CRTON LECHLERI Abstrcts

J Ethnopharmacol. 2012 Dec 18;144(3):747-53. doi: 10.1016/j.jep.2012.10.032. Epub 2012 Oct 30.

Croton lechleri sap and isolated alkaloid taspine exhibit inhibition

against human melanoma SK23 and colon cancer HT29 cell lines.
Montopoli M, Bertin R, Chen Z, Bolcato J, Caparrotta L, Froldi G.

Source
Department of Pharmaceutical and Pharmacological Sciences, Padua University, Largo E. Meneghetti 2,
Padua, Italy.

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE:
Croton lechleri Mull. Arg. (Euphorbiaceae) is a traditional medicinal plant which produces a red sap,
traditionally known as "Sangre de Drago"; it is used in folk medicine externally for wounds, fractures, and
haemorrhoids, internally for intestinal and stomach ulcers and also for the empirical cure of cancers.
MATERIALS AND METHODS:
We investigated the effects of Croton lechleri sap and taspine in comparison with taxol and vinblastine on the
growth of human cancer cell lines of SK23 (melanoma), LoVo and HT29 (colorectal cancer) using MTT and
Trypan blue assays. Further, we studied cell cycle by flow cytometry and detected acetylated--tubulin by
confocal microscope.
RESULTS:
Croton lechleri inhibited cell proliferation starting from 1 g/mL in SK23 cells, whereas 10 times higher
concentrations were required for growth inhibition of HT-29 and LoVo cell lines. Also taspine (0.1 g/mL)
inhibited the SK23 and HT29 cell proliferation. Further, assay was assessed on SK23 and HT29 cell lines
with 24-48 h treatment with sap and taspine. Both sap and taspine inhibited cancer cell proliferation; taspine
showed higher activity on SK23 cells, which was significantly increased after 48 h of SK23 treatment. Using
confocal microscopy we observed that Croton lechleri (1 g/mL) caused a loss of microtubule structure,
whereas taspine (0.5 g/mL) caused an increase in acetylated -tubulin and a modification of cellular
morphology, mainly in SK23 cells. Croton lechleri sap 10 and 50 g/mL influence cell cycle; 50 g/mL sap
caused a dramatic reduction of cells in G(1)/G(0) and S phases with a great increase of subG(0) cells.
CONCLUSIONS:
The data showed that Croton lechleri and taspine could inhibit cell proliferation with higher potency against
melanoma SK23 cells, supporting the empirical use of the sap as anticancer in ethnomedicine and taspine
as a possible anticancer agent.
Planta Med. 1989 Apr;55(2):140-3.

Taspine is the cicatrizant principle in Sangre de Grado extracted from

Croton lechleri.
Vaisberg AJ, Milla M, Planas MC, Cordova JL, de Agusti ER, Ferreyra R, Mustiga MC, Carlin L, Hammond
GB.

Abstract

Sangre de Grado extract used by Peruvian natives as a cicatrizant agent, was collected from trees of the
species Croton lechleri growing in the Peruvian jungle. The Sangre de Grado was found to contain one
alkaloid identified as taspine and which was shown to be the active cicatrizant principle by an in vivo test in
mice. This alkaloid exhibited a dose-related cicatrizant effect and an ED50 of 0.375 mg/kg. Experiments with
taspine hydrochloride in order to study its mechanism of action in cell culture systems showed that the
alkaloid was non-toxic to human foreskin fibroblasts at concentrations below 150 ng/ml and that it had no
effect on cell proliferation. On the other hand, taspine hydrochloride was found to increase the migration of
human foreskin fibroblasts. This effect on the migration of fibroblasts is probably the mechanism by which
Sangre de Grado and taspine hydrochloride accelerate the wound healing process. Using the two-stage
mouse skin carcinogenesis system, we have been able to show that neither Sangre de Grado nor taspine
hydrochloride had carcinogenic or tumour promoter activity after 17 months of treatment.
Proc Soc Exp Biol Med. 1993 May;203(1):18-25.

Enhancement of wound healing by the alkaloid taspine defining

mechanism of action.
Porras-Reyes BH, Lewis WH, Roman J, Simchowitz L, Mustoe TA.

