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Scorpions and their venoms have been used in traditional medicine for thousands of years in China, India and Africa. The scorpion venom is a highly complex mixture of salts, nucleotides, biogenic amines, enzymes, mucoproteins, as well as peptides and proteins (e.g. neurotoxins). One of the recently observed biological properties of animal venoms and toxins is that they possess anticancer potential. An increasing number of studies have shown that scorpion venoms and toxins can decrease cancer growth, induce apoptosis and inhibit cancer progression and metastasis in vitro and in vivo. Several active molecules with anticancer activities, ranging from inhibition of proliferation and cell cycle arrest to induction of apoptosis and decreasing cell migration and invasion, have been isolated from scorpion venoms. These observations have shed light on the application of scorpion venoms and toxins as potential novel cancer therapeutics. This mini-review focuses on the anticancer potential of scorpion venoms and toxins and the possible mechanisms for their antitumor activities.
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Experimental Biology and Medicine
The online version of this article can be found at:
DOI: 10.1177/1535370213513991
published online 5 March 2014Exp Biol Med (Maywood)
Jian Ding, Pei-Jou Chua, Boon-Huat Bay and P Gopalakrishnakone
Scorpion venoms as a potential source of novel cancer therapeutic compounds
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Scorpion venoms as a potential source of novel cancer
therapeutic compounds
Jian Ding, Pei-Jou Chua, Boon-Huat Bay and P Gopalakrishnakone
Venom and Toxin Research Programme, Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore,
Singapore 117 597
Corresponding author: P Gopalakrishnakone. Email:
Scorpions and their venoms have been used in traditional medicine for thousands of years in China, India and Africa. The scorpion
venom is a highly complex mixture of salts, nucleotides, biogenic amines, enzymes, mucoproteins, as well as peptides and
proteins (e.g. neurotoxins). One of the recently observed biological properties of animal venoms and toxins is that they possess
anticancer potential. An increasing number of studies have shown that scorpion venoms and toxins can decrease cancer growth,
induce apoptosis and inhibit cancer progression and metastasis in vitro and in vivo. Several active molecules with anticancer
activities, ranging from inhibition of proliferation and cell cycle arrest to induction of apoptosis and decreasing cell migration and
invasion, have been isolated from scorpion venoms. These observations have shed light on the application of scorpion venoms
and toxins as potential novel cancer therapeutics. This mini-review focuses on the anticancer potential of scorpion venoms and
toxins and the possible mechanisms for their antitumor activities.
Keywords: Scorpion, venoms and toxins, anticancer potential, apoptosis
Experimental Biology and Medicine 2014; 0: 1–7. DOI: 10.1177/1535370213513991
The scorpion, which is one of the oldest creatures known,
has existed on earth for more than 400 million years.
Scorpions are known to be widely distributed all over the
world, and there are over 1500 species that have been
reported thus far.
Scorpions have developed a negative
reputation due to their stings and envenomation, usually
resulting in pain, swelling, hypertension, cardiac arrhyth-
mia and other systemic manifestations.
Scorpion envenom-
ation is a public health hazard in tropical and subtropical
regions. More than 1,200,000 scorpion stings are reported to
occur yearly with the number of deaths possibly exceeding
3250 per year worldwide. There is therefore, the need for
improvement in specific (antivenom) and systematic
However, human beings have also derived benefits from
the scorpion. In China, fried scorpions are popularly con-
sumed as food, and scorpion or snake wines are used to
strengthen the immune system.
The scorpion and its
venom have been applied in traditional medicine for thou-
sands of years in China, India and Africa. For example, in
China, the dried whole bodies of scorpions have been
widely used as an antiepilepsy and analgesic agent since
the Song Dynasty (A.D. 960-1279).
The Buthidae family of
scorpions has been widely studied for medical applications.
The scorpion venom is a highly complex mixture produced
from the venom gland to immobilize/paralyze the prey or to
defend against predators. The venom which is found in
the telson contains salts, nucleotides, biogenic amines,
enzymes such as phospholipase, hyaluronidase, L-amino
acid oxidase, metalloproteinase, serine protease, mucopro-
teins, as well as small peptides which are known to interact
with various ion channels in excitable cell membranes,
making them good candidates for drug design in
the pharmaceutical industry.
A number of antimicrobial
peptides have also been isolated and reported to be bio-
active against bacteria, fungi, yeasts and viruses
including Mucroporin-M1 which inhibits the amplification
of hepatitis virus B and Kn2-7 which possesses anti-HIV-1
This mini-review explores the significance of scorpion
venoms as anticancer agents and provides biological
insights into their mechanism (s) of action.
Scorpion venoms as potential cancer
According to the World Health Organization, cancer has
replaced heart disease to become the leading cause of
ISSN: 1535-3702 Experimental Biology and Medicine 2014; 0: 1–7
Copyright ß2014 by the Society for Experimental Biology and Medicine
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mortality worldwide, leading to 7.6 million deaths
(around 13% of all deaths) in 2008.
Cancers of the
lung, stomach, liver, colon and breast are known to be
the highest contributors to cancer mortality each year.
Even though treatment for cancer improved considerably
over the past decade resulting in increased patient sur-
vival and better quality of life, early screening and diag-
nosis still play a very important role in improving the
patient’s survival rate, since many cancers have a high
chance of cure if detected early and treated adequately.
Surgical resection of the primary tumor and regional
lymph nodes is the main and most effective way to
treat most patients with solid tumors.
Adjuvant and
neo-adjuvant therapies (chemotherapy and radiotherapy)
are known to benefit patients by increasing their survival
remarkably. However, the side effects and risks of treat-
ment resistance and toxicity are of major concern. Newly
emerging targeted therapy opens a novel avenue for sur-
gical oncologists and clinicians to better understand the
molecular mechanism of cancer and provide alternative
and effective approaches to combat cancer.
One of the recently discovered biological properties of
scorpion venom and toxin is that they possess anticancer
potential. An increasing number of experimental and pre-
clinical investigations have demonstrated that crude scor-
pion venom and some purified proteins and peptides can
impair cancer proliferation, arrest cell cycle, induce cell
apoptosis and inhibit cancer metastasis in in vitro or
in vivo setting. The anticancer effect and efficacy of scorpion
venoms have been tested in glioma, neuroblastoma, leuke-
mia, lymphoma, breast, lung and prostate cancer.
Chinese red scorpion (Buthus martensii
Karsch) venom
Buthus martensii Karsch (BmK) (Figure 1), also known as
Chinese red scorpion, belongs to the Buthidea family and
can be extensively found from north western China to
Mongolia and Korea. The medical use of BmK scorpion
dates back to the Song Dynasty of China (A.D. 960-1279).
To date, this scorpion venom has been well described as
having antiepileptic, analgesic, anti-rheumatic and antican-
cer potential.
Among all the scorpions used in cancer
research, BmK is probably the first to have been reported to
possess antitumor properties.
BMK scorpion venom has
been well studied in China, with several active molecules
having been isolated and characterized, making this scor-
pion venom a good source for the development of antic-
ancer agents.
In 1987, Zhang Futong, extracted a solution from the
dried whole body of the BmK scorpion (Quan Xie in
traditional Chinese medicine) and administered the extract
subcutaneously to mice with reticulum cell sarcoma and
MA-737 mammary carcinoma at a dose of 0.04 g/mouse
every other day for five times.
On the 8th day following
administration, the inhibitory rate of growth was 55.5% in
reticulum cell sarcoma and 30.4% in mammary carcinoma,
respectively. There was a decrease in DNA content in the
tumor tissues after BmK venom treatment. This seminal
finding formed the basis for the escalating reports on the
anticancer potential of BmK scorpion venom.
Several groups later described the anticancer effects of
the crude scorpion venom of BmK in vitro or in vivo.
However, scientific literatures on the BMK venom which
are published in Chinese will not be included in this
review. Wang and Ji observed that the crude venom extract
from BmK induced apoptosis of malignant glioma U251-
MG cells in vitro especially at a dose of 10 mg/mL but
was not cytotoxic to BEL7404 hepatocellular carcinoma
cells and C400 Chinese hamster ovary cells.
