a result it is observed that
very few lactiferous species have been studied in
Angiogenic Properties Of Latex Current Angiogenesis, 2015, Vol. 4, No. 1 15

Table 1. Lactiferous species with angiogenic properties.

Biological
N Species Family Popular name Knowledge Biological model (Reference)
activity

1 Aloe vera Asphodelace Aloe A E Wound healing [33]

Bark cloth tree, antiaris, or false

2 Antiaris toxicaria Moraceae B S Cell culture [34]
iroko

tropical milkweed, or cotton

3 Asclepias curassavica Asclepiadaceae A E [35]
bush

4 Bambusa arumdinaceae Poaceae Indian thorny bamboo A E [36]

Blood coagulation [37]; Wound

5 Calotropis gigantea Apocynaceae Crown flower A S
healing [38];

Sodom apple, stabragh, or rubber

6 Calotropis procera Apocynaceae A S Wound healing [39-41]
bush

Sodom apple, stabragh, or rubber

Calotropis procera Apocynaceae B S Cell culture [42-45]
bush

Healing of ulcers [46]; Wound

healing [47]; Cell proliferation [48];
7 Carica candamarcensis Caricaceae Mountain pawpaw, or papayuelo A S
Cell culture [49]; Healing of burns
[50]

8 Carica papaya Caricaceae Papaya A S Healing of burns [51]

Croton sp Euphorbiaceae Rushfoil B E [52]

9 Croton celtidifolius Euphorbiaceae B S Cell culture [53]

10 Croton churutensis Euphorbiaceae A E Wound healing [54]

11 Croton lechleri Euphorbiaceae Drago A S Cell culture [55]

Croton lechleri Euphorbiaceae Drago B S Cell culture [56]

12 Euphorbia antiquorum Euphorbiaceae Malayan Spurge Tree B S Cell culture [57]

13 Euphorbia caducifolia Euphorbiaceae Leafless Milk Hedge B S [58]

Euphorbia caducifolia Euphorbiaceae Leafless Milk Hedge A S Wound healing [59]

14 Euphorbia candelabum Euphorbiaceae Candelabra-tree A E [60]

15 Euphorbia dendroides Euphorbiaceae Tree Spurge B S Cell culture [61]

16 Euphorbia milii Euphorbiaceae Crown of thorns, or Christ plant A S Wound healing [62]

Indian Spurge Tree or Common Wound healing [63]; Clot induction

17 Euphorbia nivulia Euphorbiaceae A S
milk hedge [64]

Aveloz, firestick plants, Indian

18 Euphorbia tirucalli Euphorbiaceae A E [60]
tree spurge, or milk bush

Aveloz, firestick plants, Indian

Euphorbia tirucalli Euphorbiaceae A S Wound healing [65]
tree spurge, or milk bush

Aveloz, firestick plants, Indian

Euphorbia tirucalli Euphorbiaceae B S Microtubule organization [66]
tree spurge, or milk bush

Cell culture [24, 67-70]; Toxicity

19 Ficus carica Moraceae Fig B S
[71]

Chick chorioallantoic membrane

20 Hancornia speciosa Apocynaceae Mangabeira, Mangaba A S
[10]
16 Current Angiogenesis, 2015, Vol. 4, No. 1 de Almeida et al.

(Table 1) contd...

Biological
N Species Family Popular name Knowledge Biological model (Reference)
activity

Nerve regeneration [72-74]; Tympa-

num regeneration [75]; skin sensitiv-
ity [76]; bone regeneration [77-82];
wound healing [83-86]; chick
chorioallantoic membrane [84,87];
21 Hevea brasiliensis Euphorbiaceae Rubber tree, sharinga tree A S
retinal and iris neovascularization
[88-89]; osseointegration of dental
implants [90]; Tooth regeneration
[91]; neovaginoplasty [92]; bladder
augmentation [93]

Hevea brasiliensis Euphorbiaceae Rubber tree, sharinga tree B S Cell culture [94-97]

22 Himatanthus articulatus Apocynaceae Himatanthus B S Genotoxicity [11]

23 Himatanthus drasticus Apocynaceae Janauba B E [98]

Himatanthus drasticus Apocynaceae Janauba B S Cell culture [12]