Source
Division of Plastic Surgery, Washington University School of Medicine, Saint Louis, Missouri 63110.

Abstract
Taspine (mol wt 369,000) is an alkaloid extracted from trees of Croton (family Euphorbiaceae) of the western
Amazon region that has been used by natives and others as a vulnerary agent. Taspine was purified from
tree sap to test its healing properties using different topical concentrations in the paired rat surgical incision
model. Wound tensile strength and histology were evaluated. Samples treated with 250 micrograms, but not
those treated with 50 micrograms or 10 micrograms, had significant higher values for MBS than paired
controls (26%, P < 0.005, and 30%, P < 0.001, by Days 5 and 7, respectively). Taspine did not modify MBS
at Day 12. Sample treated with 250 micrograms had significantly greater mononuclear cellular infiltration at
Days 5 and 7 but not at Day 12. To better understand the effect of taspine as an enhancer of wound healing,
we conducted in vitro studies in cell cultures. Taspine stimulated chemotaxis for fibroblasts. Taspine did not
have an effect on specific assays for macrophage chemotaxis, neutrophil activation, fibroblast proliferation,
or matrix assembly. Taken together, the data suggest that taspine promotes early phases of wound healing
in a dose-dependent manner with no substantial modification thereafter. Its mechanism of action is probably
related to its chemotactic properties on fibroblasts and is not mediated by changes in extracellular matrix.
J Altern Complement Med. 2003 Dec;9(6):877-96.

Review of sangre de drago (Croton lechleri)--a South American tree sap

in the treatment of diarrhea, inflammation, insect bites, viral infections,
and wounds: traditional uses to clinical research.
Jones K.

Source
Armana Research, Inc., Halfmoon Bay, British Columbia, Canada. armana@dccnet.com

Abstract
OBJECTIVE:
The objective of this review is to provide an overview of the pharmacologic evidence that may or may not
support clinical and ethnomedical uses of the sap of sangre de drago (dragon's blood; Croton lechleri Mll.

Arg.). Data sources used were BIOSIS, EMBASE, PubMed, TOXLIT, International Pharmaceutical Abstracts,
manual searches, papers on file from peer-reviewed journals, textbooks available at Armana Research, Inc.,
and researchers in the field of South American botanical medicine.
CONCLUSIONS:
The results of in vitro and in vivo studies largely support the majority of ethnomedical uses of sangre de
drago including the treatment of diarrhea, wounds, tumors, stomach ulcers, herpes infection, the itching, pain
and swelling of insect bites, and other conditions. Clinical studies of sangre de drago products have reported
positive results in the treatment of traveler's and watery diarrhea and the symptoms of insect bites. Because
the sap has shown low toxicity and preparations used in clinical studies were well tolerated, further clinical
and pharmacologic studies are anticipated. Acknowledgment of the diversity in the chemical makeup of the
sap from one geographic area to another and the recent characterization of alkaloid chemotypes of sangre
de drago will require that materials developed for clinical use are standardized.
Exp Dermatol. 2010 Sep;19(9):796-9. doi: 10.1111/j.1600-0625.2010.01090.x.

Effects of sangre de drago in an in vitro model of cutaneous neurogenic

inflammation.
Pereira U, Garcia-Le Gal C, Le Gal G, Boulais N, Lebonvallet N, Dorange G, Lefeuvre L, Gougerot A, Misery
L.

Source
University of Western Brittany, Laboratory of Nervous Factors and Tissular Struturation (EA 4326), Brest,
France.

Abstract
Sangre de drago (SD) is a viscous bright red resin collected from Croton lechleri trees that grow in the South
American jungle. This sap is used extensively in the native pharmacopoeia to treat skin disorders. Its
effectiveness as an inhibitor of neurogenic inflammation has been recently demonstrated. To understand the
underlying mechanisms of these effects, we examined the ability of SD to reduce substance P (SP) release
in an in vitro model of cutaneous neurogenic inflammation (CNI). This model is based on an enzyme
immunoassay of SP (an inducer of CNI) in a porcine co-culture of dorsal root ganglion neurons and
keratinocytes. After incubation with different concentrations of SD, we noted an immediate and significant
dose-dependent decrease in basal SP release, with average values of 32% at 1% SD (v/v) and 26% at 0.1%
(v/v). On the other hand, pretreatment (72 or 1 h) of the co-culture with 1% SD (v/v) was sufficient to induce
a 111% (72 h) or 65% (1 h) inhibition of capsaicin-induced SP release, while 0.1% SD (v/v) triggered a 109%
(72 h) or 30% (1 h) inhibition. We conclude that sangre de drago is a potent inhibitor of CNI through direct
inhibition of neuropeptide release by sensory afferent nerves.
Altern Med Rev. 2001 Dec;6(6):567-79.