For the
in vivo study, BmK venom was assessed using severe com-
bined immunodeficiency mice bearing U251-MG tumor
xenografts. Both tumor volumes and weights were signifi-
cantly reduced compared with the control group after
20 mg/kg BmK venom treatment for 21 days. The authors
proposed ion channels as targets for BmK venom in glioma
cells. Another study by Gao et al.
found that BmK
venom could also inhibit growth of human Jurkat and
Raji lymphoma cells by arresting the cell cycle and inducing
apoptosis as evidenced by Annexin-V and propidium
iodide staining and flow cytometry assay. Treatment with
the BmK venom has been demonstrated to inactivate the
PI3K/Akt signal pathway by increasing phosphatase and
tensin homolog (PTEN) expression in Raji cells, whereas, in
Jurkat cells, a PTEN-negative cell line, up-regulation of p27
(a cell cycle inhibitor) may partially account for the antic-
ancer effect.
In light of several reports on the anticancer potential of
BmK crude venom, researchers attempted to purify and
isolate the anticancer agent in BmK venom with techniques
such as size-exclusive gel filtration, ion exchange chroma-
tography and high-performance liquid chromatography.
Polypeptide extract from the scorpion venom (PESV), a
group of polypeptides comprising 50–60 amino acids
extracted from crude venom of BmK, was reported to
induce growth inhibition and apoptosis of DU 145 human
prostate cancer cell.
PESV treatment on DU 145 cells
resulted in a significantly dose-dependent inhibition of pro-
liferation with G1 phase arrest in cell cycle, accompanied by
enhanced expression of p27 and a decrease in cyclin E.
PESV treatment also induced a high apoptosis index,
which was verified by the TdT-mediated dUTP-biotin
nick-end labeling (TUNEL) assay and probably due to an
Figure 1 Buthus martensii Karsch (Chinese red scorpion). Specimen from
Jiangsu Province, PR China. Arrow indicates telson, the venom-producing gland.
(A color version of this figure is available in the online journal)
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increase in pro-apoptotic protein Bax. A recent study
reported that another partially purified component from
BmK scorpion venom (SVCIII), obtained after gel filtration
with a molecular weight of approximate 70–80 kDa, could
inhibit cell proliferation of THP-1 and Jurkat human leuke-
mia cells and caused cell cycle arrest at G1 phase.
A decrease of cyclin D1 expression was observed in a
dose-dependent manner after SVCIII treatment. The anti-
proliferative effect has been attributed to the suppression
of NF-kB activation.
Two anticancer peptides have been purified and charac-
terized from BmK scorpion venom. Early in 2002, Liu and
colleagues first isolated an analgesic-antitumor peptide
(AGAP) from BmK scorpion venom with a series of purifi-
cation steps.
This peptide had a relative molecular mass of
6280 Da and exerted antitumor effects in the mouse S-180
fibro sarcoma model and Ehrlich ascites tumor model. The
AGAP gene was determined, cloned and expressed in the
Escherichia coli system in 2003 by the same group (GeneBank
No. AF464898) and the protein showed effective analgesic
and antitumor activities.
Subsequently, BmK AGAP was
classified as a voltage-gated sodium channel scorpion
toxin and three transcription regulatory elements were elu-
cidated in the BmK AGAP intron.
A recombinant fusion
protein SUMO-AGAP which combined a small ubiquitin-
related modifier to AGAP was proven to have antitumor
Further study showed that SUMO-AGAP inhib-
ited cell proliferation and migration of SHG-44 human
malignant glioma cells by inducing cell cycle arrest and
interfering with the p-Akt, NF-kB, Bcl-2 and MAPK signal-
ing pathways.
BmKCT, another purified anticancer peptide from BmK
with 68% homology to chlorotoxin (a promising antiglioma
toxin that will be discussed later), was cloned from a cDNA
library made from the venom glands of the BmK scorpion.
BmKCT contains 59 amino acid residues and comprises a
mature toxin of 35 residues with four disulfide bridges and
a signal peptide of 24 residues. Subsequently, the recombin-
ant peptide of BmKCT was shown to inhibit the growth of
glioma cells (SGH-44) dose-dependently with IC50 value of
approximately 0.28 mM while showing no toxicity to normal
astrocytes under the same condition.
Whole-cell patch-
clamp technique indicated that the chloride current in
SHG-44 glioma cells was inhibited by BmKCT in a vol-
tage-dependent manner (up to 55.86% inhibition at
0.14 mM treatment) and histological analysis of tissues
from BmKCT-treated mice showed that the brain was one
of the targets of this toxin. Furthermore, in vivo evidence
from Fan et al. using the glioma/SD rat model
strated that BmKCT toxin inhibited glioma proliferation
and tumor metastasis and
I-labeled or Cy5.5-conjugated
BmKCT selectively targeted the glioma in situ. All these
observations provide evidence for the potential therapeutic
application of BmKCT for glioma diagnosis and treatment.
Two scorpion enzymes, isolated by our research group
from BmK scorpion venom, have also been reported to pos-
sess anticancer potential. One is the serine proteinase-like
protein named BmK-CBP, which can dose-dependently
bind with human breast cancer cells MCF-7.
The other,
BmHYA1, a homogeneous hyaluronidase from the BmK
scorpion, was shown to modulate the expression of CD44,
a cell surface marker in the MDA-MB-231 breast cancer
cell line.
Scorpion venom targeted ion channels
A novel and promising field of cancer research is targeting
and Cl
ion channels in cancer, given that
altered or abnormal expression and activity of ion channels
are related to cancer processes and pathology including cell
volume and motility, cell proliferation and death, as well as
cell adhesion, migration and invasion. Moreover, blocking
ion channel activity can impair cancer growth and
Functional expression of voltage-gated sodium channels
has been reported to be associated with several strongly
metastatic carcinomas, such as breast and prostate cancer,
as evidenced by their over-expression in aggressive cancer-
derived cell lines and biopsies as well as its role in control-
ling multiple steps of metastatic cascades.
Fraser and
observed that functional expression of
1.5 was up-regulated in metastatic human breast
cancer cells and tissues, and its activity could potentiate
cellular behaviours linked to metastasis, such as directional
motility, endocytosis and invasion. Also, a strong correl-
ation was found between Na
1.5 expression and lymph
node metastasis in a clinical study. Similar findings were
also observed for the involvement of Na
1.7 in prostate
Compared to Na
channels, K
channels are mainly
implicated in cancer cell proliferation and survival. There
is a tight relationship between K
expression and cell pro-
liferation and apoptosis, but the underlying mechanism is
still not clear. Generally, by regulating the membrane poten-
tial, K
channels can control the Ca
fluxes and cell
volume, and therefore exert their role in cell cycle regula-
tion and cell death.
A number of K
channels have been
detected to be abnormally expressed in many primary can-
cers. K
1.3 has been analyzed in gliomas, colon, prostate
and breast cancers.
The aberrant expression of K
was observed to promote cancer cell growth. The roles of
1.5, K
10.1 and K
3.1 have been studied in gliomas,
colon cancer and melanoma. K
11.1, also known as hERG,
is expressed in several cancers, including leukemia, neuro-
blastoma, stomach and colorectal cancers. The blockage of
11.1 with a channel inhibitor or siRNA interference can
impair cell proliferation in vitro and reduce cell invasive-
ness, making it a novel therapeutic target for cancer.
Among the peptides found in scorpion venoms, the most
well-studied are the long-chain toxins with 60–70 amino
acid residues cross-linked by four disulfide bridges,
which interact with Na
channels. Short-chain toxins with
30–40 amino acid residues are known to modulate K
(chloride ion) channels.
Compared to massive Na
channel toxins, only few calcium channel-related toxins
(with a variable number of amino acids) have been purified
or cloned from scorpion venoms.
Chlorotoxin (CTX), a 36–amino acid small peptide, first
purified from the Leiurus quinquestriatus scorpion venom in
1993, contains a single tyrosine residue that is available for
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radioiodination, eight cysteine residues, and four disulfide
Originally, CTX was described as a Cl
blocker that acts as a paralytic agent for small insects and
other arthropods. CTX had been largely applied as a tool in
the study of voltage-gated chloride channel until the sem-
inal findings of Ullrich and co-workers in cancer
They adapted the whole cell patch-clamp rec-
ording technique to identify and characterize the voltage-
activated outwardly-rectifying Cl
currents in human
astrocytoma/glioblastoma cells. Cl
currents were
observed in all tumor cells of glial origin (primary cultures
of six freshly resected brain tumors and seven established
human astrocytoma cell lines), while interestingly they
were absent in normal non-malignant glial cells or non-
glial tumors such as melanoma, breast, rhabdomyosarcoma
and neuroblastoma. Their study also demonstrated that
CTX could block the Cl
current and inhibit cell prolifer-
ation of astrocytoma cells.