Barbados nut, purging nut, or

24 Jatropha curcas Euphorbiaceae B S Cell culture [99]
physic nut

Buck-thorn, cimora misha, or

25 Pedilanthus tithymaloides Euphorbiaceae A S Clot induction [64]
devil's backbone

Buckthorn, misha, or devil's

Pedilanthus tithymaloides Euphorbiaceae B S Cell culture [45]
backbone

Frangipani, red paucipan, red-

26 Plumeria rubra Apocynaceae A S Wound healing [100]
jasmine

27 Synadenium grantii Euphorbiaceae African milk bush A S Clot induction [64]

Synadenium grantii Euphorbiaceae African milk bush B S Cell culture [101]

Chick chorioallantoic membrane

28 Synadenium umbellatum Pax Euphorbiaceae Cola-nota A S
[102]

Synadenium umbellatum Pax Euphorbiaceae Cola-nota B S Cell culture [103]

29 Wrightia tinctoria Apocyanaceae Jaundice curative tree A S Wound healing [104]

N: number of species; A: angiogenesis activity; B: antiangiogenesis activity; E: ethnobotanic knowledge; and S: Scientific knowledge.

relation to angiogenesis. From a total of 35,000 3.5. Lactiferous Stimulators of Angiogenesis

species and more than 40 families, only 29 species
belonging to 7 families have their angiogenic poten-
tial described in scientific research. The studied
families are Euphorbiaceae (57.4%), following by
Apocynaceae (19.5%), Moraceae (8.5%), Cari-
caceae (7.3%), Asclepiadaceae (4.9%), Asphode-
laceae (1.2%) and Poaceae (1.2%). The species
with great number of studies is Hevea brasiliensis.
Table 1 also shows the articles based on popular
knowledge (Ethnobotany articles) and the articles
based on experimental researches (Scientific arti-
cles). Angiogenic activity is reported in 59% of ar-
ticles and antiangiogenic propertiy in 41% (Table
1). The most studied lactiferous species and their
biological properties are discussed in details below.
Latex from several plant species have been re-
ported to stimulate the angiogenesis (Table 1).
Angiogenesis is a normal and vital process in
growth and development, as well as in wound
healing in the formation of granulation tissue. This
process enables nutrient supply to sustain cell me-
tabolism and create an intact delivery system and
it occurs in several well-characterized stages. An-
giogenesis initiates with relaxation of cell contacts
and disruption of the outer pericyte layer. Hence,
endothelial cells become free to migrate and pro-
liferate to form new vessels [105]. The mechanism
of angiogenesis regulation is still a matter of de-
bate. Some angiogenic molecules, referred to as
Angiogenic Properties Of Latex
growth factors, are known to trigger proliferation
of endothelial cells [106], while the so-called
antiangiogenic factors inhibit cell propagation
[107]. This review identified 21 species with angi-
ogenic potential, from that three species can be
highlighted by presenting more than three scien-
tific articles: Hevea brasiliensis (19 articles);
Carica candamarcensis (5 articles) and Calotropis
procera (3 articles).
Hevea brasiliensis: In 1993, Mrué and co-
workers obtained a membrane using latex from
Hevea brasiliensis which was used initially in an
experimental study in dogs as prosthesis for the
replacement of cervical esophagus. As a result, it
was observed that the new material was able to
induce the neoformation of esophageal wall. Later,
other studies confirm the promising capacity of
Hevea brasiliensis latex in replacement and regen-
eration tissues. The biomembranes not only are
biocompatible but also stimulate angiogenesis, cel-
lular adhesion and extracellular matrix formation
[76]. Such properties can be observed in studies of
different tissues, such as wound healing in cutane-
ous tissues [76]; eardrum replacement [75]; bone
regeneration [79]; retina restitution [86];
neovaginoplasty [92]; osseointegration of dental
implants [90]; tooth regeneration [91] and others.
After those excellent results, a group of Brazilian
institutional investors founded the Pelenova Bio-
technology SA. In 2004, In 2004, the National
Health Surveillance Agency (ANVISA) approved
a biomembrane called Biocure®, the first Pelenova
product developed from the Hevea brasiliensis
latex. In 2009 protein fraction from rubber latex
serum was isolated and used to produce an innova-
tive product, Regederm®, which has been used for
the treatment and healing of chronic wounds of
different etiologies. Regederm® stimulates angio-
genesis and tissue granulation, accelerating the
wound healing process. The efficacy of fraction
protein was demonstrated by the cell growth of
human dermal fibroblasts, by stimulation of the
synthesis of collagen and by the inhibition of the
collagenase and extracellular matrix protection.
Regarding its safety, different in vitro and in vivo
tests were performed, such as: allergenicity, cyto-
toxicity, phototoxicity, photoallergicity, irritability
and cutaneous compatibility (http://www.peleno-
va.com.br/ingredientes-ativos.php). Recently, the