Review of antiviral and immunomodulating properties of plants of the

Peruvian rainforest with a particular emphasis on Una de Gato and
Sangre de Grado.
Williams JE.

Source
California Acupuncture College, San Diego, CA, USA. drwilliams665@home.com

Abstract

Viral diseases, including emerging and chronic viruses, are an increasing worldwide health concern. As a
consequence, the discovery of new antiviral agents from plants has assumed more urgency than in the past.
A number of native Amazonian medicines of plant origin are known to have antimicrobial and antiinflammatory activity, although only a few have been studied for their antiviral properties and
immunomodulating effects. Those most studied include: Sangre de Grado (drago) (Croton lechleri) in the
Euphorbiaceae family and Una de Gato (Uncaria tomentosa) in the Rubiaceae family. This article reviews
the chemical composition, pharmacological properties, state of current research, clinical use, and potential
antiviral and immunomodulating activity of these and other plants from the Peruvian Amazon.
Phytomedicine. 2009 Aug;16(8):768-75. doi: 10.1016/j.phymed.2009.02.003. Epub 2009 Apr 29.

Activity of sap from Croton lechleri on rat vascular and gastric smooth
muscles.
Froldi G, Zagotto G, Filippini R, Montopoli M, Dorigo P, Caparrotta L.

Source
Department of Pharmacology and Anaesthesiology, University of Padova, Padua, Italy. g.froldi@unipd.it

Abstract
The effects of red sap from Croton lechleri (SdD), Euphorbiaceae, on vascular and gastric smooth muscles
were investigated. SdD, from 10 to 1000 microg/ml, induced concentration-dependent vasoconstriction in rat
caudal arteries, which was endothelium-independent. In arterial preparations pre-constricted by
phenylephrine (0.1 microM) or KCl (30 mM), SdD also produced concentration-dependent vasoconstriction.
To study the mechanisms implicated in this effect we used selective inhibitors such as prazosin (0.1 microM),
an antagonist of alpha(1)-adrenoceptors, atropine (0.1 microM), an antagonist of muscarinic receptors, and
ritanserin (50 nM), a 5-HT(2A) antagonist; none of these influenced vasoconstriction caused by SdD.
Likewise, nifedipine (50 nM), an inhibitor of L-type calcium channels, did not modify the action of SdD.
Capsaicin (100 nM), an agonist of vanilloid receptors, also did not affect vasoconstriction by SdD. We also
investigated the action of SdD (10-1000 microg/ml) on rat gastric fundus; per se the sap slightly increased
contractile tension. When the gastric fundus was pre-treated with SdD (100 microg/ml) the contraction
induced by carbachol (1 microM) was increased, whereas that by KCl (60mM) or capsaicin (100 nM) were
unchanged. The data shows that SdD increased contractile tension in a concentration-dependent way, both
on vascular and gastric smooth muscles. The vasoconstriction is unrelated to alpha(1), M, 5-HT(2A) and
vanilloid receptors as well as L-type calcium channels. SdD increased also contraction by carbachol on rat
gastric fundus. Thus for the first time, experimental data provides evidence that sap from C. lechleri owns
constricting activity on smooth muscles.
Molecules. 2008 Jun 1;13(6):1219-29.

Identification of minor secondary metabolites from the latex of Croton

lechleri (Muell-Arg) and evaluation of their antioxidant activity.
De Marino S, Gala F, Zollo F, Vitalini S, Fico G, Visioli F, Iorizzi M.