The specifically expressed Cl
channel in glioma and its
high affinity and sensitivity to CTX led to the use of this
peptide by Soroceanu and colleagues to target gliomas in
They showed that biotinylated and fluorescence-
tagged CTX and CTX-conjugated molecules had specific
staining for glioma cells in vitro,in situ and in patient biop-
sies. Another survey of over 200 tissue biopsies from
patients with various malignancies also suggest that CTX
bind to the surface of gliomas and other embryologically
related tumors of neuroectodermal origin but not to normal
Furthermore, CTX has been reported to signifi-
cantly reduce the glioma cell migration dose-dependently
and inhibited cell invasion into fetal brain aggregates at
5mM concentration.
The receptor of CTX was initially believed to be related
to the Cl
channel from electrophysiological evidence (as
described above). Further studies with a recombinant His-
CTX revealed that the principal receptor is matrix metallo-
proteinase-2 (MMP-2), a proteinase that is present on the
surface of glioma cells, and specifically over-expressed in
gliomas and related cancers, but normally not expressed in
CTX could inhibit the enzymatic activity and
reduce the expression of MMP-2, causing disruption of
chloride channels and Cl
currents. A synthetic CTX
coupled with radioactive iodine isotope (
I-TM-601), pro-
duced by Transmolecular, Inc. (Cambridge, MA) has been
approved by the US Food and Drug Administration for
tumor imaging and diagnosis. Preclinical and Phase I clin-
ical trials have been completed in recurrent glioma patients,
with the conclusion that intracavitary dose of
I-TM-601 is
safe and minimally toxic, and that
I-TM-601 binds malig-
nant glioma with high specificity and for long duration.
Phase II trial using a higher dose of radioactivity and
repeated local administrations is currently in progress.
Because CTX binds tumor with high affinity and specificity
and shows low toxicity, it represents a promising diagnostic
agent for imaging and targeted therapies for gliomas and
other cancers.
Apart from CTX, several other scorpion toxins associated
with ion channels have been purified and investigated in
cancer research. Iberiotoxin (IbTX), a 37-amino acid neuro-
toxin from the Indian red scorpion Mesobuthus tamulus, has
been reported to block the large conductance Ca
(BK) channel and induce a slight depolarization in MCF-
7 human breast cancer cells. Cells treated with IbTX
(500 nM) were observed to accumulate in S phase of the
cell cycle but did not alter the cell proliferation rate.
Another experiment showed that blockade of the BK chan-
nels by IbTX inhibited K
currents and growth of PC-3
prostate cancer cells.
Margatoxin (MgTX), which is iso-
lated from the venom of Centruroides margartatus scorpion,
sharing a sequence homology and structural similarity with
IbTX, has a high affinity and specificity against Kv1.3. Jang
et al. found that MgTX can significantly inhibit the prolif-
eration of A549 human lung adenocarcinoma cells by reg-
ulating the G1/S cell cycle progression. Western blot
analysis showed increased expression of p21Waf1/Cip1
and decreased levels of CdK4 after 1 nM MgTX treatment.
The antiproliferative effect of MgTX was also verified in a
nude mice xenograft model, as confirmed by a reduction of
tumor volume after injecting MgTX into the tumor tissues.
Charybdotoxin (ChTX), another peptide isolated from
Leiurus quinquestriatus scorpion venom, is structurally
similar to IbTX and MgTX and acts as an inhibitor of
-activated K
channel. Studies revealed that ChTX
can inhibit the migration of NIH3T3 fibroblasts and
human melanoma cells dose-dependently by up to 61%,
possibly by depolarizing the cell membrane potential and
reducing the electrochemical driving force for Ca
which is important in the cell migration process.
in the same study, it was also observed that ChTX did not
influence the disruption of the epithelial layer of renal cells
by human melanoma cells, suggesting that K
activity was not involved in melanoma invasion.
Recent studies on the anticancer potential of
scorpion venoms and toxins
Research on animal venoms and toxins has attracted greater
interest because of advances in genomic and proteomic
approaches such as the venomous systems genome pro-
In addition, new emerging research regarding the
relationship between ion channels and cancer progression
and therapy has paved the way for novel clinical applica-
tions for scorpion venoms and toxins, given that scorpion
venoms contain many disulfide-rich peptides and proteins
which display high specificity, good permeability and sta-
bility against cancer cells.
In the last decade, more evi-
dence has accumulated regarding the anticancer effect of
scorpion venoms and toxins from different species and tar-
geting assorted cancers.
In 2007, Gupta et al.
reported the antiproliferative and
apoptogenic activities induced by Heterometrus bengalensis
Koch (Indian black scorpion) against human leukemic U937
and K562 cell lines, characterized by cell cycle arrest, mem-
brane blebbing, chromatin condensation and DNA degrad-
ation. The molecule of interest was subsequently purified
and named Bengalin, a 72-kDa protein with an N-terminal
sequence that shared no similarity with any protein in the
scorpion toxin database. The IC50 of Bengalin was deter-
mined as 3.7 mg/mL and 4.1 mg/mL for U937 and K562
human leukemic cells, respectively, without affecting
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normal human lymphocytes. Bengalin induced apoptosis
as confirmed by damaged nuclei, sub G1 peak, DNA frag-
mentation as well as decreased telomerase activity.
Furthermore, Bengalin caused the loss of mitochondrial
membrane potential, decreased the expression of heat
shock protein (HSP) 70 and 90, activated caspase-3, 9 and
induced cleavage of poly (ADP-ribose) polymerase.
observations indicated activation of a mitochondrial death
cascade, involving inhibition of HSPs by Bengalin.
Two peptides named neopladine 1 and neopladine 2, iso-
lated from Tityus discrepans scorpion venom, were reported
to be effective in inducing apoptosis and necrosis of SKBR3
breast cancer cells with negligible effect on non-malignant
MA104 monkey kidney cells.
showed that neopladines bind to the surface of SKBR3 cell
and triggered FasL and Bcl-2 expression. We have also
found that the Indian red scorpion (Mesobuthus tamulus)
venom decreased the cell viability of human breast cancer
cells dose-dependently with minimal cytotoxic effect on
normal breast epithelial cells in vitro (unpublished data).
Another research finding showed that scorpion venom
from Odontobuthus doriae inhibited cell growth and induced
apoptosis in SH-SY5Y human neuroblastoma cells and
MCF-7 breast cancer cells.
Moreover, Odontobuthus
doriae venom increased intracellular oxidative stress as evi-
denced by an increase in reactive nitrogen intermediates
and depression of glutathione and catalases in MCF-7
cells, which may contribute to the induction of apoptosis.
The cytotoxicity of another scorpion venom Androctonus
crassicauda was also screened using MCF-7 and SH-SY5Y
cell lines.
Similarly, Androctonus crassicauda venom
caused the suppression of cell growth by S-phase cell
cycle arrest and induced apoptosis by increasing nitric
oxide production, thereby, activating caspase-3 and depo-
larizing mitochondrial membrane. The above findings sug-
gest that the Odontobuthus doriae and Androctonus
crassicauda scorpion venoms may be potential sources for
isolating effective anticancer molecules.
Cytotoxic proteins such as Bengalin and Neopladine 1
and 2 with molecular weight more than 10 kDa are able to
inhibit cell viability and induce apoptosis or necrosis in
cancer cells while showing negligible cytotoxicity to
normal cells. Hence, such proteins are promising for
developing as anticancer drugs.
Besides cancer therapy, scorpion venoms have also been
applied in diagnostic imaging of tumor, mainly based on
the conjugates of CTX and its homological peptides (e.g.
BmKCT) to delineate the tumor margins. Researchers
have combined CTX with other radioactive or fluorescence
molecules, such as
I, Cy5.5, and iron oxide nanoparticles
coated with polyethylene glycol, and synthesized various
probes that can be detected by g-camera, single photon
emission computed tomography or magnetic resonance
Due to the binding specificity of CTX and
the use of nanovectors, the CTX-conjugated probes can
cross the blood-brain barrier and work as imaging agents
in tumors of the central nervous system. In addition, the
CTX-conjugated nanoparticles are now being developed
as a carrier of DNA in gene therapy in glioma.
In summary, the anticancer effects of scorpion venoms and
toxins have been reported for several scorpion species and
in different cancer types, in both in vitro and in vivo settings.
Scorpion venoms with anticancer properties and possible
mechanisms of action are summarized in Table 1. It can be
clearly seen that the anticancer effects are achieved mainly
via targeting ion channels on cell membrane, or exerting
antiproliferative or apoptotic activities by cell cycle arrest
or induction of caspase-dependent apoptosis pathways.