Valeant Pharmaceuticals International Inc, a mul-
tinational specialty drugs company, became a
Current Angiogenesis, 2015, Vol. 4, No. 1 17
commercial bussiness partner from PeleNova Bio-
technology SA in marketing their products.
Associating this commercial drug discovery
with the data of scientific production by country
obtained in the present research; it is shown that
the findings of Mrué and co-workers stimulate the
study of latex angiogenic potential in Brazil. This
is the probable reason for that country to be re-
sponsible for almost 52% from all knowledge in
this field, even though the main latex producers
are found in Asia.
Carica candamarcensis: In 2003, Salas and co-
workers identified proteolytic enzymes localized
in the fruit of C. candamarcensis [49]. One frac-
tion obtained from that latex and called P1G10 has
been shown: accelerate healing of chemically in-
duced gastric ulcer [46]; enhance wound healing
of skin [47, 48]; and accelerate healing of burns
[50]. Different models were used to evaluate the
angiogenic property of C. candamarcensis latex,
such as: rodent model and culture cells (L929 fi-
broblast, MDA-MB231 and BHK-21 mammalian
cells). These results confirm the healing properties
of this enzyme to a different type of trauma and
open ways to future clinical applications. How-
ever, up to now, no commercial products from C.
candamercensis latex are available.
Calotropis procera: Based on its traditional
use, in 1999, Rasik and co-workers used this plant
and selected the latex of C. procera for evaluation
of its wound healing potential. The latex signifi-
cantly augmented the healing process by markedly
increasing collagen, DNA and protein synthesis and
epithelisation leading to the reduction in the wound
area. Later, a marked reduction was shown in the
quantity and size of collagen fibres of rabbits
treated with this latex, suggesting an anti-keloidal
function of C. procera latex [40]. Recently, solu-
ble proteins extracted from the latex of C. procera
were added to polyvinyl alcohol-based to make a
membrane. This product intensified the fibropla-
sias and collagen deposition, thus stimulating the
healing process. The experiments with C. procera
were performed using rabbits and guinea pigs. Be-
sides promising results, no commercial products
from C. candamercensis latex are available.
3.6. Lactiferous Inhibitor of Angiogenesis
Angiogenesis is also involved in many patho-
logical processes, such as tumor development, ar-
18 Current Angiogenesis, 2015, Vol. 4, No. 1
thritis, cardiovascular diseases, and other chronic
inflammatory diseases [108-111]. Recently, the
main focus of angiogenesis inhibitor drugs is on
anti-cancer or chemoprevention therapies [112].
This is why, angiogenesis and vascularization pro-
vide an important avenue for extravasation of me-
tastatic tumor cells for the circulation in other or-
gan sites. This review identified 16 species with
antiangiogenic potential, from that two species can
be highlighted: Ficus carica (6 articles) and Calo-
tropis procera (5 articles).
Ficus carica: the first work that suggests the
anticancer properties from F. carica latex was pre-
sented by Menechini et al., 1999. After that other
researches were performed using different tumor
cells lineages and all showed strong antiangio-
genic and antiproliferative activities from latex
extracts of F. carica [68]. The studies were real-
ized using different cancer cell lines cultures. It is
important to say that this latex inhibited the prolif-
eration of cancer cell without any cytotoxic effect
on human normal cells [70]. The authors sug-
gested that F. carica latex could be a candidate as
a potential agent for the prevention of angiogene-
sis in cancer and other chronic disorders. How-
ever, no commercial drug was obtained from this
latex up to now.
Calotropis procera: the articles identified in
this search have shown C. procera latex with an-
giogenic and antiangiogenic properties. In relation
to the antiangiogenic properties, the first study was
from Choedon and co-workers in 2006. They
showed that the treatment with C. procera latex
generates a complete protection against hepatocar-
cinogenesis. The anticancer potential of the pro-
teins from C. procera latex used as biological as-
say for different cell lines culture has been con-
firmed in other articles [23, 43-44]. The analysis
of the mechanism of action suggests that latex pro-
tein is a target for DNA topoisomerase I triggering
apoptosis in cancer cell lines [44]. Besides the pro-
teins, the cardiotonic steroid (UNBS1450 01) de-
rived from C. procera latex, has also shown anti-
proliferative and cell death-inducing activities
[43].
Eight species identified in the present research
were shown to have both angiogenic and antiangi-
ogenic activity. This was the case of Calotropis
procera, Croton lecheri, Euphorbia caducifolia,
Euphorbia tirucalli, Hevea brasiliensis, Pedilan-
de Almeida et al.