Source
Dipartimento di Chimica delle Sostanze Naturali, Universit degli Studi di Napoli Federico II,Via D.
Montesano 49, I-80131 Napoli, Ita. sidemari@unina.it

Abstract
Dragon's blood (Sangre de drago), a viscous red sap derived from Croton lechleri Muell-Arg
(Euphorbiaceae), is extensively used by indigenous cultures of the Amazonian basin for its wound healing
properties. The aim of this study was to identify the minor secondary metabolites and test the antioxidant
activity of this sustance. A bioguided fractionation of the n-hexane, chloroform, n-butanol, and aqueous

extracts led to the isolation of 15 compounds: three megastigmanes, four flavan-3-ols, three
phenylpropanoids, three lignans, a clerodane, and the alkaloid taspine. In addition to these known
molecules, six compounds were isolated and identified for the first time in the latex: blumenol B, blumenol C,
4,5-dihydroblumenol A, erythro-guaiacyl-glyceryl-beta-O-4'- dihydroconiferyl ether, 2-[4-(3-hydroxypropyl)-2methoxyphenoxy]-propane-1,3-diol and floribundic acid glucoside. Combinations of spectroscopic methods
((1)H-, (13)C- NMR and 2D-NMR experiments), ESI-MS, and literature comparisons were used for
compound identification. In vitro antioxidant activities were assessed by DPPH, total antioxidant capacity and
lipid peroxidation assays. Flavan-3-ols derivatives (as major phenolic compounds in the latex) exhibited the
highest antioxidant activity.
Planta Med. 2003 Sep;69(9):785-94.

Immunomodulatory activity and chemical characterisation of sangre de

drago (dragon's blood) from Croton lechleri.
Risco E, Ghia F, Vila R, Iglesias J, Alvarez E, Caigueral S.

Source
Unitat de Farmacologia i Farmacognsia, Facultat de Farmcia, Universitat de Barcelona, Av. Diagonal 643,
08028 Barcelona, Spain.

Abstract
The immunomodulatory activity of the latex from Croton lechleri (sangre de drago) was determined by in vitro
assays. Classical (CP) and alternative (AP) complement pathways activities were determined in human
serum. Intracellular generation of reactive oxygen species (ROS) by human polymorphonuclear leukocytes
(PMNs) and monocytes, and phagocytosis of opsonised fluorescent microspheres were measured by flow
cytometry. Free radical scavenging activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH).
Activity on proliferation of murine lymphocytes was also investigated. In addition, anti-inflammatory activity
was assayed in vivo by carrageenan-induced rat paw oedema test. Some of the activities were compared
with those of the isolated alkaloid taspine. Sangre de drago from Croton lechleri showed immunomodulatory
activity. It exhibited a potent inhibitory activity on CP and AP of complement system and inhibited the
proliferation of activated T-cells. The latex showed free radical scavenging capacity. Depending on the
concentration, it showed antioxidant or prooxidant properties, and stimulated or inhibited the phagocytosis.
Moreover, the latex has strong anti-inflammatory activity when administered i. p. Taspine cannot be
considered the main responsible for these activities, and other constituents, probably proanthocyanidins,
should be also involved.
J Ethnopharmacol. 2004 Dec;95(2-3):437-45.

Mutagenic and antioxidant activities of Croton lechleri sap in biological

systems.
Lopes MI, Saffi J, Echeverrigaray S, Henriques JA, Salvador M.

Source
Instituto de Biotecnologia da Universidade de Caxias do Sul (UCS), Rua Francisco Getlio Vargas, 1130
Caxias do Sul, RS, Brazil.

Abstract
The sap of Croton lechleri Muell.-Arg (Euphorbiaceae), called Dragon's blood, is used in folk medicine as a
cicatrizant, anti-inflammatory and to treat cancer. In this research, the antioxidant activity of Croton lechleri
sap was evaluated against the yeast Saccharomyces cerevisiae and against maize plantlets treated with the
oxidative agents apomorphine and hydrogen peroxide. The mutagenic activity of the sap was also analyzed
using the Salmonella/microsome assay (Salmonella typhimurium TA97a, TA98, TA100, TA102, TA1535) and