Currently, only a few scorpion species have been inves-
tigated for anticancer effects. As many of the studies have
been carried out in the in vitro setting, testing the antitumor
potential of scorpion venoms/toxins in animal models is
important for preclinical research work and drug design.
Although purification and characterization of the active
components which exert anticancer effects from crude
venoms still remain a challenge, there is potential for the
use of scorpion venoms as novel cancer therapeutics.
Table 1 Summary of the important molecules with anticancer potential and possible mechanisms
Molecules Scorpion species Tested cancer models Possible mechanisms References
BmK AGAP Buthus martensii Karsch Mouse fibro sarcoma, Rhrlich ascites
tumor, SHG-44 glioma cells
Voltage gated sodium channel toxin,
interfering p-AKT, NF-kB, Bcl-2 and
MAPK signaling pathway
BmKCT Buthus martensii Karsch SHG-44 glioma cells, glioma/SD rat Inhibit chloride current and selectively
target glioma
Chlorotoxin Leiurus quinquestriatus Glioma cells, animal models and clin-
ical trials
Inhibit chloride current, bind to matrix
metalloproteinase-2 (MMP-2)
Iberiotoxin Mesobuthus tamulus MCF-7 breast cancer cells Block large conductance Ca2þactivated
Kþ(BK) channel
53, 54
Magatoxin Centruroides margartatus A549 human lung adenocarcinoma
cells and xenograft model
Inhibit Kv 1.3, increase expression of
p21Waf1/Cip1 and decrease CdK4
Charybdotoxin Leiurus quinquestriatus NIH3T3 fibroblasts and human melan-
oma cells
Inhibit cell migration does-dependently 56
Bengalin Heterometrus bengalensis Koch human leukemic U937 and K562 cells Induce caspase apoptosis pathway by
loss of mitochondrial membrane
potential and decreased HSP 70 and 90
59, 60
Neopladine 1 and 2 Tityus discrepans SKBR3 breast cancer cell line Trigger FasL and BcL-2 expression 61
Ding et al. Scorpion venoms as a potential source of novel cancer therapeutic compounds 5
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Author contributions: JD wrote the first draft of the paper
and made subsequent revisions. PJC, BHB and PG gave
comments and suggestions during the writing of the
paper and made amendments to the pre-final draft. All
authors reviewed the final draft of the manuscript before
This work was supported by Grant NMRC/EDG/1013/2010.
JD is a recipient of the National University of Singapore
Research Scholarship.
1. Simard MJ, Watt DD. Venoms and toxins. Stanford: Stanford University
Press, 1990
2. Bawaskar HS, Bawaskar PH. Scorpion sting: update. J Assoc Physicians
India 2012;60:46–55
3. Chippaux JP, Goyffon M. Epidemiology of scorpionism: a global
appraisal. Acta tropica 2008;107:71–9
4. Ye HY, Liu JX, Zen J, Huang XH, Zhu ZP, Lai F. The Chronic Effect of
Snake Wine on the Anti-inflammatory. J Gannan Med Coll 2003;23:123–6
5. Zhou XH, Yang D, Zhang JH, Liu CM, Lei KJ. Purification and N-
terminal partial sequence of anti-epilepsy peptide from venom of the
scorpion Buthus martensii Karsch. Biochem J 1989;257:509–17
6. Shao J, Kang N, Liu Y, Song S, Wu C, Zhang J. Purification and char-
acterization of an analgesic peptide from Buthus martensii Karsch.
Biomed Chromatogr 2007;21:1266–71
7. Andreotti N, Jouirou B, Mouhat S, Mouhat L, Sabatier JM.
Comprehensive Natural Products II. Oxford: Elsevier, 2010
8. Ahn MY, Ryu KS, Lee YW, Kim YS. Cytotoxicity and L-amino acid
oxidase activity of crude insect drugs. Arch Pharm Res 2000;23:477–81
9. Zhao Z, Hong W, Zeng Z, Wu Y, Hu K, Tian X, Li W, Cao Z. Mucroporin-
M1 inhibits hepatitis B virus replication by activating the mitogen-
activated protein kinase (MAPK) pathway and down-regulating
HNF4alpha in vitro and in vivo. J Biol Chem 2012;287:30181–90
10. Chen Y, Cao L, Zhong M, Zhang Y, Han C, Li Q, Yang J, Zhou D, Shi W,
He B, Liu F, Yu J, Sun Y, Cao Y, Li Y, Li W, Guo D, Cao Z, Yan H. Anti-
HIV-1 activity of a new scorpion venom peptide derivative Kn2-7. PLoS
One 2012;7:e34947
11. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer
statistics. CA Cancer J Clin 2011;61:69–90
12. Srinivas PR, Kramer BS, Srivastava S. Trends in biomarker research for
cancer detection. The Lancet Oncology 2001;2:698–704
13. Reed M. Principles of cancer treatment by surgery. Surgery (Oxford)
14. Malinowsky K, Wolff C, Gundisch S, Berg D, Becker K. Targeted
therapies in cancer - challenges and chances offered by newly devel-
oped techniques for protein analysis in clinical tissues. J Cancer
15. Gomes A, Bhattacharjee P, Mishra R, Biswas AK, Dasgupta SC, Giri B.
Anticancer potential of animal venoms and toxins. Indian J Exp Biol
16. Heinen TE, da Veiga AB. Arthropod venoms and cancer. Toxicon
17. Zhang FT, Xu ZS, Qi YX. A preliminary research of the antineoplasia
effects induced by Buthus martensii of Chinese drug-I. Observation of
the effect on mice with tumor. J Gannan Med Coll 1987;6:1–5
18. Wang WX, Ji YH. Scorpion venom induces glioma cell apoptosis in vivo
and inhibits glioma tumor growth in vitro. J Neurooncol 2005;73:1–7
19. Gao F, Li H, Chen YD, YuXN, Wang R, Chen XL. Upregulation of PTEN
involved in scorpion venom-induced apoptosis in a lymphoma cell line.
Leukemia Lymphoma 2009;50:633–41
20. Deutscher MP. Protein purification : guide to protein purification. San
Diego: Academic Press, 1990
21. Zhang YY, Wu LC, Wang ZP, Wang ZX, Jia Q, Jiang GS, Zhang WD.
Anti-proliferation effect of polypeptide extracted from scorpion venom
on human prostate cancer cells in vitro. J Clin Med Res 2009;1:24–31
22. Song X, Zhang G, Sun A, Guo J, Tian Z, Wang H, Liu Y. Scorpion venom
component III inhibits cell proliferation by modulating NF-kappa B
activation in human leukemia cells. Exp Ther Med 2012;4:146–50
23. Liu YF, Hu J, Zhang JH, Wang SL, Wu CF. Isolation, purification, and N-
terminal partial sequence of an antitumor peptide from the venom of
the Chinese scorpion Buthus martensii Karsch. Prep Biochem Biotechnol
24. Liu YF, Ma RL, Wang SL, Duan ZY, Zhang JH, Wu LJ, Wu CF.
Expression of an antitumor-analgesic peptide from the venom of
Chinese scorpion Buthus martensii karsch in Escherichia coli. Protein
Expr Purif 2003;27:253–8
25. Cui Y, Liu Y, Chen Q, Zhang R, Song Y, Jiang Z, Wu C, Zhang J. Genomic
cloning, characterization and statistical analysis of an antitumor-
analgesic peptide from Chinese scorpion Buthus martensii Karsch.
Toxicon 2010;56:432–9
26. Cao P, Yu J, Lu W, Cai X, Wang Z, Gu Z, Zhang J, Ye T, Wang M.
Expression and purification of an antitumor-analgesic peptide from the
venom of Mesobuthus martensii Karsch by small ubiquitin-related
modifier fusion in Escherichia coli. Biotechnol Prog 2010;26:1240–4
27. Zhao Y, Cai X, Ye T, Huo J, Liu C, Zhang S, Cao P. Analgesic-antitumor
peptide inhibits proliferation and migration of SHG-44 human malig-
nant glioma cells. J Cell Biochem 2011;112:2424–34
28. Zeng XC, Li WX, Zhu SY, Peng F, Zhu ZH, Wu KL, Yang FH. Cloning
and characterization of a cDNA sequence encoding the precursor of a
chlorotoxin-like peptide from the Chinese scorpion Buthus martensii
Karsch. Toxicon 2000;38:1009–14
29. Fu YJ, Yin LT, Liang AH, Zhang CF, Wang W, Chai BF, Yang JY, Fan XJ.
Therapeutic potential of chlorotoxin-like neurotoxin from the Chinese
scorpion for human gliomas. Neurosci Lett 2007;412:62–7
30. Fan S, Sun Z, Jiang D, Dai C, Ma Y, Zhao Z, Liu H, Wu Y, Cao Z, Li W.
BmKCT toxin inhibits glioma proliferation and tumor metastasis.