thus tithymaloides, Synadenium grantii and Syna-
denium umbellatum. Those divergent biological
activities were related to different articles which
used different methodologies and biological mod-
els. In addition, factors such as: sample concentra-
tions, use of crude latex or isolated biocompounds,
and addition of latex stabilizers or other chemical
compounds can influence directly the results ob-
tained. Other important aspect to be considered is
the chemical variation of the latex due to the geo-
graphic localization, harvest time, climate condi-
tions, cultivation handling, age of vegetable mate-
rial, period and storing conditions, among others
[113]
3.7. Functional Biocompounds
A great variety of chemicals (mostly secondary
metabolites but some primary metabolites) and
proteins have been found from the plant latex and
other exudates [114]. Some latex compounds have
shown an angiogenic function, but there are very
few studies about the molecular or chemical char-
acterization of these compounds. Also, no molecu-
lar mechanism of action has been described to la-
tex compounds and there are few studies that
showed the safety and effectiveness of latex com-
pounds in clinical trials. Regarding the biocom-
pounds, this review identifies that the 73.41% of
articles with latex used the crude latex in their ex-
perimental analysis. Only 26.52% of the articles
published up to now, used some isolated com-
pound in their experimental analysis. The classes
of biocompounds studied were: proteins, steroids,
glycosides and diterpenoids. The main proteins
identified were P1 (Hevea brasiliensis); rhBMP2
(Hevea brasiliensis); CMS2MS2 cysteine prote-
ases (Carica candamarcensis) and glycosylated
cysteine protease (Euphorbia nivulia). The ster-
oids identified were 6-O-acyl-beta D-glucosyl-beta
stosterols in Ficus carica, Inganen ester in
Euphorbia tirucalli and cardiotonic steroid
(UNBS1450 01) in Calotropis procera. The glyco-
side identified was cardiac glycosides in Antiaris
toxicaria. Finally, jatrophane diterpenoids were
identified in Euphorbia dendroides.
4. CONCLUSION
The development of drugs capable of enhanc-
ing or inhibiting the cell proliferation is an area of
expansion in modern biomedical sciences. Aim-
Angiogenic Properties Of Latex
ing to understand the role of latex in angiogene-
sis, we performed a survey on the global litera-
ture trying to identify the main species used in
medicine to regenerate tissues or treat the can-
cers. We identified only 29 lactiferous employed
to stimulate or inhibit angiogenesis. This repre-
sents less than 0.1% of the lactiferous species,
which shows that the potential for finding new
therapeutic compounds in latex is yet enormous
and needs to be better explored. Regarding the
literature survey, our bibliometrics data showed
that the latex used in medicine for regenerative
proposal is a very recent topic, but there is a sig-
nificant increase in the number of articles in the
last years, indicating that research has recently
received more attention. Other bibliometrics ap-
proaches used in this work, such as number of
citations, impact factor of the journals, number of
journals, countries of publications, average
authorship and collaboration network showed a
continuous increase in both quantitative and
qualitative parameters in the studies of latex utili-
zation in the angiogenesis process. In relation to
the development and release of new drugs, de-
spite the promising results, there is still a lot to
consider so that the extracted latex compounds
become really an alternative for the treatment of
various diseases. Among the weaknesses in this
field, it is necessary to point: the molecular char-
acterization of latex; the establishment of molecu-
lar mechanism of action; and demonstration of
latex biocompounds safety and effectiveness in
clinical trials. We believe that these weaknesses
are the consequence of very recent discovery of
the angiogenic property from latex, and these
weaknesses probably will decrease in the near
future once the importance of this finding and the
necessity of new drugs in medical sciences are
realized. The results presented in the present
work are important to spread knowledge about
the use of latex as a new biomaterial employed in
medicine, indicated trends, stimulated collabora-
tions which could standardize the laboratory
techniques and reduce costs, and point out the
technical difficulty for the development of new
drugs.
CONFLICT OF INTEREST
The authors confirm that this article content has
no conflict of interest.
Current Angiogenesis, 2015, Vol. 4, No. 1 19
ACKNOWLEDGEMENTS
This research was supported by a Research
Grant Project from Brazilian funding agencies
MCT/CNPq, FNDCT, CAPES, FAPEG.
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Received: November 30, 2015 Revised: January 29, 2016 Accepted: February 23, 2016
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