in cells of the yeast Saccharomyces cerevisiae. The results showed that Croton lechleri sap possesses
significant antioxidant activity against the oxidative damages induced by apomorphine in Saccharomyces
cerevisiae under all the conditions studied. However, in the case of hydrogen peroxide, antioxidant activity of
the sap was detected only in cells in the stationary phase of growth. The sap was also able to protect cells of
the maize plantlets from the toxic effect of apomorphine. This sap showed mutagenic activity for strain
TA1535 of Salmonella typhimurium in the presence of metabolic activation and a weak mutagenic activity for
strain TA98. These strains detect base pair substitutions and frameshift mutations, respectively. Mutagenicity
was also observed in a haploid Saccharomyces cerevisiae strain XV185-14c for the lys1-1, his1-7 locusspecific reversion and hom3-10 frameshift mutations
Planta Med. 1994 Dec;60(6):541-5.

Studies on the anti-tumour, anti-bacterial, and wound-healing properties

of dragon's blood.
Chen ZP, Cai Y, Phillipson JD.

Source
Department of Pharmacognosy, School of Pharmacy, University of London, U.K.

Abstract
Three in-vitro assays have been adopted to examine the cytotoxicity and anti-bacterial activity of the bloodred sap of Croton lechleri from Ecuador, and to examine its effect upon the proliferation of endothelial cells.
The sap was found not to be cytotoxic. Several simple phenolic compounds and diterpenes showed a potent
anti-bacterial activity. The sap has little effect upon the proliferation of endothelial cells, and no single active
ingredient was identified. A mechanism for the wound-healing property of the sap has been proposed.
Phytomedicine. 1994 Sep;1(2):77-106. doi: 10.1016/S0944-7113(11)80026-7.

SP-303, an antiviral oligomeric proanthocyanidin from the latex of

Croton lechleri (Sangre de Drago).
Ubillas R, Jolad SD, Bruening RC, Kernan MR, King SR, Sesin DF, Barrett M, Stoddart CA, Flaster T, Kuo J,
Ayala F, Meza E, Castael M, McMeekin D, Rozhon E, Tempesta MS, Barnard D, Huffman J, Smee D,
Sidwell R, Soike K, Brazier A, Safrin S, Orlando R, Kenny PT, Berova N, Nakanishi K.

Source
Shaman Pharmaceuticals, 213 East Grand Avenue, South San Francisco, CA 94080-4812, U.S.A.

Abstract
SP-303, a large proanthocyanidin oligomer isolated from the latex of the plant species Croton lechleri
(Eupborbiaceae) has demonstrated broad activity against a variety of DNA and RNA viruses. In cell culture,
SP-303 exhibits potent activity against isolates and laboratory strains of respiratory syncytial virus (RSV),
influenza A virus (FLU-A) and parainfluenza virus (PIV). Parallel assays of SP-303 and ribavirin showed
comparable activity against these viruses. SP-303 also exhibits significant inhibitory activity against
herpesvirus (HSV) types 1 and 2, including herpesviruses resistant to acyclovir and foscarnet. Inhibition was
also observed against hepatitis A and B viruses. The antiviral mechanism of SP-303 seems to derive from its
direct binding to components of the viral envelope, resulting in inhibition of viral attachment and penetration
of the plasma membrane. Antiviral effects of SP-303 were measured by three distinct methods: CPE, MTT
and precursor uptake/incorporation. Cytotoxicity endpoints were markedly greater than the respective
antiviral endpoints. SP-303 exhibited activity in RSV-infected cotton rats and African green monkeys, PIV-3infected cotton rats, HSV-2 infected mice and guinea pigs and FLU-A-infected mice. The most successful
routes of SP-303 administration for producing efficacy were: topical application to HSV-2- genital lesions in
mice and guinea pigs, aerosol inhalation to FLU-A-infected mice and PIV-3-infected cotton rats, and oral

dosage to RSV-infected cotton rats. A variety of toxicological evaluations demonstrated the safety of SP-303,
particularly orally, which was predictable, since condensed tannins are a common dietary component. It is
notable that the larger proanthocyanidins as a class have high antiviral activity, whereas most of the
monomers are inactive. Clinical trials are ongoing to evaluate SP-303 as a therapeutic antiviral agent