Cancer Lett 2010;291:158–66
31. Gao R, Zhang Y, Gopalakrishnakone P. Purification and N-terminal
sequence of a serine proteinase-like protein (BMK-CBP) from the
venom of the Chinese scorpion (Buthus martensii Karsch). Toxicon
32. Feng L, Gao R, Gopalakrishnakone P. Isolation and characterization of a
hyaluronidase from the venom of Chinese red scorpion Buthus mar-
tensi. Comp Biochem Physiol C Toxicol Pharmacol 2008;148:250–7
33. Arcangeli A, Crociani O, Lastraioli E, Masi A, Pillozzi S, Becchetti A.
Targeting ion channels in cancer: a novel frontier in antineoplastic
therapy. Curr Med Chem 2009;16:66–93
34. Prevarskaya N, Skryma R, Shuba Y. Ion channels and the hallmarks of
cancer. Trends Mol Med 2010;16:107–21
35. Onkal R, Djamgoz MB. Molecular pharmacology of voltage-gated
sodium channel expression in metastatic disease: clinical potential of
neonatal Nav1.5 in breast cancer. Eur J Pharmacol 2009;625:206–19
36. Fraser SP, Diss JK, Chioni AM, Mycielska ME, Pan H, Yamaci RF, Pani F,
Siwy Z, Krasowska M, Grzywna Z, Brackenbury WJ, Theodorou D,
Koyuturk M, Kaya H, Battaloglu E, De Bella MT, Slade MJ, Tolhurst R,
Palmieri C, Jiang J, Latchman DS, Coombes RC, Djamgoz MB. Voltage-
gated sodium channel expression and potentiation of human breast
cancer metastasis. Clin Cancer Res 2005;11:5381–9
37. Fraser SP, Salvador V, Manning EA, Mizal J, Altun S, Raza M,
Berridge RJ, Djamgoz MB. Contribution of functional voltage-gated
Naþchannel expression to cell behaviors involved in the metastatic
cascade in rat prostate cancer: I. Lateral motility. J Cell Physiol
38. Mycielska ME, Fraser SP, Szatkowski M, Djamgoz MB. Contribution of
functional voltage-gated Naþchannel expression to cell behaviors
involved in the metastatic cascade in rat prostate cancer: II. Secretory
membrane activity. J Cell Physiol 2003;195:461–9
39. Diss JK, Stewart D, Pani F, Foster CS, Walker MM, Patel A, Djamgoz MB.
A potential novel marker for human prostate cancer: voltage-gated
sodium channel expression in vivo. Prostate Cancer Prostatic Dis
6Experimental Biology and Medicine
at NATIONAL UNIV SINGAPORE on March 10, 2014ebm.sagepub.comDownloaded from
XML Template (2014) [4.3.2014–11:34am] [1–7]
//blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/EBMJ/Vol00000/130172/APPFile/SG-EBMJ130172.3d (EBM) [PREPRINTER stage]
40. Becchetti A. Ion channels and transporters in cancer. 1. Ion channels and
cell proliferation in cancer. Am J Physiol Cell Physiol 2011;301:C255–65
41. Felipe A, Vicente R, Villalonga N, Roura-Ferrer M, Martinez-Marmol R,
Sole L, Ferreres JC, Condom E. Potassium channels: new targets in
cancer therapy. Cancer Detect Prev 2006;30:375–85
42. Asher V, Sowter H, Shaw R, Bali A, Khan R. Eag and HERG potassium
channels as novel therapeutic targets in cancer. World J Surg Oncol
43. Goudet C, Chi CW, Tytgat J. An overview of toxins and genes from the
venom of the Asian scorpion Buthus martensi Karsch. Toxicon
44. Zhijian C, Yun X, Chao D, Shunyi Z, Shijin Y, Yingliang W, Wenxin L.
Cloning and characterization of a novel calcium channel toxin-like gene
BmCa1 from Chinese scorpion Mesobuthus martensii Karsch. Peptides
45. DeBin JA, Maggio JE, Strichartz GR. Purification and characterization of
chlorotoxin, a chloride channel ligand from the venom of the scorpion.
Am J Physiol 1993;264:C361–9
46. Ullrich N, Sontheimer H. Biophysical and pharmacological character-
ization of chloride currents in human astrocytoma cells. Am J Physiol
47. Ullrich N, Gillespie GY, Sontheimer H. Human astrocytoma cells
express a unique chloride current. Neuroreport 1996;7:1020–4
48. Soroceanu L, Gillespie Y, Khazaeli MB, Sontheimer H. Use of chloro-
toxin for targeting of primary brain tumors. Cancer Res 1998;58:4871–9
49. Lyons SA, O’Neal J, Sontheimer H. Chlorotoxin, a scorpion-derived
peptide, specifically binds to gliomas and tumors of neuroectodermal
origin. Glia 2002;39:162–73
50. Soroceanu L, Manning TJ Jr, Sontheimer H. Modulation of glioma cell
migration and invasion using Cl() and K(þ) ion channel blockers.
J Neurosci 1999;19:5942–54
51. Deshane J, Garner CC, Sontheimer H. Chlorotoxin inhibits glioma cell
invasion via matrix metalloproteinase-2. J Biol Chem 2003;278:4135–44
52. Mamelak AN, Rosenfeld S, Bucholz R, Raubitschek A, Nabors LB,
Fiveash JB, Shen S, Khazaeli MB, Colcher D, Liu A, Osman M,
Guthrie B, Schade-Bijur S, Hablitz DM, Alvarez VL, Gonda MA. Phase I
single-dose study of intracavitary-administered iodine-131-TM-601 in
adults with recurrent high-grade glioma. J Clin Oncol 2006;24:3644–50
53. Bloch M, Ousingsawat J, Simon R, Schraml P, Gasser TC, Mihatsch MJ,
Kunzelmann K, Bubendorf L. KCNMA1 gene amplification promotes
tumor cell proliferation in human prostate cancer. Oncogene
54. Ouadid-Ahidouch H, Roudbaraki M, Ahidouch A, Delcourt P,
Prevarskaya N. Cell-cycle-dependent expression of the large
Ca2þ-activated Kþchannels in breast cancer cells. Biochem Biophys Res
Commun 2004;316:244–51
55. Jang SH, Choi SY, Ryu PD, Lee SY. Anti-proliferative effect of Kv1.3
blockers in A549 human lung adenocarcinoma in vitro and in vivo. Eur J
Pharmacol 2011;651:26–32
56. Schwab A, Reinhardt J, Schneider SW, Gassner B, Schuricht B. K(þ)
channel-dependent migration of fibroblasts and human melanoma
cells. Cell Physiol Biochem 1999;9:126–132
57. Menez A, Stocklin R, Mebs D. ‘Venomics’ or: The venomous systems
genome project. Toxicon 2006;47:255–9
58. King GF. Venoms as a platform for human drugs: translating toxins into
therapeutics. Expert Opin Biol Ther 2011;11:1469–84
59. Gupta SD, Debnath A, Saha A, Giri B, Tripathi G, Vedasiromoni JR,
Gomes A. Indian black scorpion (Heterometrus bengalensis Koch)
venom induced antiproliferative and apoptogenic activity against
human leukemic cell lines U937 and K562. Leuk Res 2007;31:817–25
60. Gupta SD, Gomes A, Debnath A, Saha A. Apoptosis induction in
human leukemic cells by a novel protein Bengalin, isolated from Indian
black scorpion venom: through mitochondrial pathway and inhibition
of heat shock proteins. Chem Biol Interact 2010;183:293–303
61. D’Suze G, Rosales A, Salazar V, Sevcik C. Apoptogenic peptides from
Tityus discrepans scorpion venom acting against the SKBR3 breast
cancer cell line. Toxicon 2010;56:1497–505
62. Zargan J, Sajad M, Umar S, Naime M, Ali S, Khan HA. Scorpion
(Odontobuthus doriae) venom induces apoptosis and inhibits DNA
synthesis in human neuroblastoma cells. Mol Cell Biochem
63. Zargan J, Umar S, Sajad M, Naime M, Ali S, Khan HA. Scorpion venom
(Odontobuthus doriae) induces apoptosis by depolarization of mito-
chondria and reduces S-phase population in human breast cancer cells
(MCF-7). Toxicol In Vitro 2011;25:1748–56
64. Zargan J, Sajad M, Umar S, Naime M, Ali S, Khan HA. Scorpion
(Androctonus crassicauda) venom limits growth of transformed cells
(SH-SY5Y and MCF-7) by cytotoxicity and cell cycle arrest. Exp Mol
Pathol 2011;91:447–54
65. Veiseh M, Gabikian P, Bahrami SB, Veiseh O, Zhang M, Hackman RC,
Ravanpay AC, Stroud MR, Kusuma Y, Hansen SJ, Kwok D, Munoz NM,
Sze RW, Grady WM, Greenberg NM, Ellenbogen RG, Olson JM. Tumor
paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization
of cancer foci. Cancer Res 2007;67:6882–8
66. Fu Y, An N, Li K, Zheng Y, Liang A. Chlorotoxin-conjugated nanopar-
ticles as potential glioma-targeted drugs. J Neurooncol 2012;107:457–62
67. Huang R, Ke W, Han L, Li J, Liu S, Jiang C. Targeted delivery of
chlorotoxin-modified DNA-loaded nanoparticles to glioma via intra-
venous administration. Biomaterials 2011;32:2399–406
Ding et al. Scorpion venoms as a potential source of novel cancer therapeutic compounds 7
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... Scorpions and their venoms have been used in traditional medicine for thousands of years in China, India and Africa (9). Their venom contains a complex mixture of peptides, enzymes, mucoproteins, and some other proteins (9) which are biologically active and have anticancer properties (10). ...
... Scorpions and their venoms have been used in traditional medicine for thousands of years in China, India and Africa (9). Their venom contains a complex mixture of peptides, enzymes, mucoproteins, and some other proteins (9) which are biologically active and have anticancer properties (10). An increasing number of studies have shown that scorpion venoms and toxins can decrease cancer growth, induce apoptosis and inhibit cancer progression and metastasis in vitro and in vivo (9,10). ...
... Their venom contains a complex mixture of peptides, enzymes, mucoproteins, and some other proteins (9) which are biologically active and have anticancer properties (10). An increasing number of studies have shown that scorpion venoms and toxins can decrease cancer growth, induce apoptosis and inhibit cancer progression and metastasis in vitro and in vivo (9,10). Anticancer peptides derived from scorpion venom are important resources of natural components for the design of tumor-targeting drugs (11). ...
Full-text available
New natural substances obtained from scorpion venoms could be promising approaches for the treatment of cancers. Scorpion venom is a fully mixed compound that containing enzymes, non-enzymes, ions, and other organic compounds that induces apoptosis and necrosis in mammalian cells. In this study, the cytotoxicity effects, redox potential, and the ability of apoptosis induction of Odontobuthus bidentatus scorpion venom on MCF-7 cells were investigated. To do this, the MCF-7 cells were treated with the scorpion venom. MTT and neutral red assays was used to evaluate the cytotoxicity. Catalase, GSH and NO assays are used to determine the cells redox potential. Caspase-3 and cytochrome c release assays were exploited to investigate the apoptosis. The results of MTT and neutral red tests showed that O. bidentatus crude venom has cytotoxic effects on MCF-7 cells. Moreover, the results of catalase, GSH and NO assays showed that the crude venom could change the redox potential of MCF-7 cells, dose dependently which eventually lead to apoptosis. Also, the results of caspase-3 and the release of cytochrome c confirmed cell apoptosis. These results suggest that O. bidentatus venom is a suitable source of apoptosis-inducing compounds.
... Some molecules extracted from scorpion venoms exhibit a selective cytotoxic effect in vitro against a broad type of cancer cell lines [21]. The anti-cancer activity of substances extracted from scorpion venoms has been studied in several types of cancers such as lymphoma, leukemia, glioma, neuroblastoma, cancer of the lung, breast, prostate and pancreas [22]. In vivo and in vitro studies revealed that the toxins existing in scorpion venom are able to inhibit cancer growth, induce apoptosis and limit progression and metastasis [22]. ...
... The anti-cancer activity of substances extracted from scorpion venoms has been studied in several types of cancers such as lymphoma, leukemia, glioma, neuroblastoma, cancer of the lung, breast, prostate and pancreas [22]. In vivo and in vitro studies revealed that the toxins existing in scorpion venom are able to inhibit cancer growth, induce apoptosis and limit progression and metastasis [22]. These studies have shed light on the important of applying toxins extracted from scorpion venom as novel candidate for cancer therapies [22]. ...
... In vivo and in vitro studies revealed that the toxins existing in scorpion venom are able to inhibit cancer growth, induce apoptosis and limit progression and metastasis [22]. These studies have shed light on the important of applying toxins extracted from scorpion venom as novel candidate for cancer therapies [22]. Neurotoxins isolated from scorpion venom have been reported as ligands of high affinity for many ion channels. ...
Full-text available
Hepatocellular carcinoma (HCC) is the most dominant primary liver cancer, which can be caused by chronic hepatitis virus infections and other environmental factors. Resection, liver transplantation, and local ablation are only a few of the highly effective and curative procedures presently accessible. However, other complementary treatments can reduce cancer treatment side effects. In this present work, we evaluated the activity of Moroccan scorpion venom Buthus occitanus and its fractions obtained by chromatography gel filtration against HCC cells using a 3D cell culture model. The venom was fractionated by gel filtration chromatography, each fraction and the crude venom was tested on normal hepatocytes (Fa2N-4 cells). Additionally, the fractions and the crude venom were tested on MCTSs (multicellular tumor spheroids), and this latter was generated by cultivate Huh7.5 cancer cell line with WI38 cells, LX2 cells, and human endothelial cells (HUVEC). Our results indicate that Buthus occitanus venom toxin has no cytotoxic effects on normal hepatocytes. Moreover, it is reported that F3 fraction could significantly inhibit the MCTS cells. Other Protein Separation Techniques (High-performance liquid chromatography) are needed in order to identify the most active molecule.
... Several studies have proved that ScVs and other natural toxins are able to induce apoptosis, reduce cancer growth, and inhibit progression and metastasis in vitro and in vivo [14]. However, several scorpion species (about 24 species) are widespread in Egypt; only a few studies highlighted antitumor activity of ScVs such as L. quinquestriatus [15]. ...
... According to the present study and other studies, there is an ample evidence that hWJ-MSCs-CM or the venom IC 50 abolish tumor growth [14,19]; to exclude this possibility, we focused in the present study on the antiproliferative potential of hWJ-MSC extracts (conditioning medium) rather than the cells [20,21], and on L. quinquestriatus IC 50 value against MCF-7 cancer cells in vitro. MTT assay revealed that the toxicity of the venom was concentration-dependent and the IC 50 of L. quinquestriatus-treated MCF-7 was 100 µg/ml as shown in (Fig. 1A, B). ...
Full-text available
Purpose The present study aimed to evaluate the anticancer potential of Egyptian scorpion Leiurus quinquestriatus venom (ScV) or human Wharton’s jelly-derived mesenchymal stem cells conditioning medium (hWJ-MSCs-CM)/CM against breast cancer (MCF-7) cell line as an alternative effective cancer biotherapy. Methods Venom (ScV) toxicity was performed recording concentration-dependent viability % and ScV IC50 value was in the order of 100 μg/ml. MCF-7 were treated with hWJ-MSCs-CM used as (25%, 50%, and 75% ml) or the IC50 of ScV. Apoptotic activity was traced via evaluation the apoptotic (Bax, Casp-3, and Casp-9) and anti-apoptotic genes (Bcl2, ALDOA, and PKM2) profile. Results Both Bax and Casp-3 showed a significant upregulation while anti-apoptotic genes were significantly downregulated. In the meantime, Casp-3 and Casp-9 protein were monitored using ELISA, and their level was less than in control. Additionally, MCF-7 apoptosis was monitored using flow cytometry recording a significant DNA accumulation in the G0–G1 and S phases in case of cell treatment with ScV or CM75% ml and 50% ml. Also, there was a significant total necrotic cells % compared with control cells, and total apoptosis under the effect of ScV or CM75% ml was significantly elevated than rest of treatment. Conclusion Apoptosis induction was both dose- and time-dependent for hWJ-MSCs-CM and ScV. According to the present study and other studies, there is an ample evidence that hWJ-MSCs-CM and the venom IC50 abolish tumor growth.
... Venomous animals including scorpions have a wide variety of natural peptide toxins which are used for predation and defense (Lewis et al., 2003). Furthermore, scorpion neurotoxins are usually used to increase natural killer cell activity; inhibit the production of tumor necrosis factor and work as antitumor in vitro and in vivo (Loret and Hammock, 2001;Ding et al., 2014;Salem et al., 2016;Bhavya et al., 2016;Béchohra et al,. 2016). ...
Full-text available
The scorpion venom consisting of a pair of gland connected to telson has great importance for their survival, assisting in feeding and self-defense. Scorpion venoms are a complex mixture of inorganic salts, free amino acids, heterocyclic components, peptides and proteins. The present study aimed to identify telson components of four scorpion species Leiurus quinquestriatus, Androctonus amoreuxi, Orthochirus innesi and Buthacus leptochelys. Five telsons separated from four species of scorpions were preserved in 100% ethanol, homogenized in acetonitrile, centrifuged and sonicated as preparation of gas chromatography mass spectrometry (GC-MS) analysis. The present study indicated variations in the number and types of amino acids, fatty acids derivatives and neurotoxin in the four scorpion species. The four species of scorpions are included: L. quinquestriatus which has 14 amino acids, 15 fatty acids and 17 neurotoxic compounds; A. amoreuxi which has 8 amino acids, 13 fatty acids and 4 neurotoxic compounds; O. innesi which has 10 amino acids, 16 fatty acids and 6 neurotoxic compounds; B. leptochelys which has 6 amino acids, 19 fatty acids and 5 neurotoxic compounds were recorded. In conclusion, concentrations of amino and fatty acids derivatives and neurotoxic compounds showed differences among the four scorpion species. Furthermore, in all scorpion species, acetamide had the highest percentage as neurotoxin, and the highest level of neurotoxins was found in L. quinquestriatus, indicating this species may be the most venomous ones.
... Scorpion, a kind of precious traditional Chinese medicine (TCM), has the effect of antitumor, sedative, and analgesic, as well as anticonvulsant, which is commonly used in the treatment of diseases such as malignant tumors, convulsions, and rheumatism [10]. e chemical constituents of scorpion venom mainly contain the polypeptide extract of scorpion venom (PESV), water-soluble components, and fat-soluble components [11]. e chemistry structural diversity of PESV contributes to greater functions, including anti-inflammatory, antibacterial, and antifibrotic effects [12]. ...
Full-text available
Objective: Interstitial lung disease (ILD) is an important complication of systemic sclerosis (SSc). The aim of this study was to investigate the effect and possible mechanism of polypeptide extract of scorpion venom (PESV) on SSc-ILD. Methods: C57/BL6 mice were injected with bleomycin to establish a SSc-ILD model. Different concentrations of PESV solution were administered to SSc-ILD mice, and dexamethasone was used as a positive control. H&E staining and Masson staining were used to observe the pathological changes. The TGF-β1 expression level was detected by immunohistochemistry. The expression of epithelial-mesenchymal transition (EMT)-related proteins was detected by Western blot, and the expression of TGF-β1/Smad pathway-related proteins was also detected. The content of inflammatory cytokines in serum and BALF was determined by ELISA. Results: Pathological analysis showed that PESV could alleviate SSc-ILD-induced pulmonary inflammation and fibrosis. Compared with the model group, the content of inflammatory cytokines IL-6 and TNF-α significantly decreased after PESV treatment. PESV could increase the expression of epithelial marker (E-cadherin) and reduce the expression of interstitial markers (collagen I, vimentin, N-cadherin, and a-SMA). In addition, PESV could reduce the expression level of TGF-β1/Smad pathway-related protein. Conclusion: PESV can attenuate SSc-ILD by regulating EMT, and the effect was linked to the TGF-β1/Smad signaling pathway, which indicated that PESV may serve as a candidate drug for SSc-ILD.
... Toxicity caused by these proteins and peptides within snake venom have been associated with high specificity and affinity for molecular markers on cells (Calderon., et al 2014), with the toxicological effects implemented in pharmaceutical agents (Lewis et al., 2003). Likewise, in snake venoms, scorpion venoms contain bioactive molecules that have shown great anti-tumour activity, by reducing cancer growth, induce apoptotic death, and inhibit metastasis progression (Díaz-García, et al.,2013;Ding, et al., 2014;Al-Asmari, et al.,2016;Tobassum, et al.,2020). Scorpion venom contain proteins and peptides with low level enzyme activity, such as polysaccharides, phospholipases, low molecular weight molecules such as serotonin, histamine, histamine releasing peptides, inorganic salts, and many basic small proteins such as neurotoxins (Pal, et al., 2015;Ga, et al., 2017). ...
Full-text available
Mammary Cancer is the most prevalent form of malignancy to occur in female dogs. With metastasised malignancies representing 50% of diagnosis, current treatments produce little efficacy towards survival and induce harsh adverse side effects, thus there is need for novel therapeutics. Venoms have been shown to exploit anti-cancer properties with specific selective effects towards many forms of human cancers, thus, the prospect of anti-cancer inhibition towards Canine Mammary Cancer is a feasible hypothesis. Utilising in-vitro cell viability assays, panels of venoms from snake, scorpions and spiders were profiled against canine mammary cancer cells lines, CMT28 and CMM26, and an immortalised normal canine kidney cell line, MDCK. Screening of these venom fractions identified selectivity towards the cancerous cells utilising venoms from the Naja genus by >70% inhibition. Mass spectrometry data of 5 fractions identified them as 3-finger toxins with 3 of the fractions identifying as novel cytotoxins and 2 matched to sequence in the database of the same species. Epidermal Growth factor receptor- 2 (HER2) is a key antigenic target in Human breast cancer and has been shown to be as a potential therapeutic target for Canine Mammary Cancer. Utilising computational modelling and molecular docking simulations, the identified cytotoxins obtained from mass spectrometry have been predicted to bind to the dimerisation loop of the extracellular domain of HER2, that is hypothesised to inhibit dimer formation. In practice Canine HER2 demonstrated to have a high binding affinity for proteins in whole snake venoms, signifying the potential of HER2 being a therapeutic target for the treatment of Canine Mammary Cancer.
... It also shows strong antitumor activity and cause impairment of cell cycle. Venom toxins may interfere with molecules essential for modulating signaling pathways relevant to cell survival and growth, apoptosis, and cell proliferation [92]. Chlorotoxin and other scorpion toxins associated with ions channels also have anti-cancer potentialities [93]. ...
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This review article describes anti-cancer activity of various animal toxins belongs to different animal groups. Cancer is a dreadful disease that is responsible for millions of deaths worldwide. For its treatment various chemotherapeutics have been used but these are costlier and show side effects. Animal toxins are noble and unique therapeutic efficacy against various cancer types. These successfully inhibit proliferation of cancer cells in vitro cell cultures as well as inside human body. Animal venom toxins stop cancer cell invasion, cell cycle arrest, proliferation, migration, and invasion, induction of apoptotic activity and neo-vascularization by blocking the signaling pathways. Bee venom toxin mainly melittin shows anticancer effects against ovarian cancer cells. It inhibits cell growth through enhancement of death receptor expressions in the human ovarian cancer cell at a dose of 0.5.2 µg/ml. It also induces apoptotic cell death in dose dependent manner. Animal toxins strongly induce selective cytotoxicity in ovarian cells through apoptotic cell death cells via dual inhibition of the Akt and mTOR signaling pathways. Animal toxins such as serine proteases, PLA 2, metalloproteases, phosphatase and esterase activity showed exhibit antineoplastic activity to various cancer cell lines.
... Scorpion venom contains neurotoxins that can interrupt physiological activities of host by targeting the excitable neurons (Quintero-Hern andez et al. 2013, Quintero-Hern andez et al. 2013, Ding et al. 2014, Zhao et al. 2016, Al-Asmari et al. 2017. Some scorpion venom peptides block the potassium channels resulting in a prolonged action potential while other peptides cause the delay in inactivation of voltage gated sodium channel (Strong et al. 2001, Bosmans andTytgat 2007). ...
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Hottentota tamulus (Fabricius, 1798) (Scorpiones: Buthidae) is among the most common venomous species of scorpions in Punjab, Pakistan. The venom of this species has high risk of morbidity and mortality. Several medicinal plants have been reported to have anti-scorpion venom potential. However, there is scarcity of scientific evidences that could prove the anti-scorpion venom potential of plant extracts. The aim of present study was to evaluate the anti-venom activity of four native plants extracts, i.e. Mangifera indica L., Achyranthes aspera L., Allium cepa L. and Ginkgo biloba L. using Swiss albino mice as model. The Methanolic/aqueous extracts of plants were mixed with LD99 of Hottenota tamulus and injected intraperitoneally. The response was recorded till 7th day of treatment. Moreover, hematological and serological analyses were performed after administration of LD50 and LD99 doses of venom. The extracts of A. aspera and A. cepa completely neutralized (100%) the effect of scorpion venom, but neutralization effect of G. biloba was comparatively less (83.3%). However, M. indica (leaves and flowers) did not neutralize the effect scorpion venom. The extracts of plants were analyzed by GC-MS for the compositional analysis. The major compounds found in A. aspera, A. cepa and G. biloba were Oleanolic acid, cyclopropane, Lupeol acetate, a cholesterol, palmitic acid and Stearic acid respectively. It is concluded that A. aspera and A. cepa completely neutralize the effect of venom and could be used in future to design anti-scorpion venom agent.
Some of the most popular invertebrate pets are scorpions, which many reflexively consider to be threatening or vermin. The reader with a keen interest in scorpion taxonomy and systematics is encouraged to consult the singular publication which provides an updated classification that is based on detailed and intensive molecular findings. Housing requires a terrarium or other form of caging and must be designed or arranged to provide as natural a habitat as practicable. Feeding scorpions in human care is not difficult because they accept a wide variety of soft-bodied insects such as crickets, katydids, grasshoppers, silk moth larvae, or, with very large scorpions, small mouse pups. The chitinous exoskeleton of scorpions is fluorescent when viewed with artificial ultraviolet illumination. Dysecdysis or difficulty molting is relatively uncommon with scorpions. Parasitic nematodes and their embryonated ova have been uncommonly reported in scorpions. The larger scorpions lend themselves to comparatively easy venom extraction.
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Spider venom is a valuable resource for the development of novel anticancer drugs. In this study, we focused on novel linear amphipathic α-helical anticancer peptide LVTX-9, which was derived from the cDNA library of the venom gland of the spider Lycosa vittata. The cytotoxicity of LVTX-9 against murine melanoma cells in the range of 1.56–200 μM was tested and found to be significantly lower than those of most anticancer peptides reported. Its IC50 was determined to be 59.2 ± 19.8 μM in a serum or 76.3 ± 12.7 μM in serum-free medium. Fatty acid modification is a promising strategy for improving peptide performance. Therefore, to enhance the cytotoxic activity of LVTX-9, fatty acid modification of this peptide was performed, and five different carbon chain length lipopeptides named LVTX-9-C12-C20 were produced. Among them, the lipopeptide LVTX-9-C18 showed the highest cytotoxic activity in relation to B16-F10 cells, whether in a serum or serum-free medium. Most importantly, the cytotoxic activity of LVTX-9-C18 was improved by about 12.9 times in a serum medium or 19.3 times in a serum-free medium compared to that of LVTX-9. Subsequently, assays including scanning electron microscopy, trypan blue staining, lactate dehydrogenase leakage assay, and hemolytic activity could indicate that the potential direct cell membrane disruption is the main mechanism of LVTX-9-C18 to induce cancer cell death. Furthermore, the LVTX-9-C18 also showed strong cytotoxicity in relation to 3D B16-F10 spheroids, which indicates it might be a promising lead for developing anticancer drugs.
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Scorpion venom contains various groups of compounds that exhibit anticancer activity against a variety of malignancies through a poorly understood mechanism. While the aberrant activation of nuclear factor κB (NF-κB) has been linked with hematopoietic malignancies, we hypothesized that scorpion venom mediates its effects by modulating the NF-κB signaling pathway. In the present study, we examined the effects of scorpion venom component III (SVCIII) on the human leukemia cell lines THP-1 and Jurkat and focused on the NF-κB signaling pathway. Our results showed that SVCIII inhibited cell proliferation, caused cell cycle arrest at G1 phase and inhibited the expression of cell cycle regulatory protein cyclin D1 in a dose-dependent manner in THP-1 and Jurkat cells. SVCIII also suppressed the constitutive NF-κB activation through inhibition of the phosphorylation and degradation of IκBα. NF-κB luciferase reporter activity was also inhibited by SVCIII. Our data suggest that SVCIII, a natural compound, may exert its antiproliferative effects by inhibiting the activation of NF-κB and, thus, has potential use in the treatment of hematopoietic malignancies, alone or in combination with other agents.
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Hepatitis B virus (HBV) is a noncytopathic human hepadnavirus that causes acute, chronic hepatitis and hepatocellular carcinoma (HCC). As the clinical utility of current therapies is limited, new anti-HBV agents and sources for such agents are still highly sought after. Here, we report that Mucroporin-M1, a scorpion venom-derived peptide, reduces the amount of extracellular HBsAg, HBeAg, and HBV DNA productions of HepG2.2.15 cells in a dose-dependent manner and inhibits HBV capsid DNA, HBV intracellular RNA replication intermediates and the HBV Core protein in the cytoplasm of HepG2.2.15 cells. Using a mouse model of HBV infection, we found that HBV replication was significantly inhibited by intravenous injection of the Mucroporin-M1 peptide. This inhibitory activity was due to a reduction in HBV promoter activity caused by a decrease in the binding of HNF4α to the precore/core promoter region. Furthermore, we confirmed that Mucroporin-M1 could selectively activate mitogen-activated protein kinases (MAPKs) and lead to the down-regulation of HNF4α expression, which explains the decreased binding of HNF4α to the HBV promoter. Moreover, when the protein phosphorylation activity of the MAPK pathway was inhibited, both HNF4α expression and HBV replication recovered. Finally, we proved that treatment with the Mucroporin-M1 peptide increased phosphorylation of the MAPK proteins in HBV-harboring mice. These results implicate Mucroporin-M1 peptide can activate the MAPK pathway and then reduce the expression of HNF4α, resulting in the inhibition of HBV replication in vitro and in vivo. Our work also opens new doors to discovering novel anti-HBV agents or sources. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Nicolas Andreotti is a Ph.D. student under the supervision of Dr. Sabatier at the ERT 62 laboratory. He also has a permanent position in a biopharmaceutical company. He works on animal peptide toxins and candidate drugs, and has contributed to approximately 10 scientific articles and 10 communications.
Pyridoxal 59-phosphate (PLP)-dependent enzymes represent about 4% of the enzymes classified by the Enzyme Commission. The versatility of PLP in carrying out a large variety of reactions exploiting the electron sink effect of the pyridine ring, the conformational changes accompanying the chemical steps and stabilizing distinct catalytic intermediates, and the spectral properties of the different coenzyme–substrate derivatives signaling the reaction progress are some of the key features of PLP and PLP-dependent catalytic action. Progress in PLP-dependent enzymes functional genomics and development of inhibitors with therapeutic activity highlight the continuous novelty of an ‘old’ class of enzymes.
Previously, we showed that migration of transformed renal epithelial cells (MDCK-F cells) is a K+ channel-dependent process [J Clin Invest 1994;93:1631]. In order to determine whether K+ channel activity is a general requirement for locomotion, we extended our observations to NIH3T3 fibroblasts and human melanoma cells. Migration of both cell types and its dependence on K+ channel activity was measured at the single cell level by time lapse photography in the absence and presence of the specific K+ channel blocker charybdotoxin (CTX). Locomotion of both cell types is inhibited by K+ channel blockade. CTX slows down migration of fibroblasts and of melanoma cells dose-dependently by up to 61 ± 11%. These findings suggest that K+ channel activity is a general prerequisite for migration. To determine whether CTX-induced inhibition of migration of fibroblasts and melanoma cells involves quantitative changes of actin filaments, we indirectly measured filamentous actin by quantitating binding of fluorescently labeled phalloidin. Whereas CTX elicits a decrease of bound phalloidin in fibroblasts there is an increase in melanoma cells. Since migration of tumor cells is required for invading surrounding tissue, we developed an assay to test whether CTX-induced inhibition of migration also impairs invasion of melanoma cells. Melanoma cells were seeded on a layer of high resistance renal epithelial cells (MDCK cells clone C7; transepithelial resistance Rte >3,000 Ωcm2) and Rte was measured daily. Rte starts to decrease 2 days after seeding of melanoma cells onto MDCK-C7 cells. By day 7, Rte has dropped to 24 ± 1.5% of control. K+ channel blockade with CTX (10 nmol/l) cannot prevent or delay this drop of Rte. Rte reaches the same level with or without CTX. These results indicate that the disruption of an epithelial layer, unlike migration of melanoma cells, cannot be modulated by K+ channel blockade.