Scorpion venoms as a potential source of novel cancer therapeutic compounds

Abstract

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
http://ebm.sagepub.com/content/early/2014/03/04/1535370213513991
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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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Minireview
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: gopalakrishnakone_pon@nuhs.edu.sg
Abstract
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
Introduction
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.
1
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.
2
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
treatments.
3
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.
4
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).
5,6
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.
7,8
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
activity.
9,10
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
therapeutics
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.
11
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.
12
Surgical resection of the primary tumor and regional
lymph nodes is the main and most effective way to
treat most patients with solid tumors.
13
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.
14
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.
15,16
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.
5,6,15,16
Among all the scorpions used in cancer
research, BmK is probably the first to have been reported to
possess antitumor properties.
16
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.
17
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.
18
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.
19
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.
19
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.
20
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.
21
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.
22
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.
23
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.
24
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.
25
A recombinant fusion
protein SUMO-AGAP which combined a small ubiquitin-
related modifier to AGAP was proven to have antitumor
activity.
26
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.
27
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.
28
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.
29
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
30
demon-
strated that BmKCT toxin inhibited glioma proliferation
and tumor metastasis and
131
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.
31
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.
32
Scorpion venom targeted ion channels
A novel and promising field of cancer research is targeting
Na
þ
,K
þ
,Ca
2þ
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
metastasis.
33,34
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.
35
Fraser and
co-workers
36
observed that functional expression of
Na
v
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
v
1.5 expression and lymph
node metastasis in a clinical study. Similar findings were
also observed for the involvement of Na
v
1.7 in prostate
cancer.
37–39
Compared to Na
þ
channels, K
þ
channels are mainly
implicated in cancer cell proliferation and survival. There
is a tight relationship between K
v
expression and cell pro-
liferation and apoptosis, but the underlying mechanism is
still not clear. Generally, by regulating the membrane poten-
tial, K
v
channels can control the Ca
2þ
fluxes and cell
volume, and therefore exert their role in cell cycle regula-
tion and cell death.
40
A number of K
v
channels have been
detected to be abnormally expressed in many primary can-
cers. K
v
1.3 has been analyzed in gliomas, colon, prostate
and breast cancers.
41
The aberrant expression of K
v
1.3
was observed to promote cancer cell growth. The roles of
K
v
1.5, K
v
10.1 and K
Ca
3.1 have been studied in gliomas,
colon cancer and melanoma. K
v
11.1, also known as hERG,
is expressed in several cancers, including leukemia, neuro-
blastoma, stomach and colorectal cancers. The blockage of
K
v
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.
42
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
þ
channels. Short-chain toxins with
30–40 amino acid residues are known to modulate K
þ
or
Cl

(chloride ion) channels.
43
Compared to massive Na
þ
or
K
þ
channel toxins, only few calcium channel-related toxins
(with a variable number of amino acids) have been purified
or cloned from scorpion venoms.
44
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
bonds.
45
Originally, CTX was described as a Cl

channel
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
research.
46,47
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
1989.
48
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
brain.
49
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.
50
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
brain.
51
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 (
131
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
131
I-TM-601 is
safe and minimally toxic, and that
131
I-TM-601 binds malig-
nant glioma with high specificity and for long duration.
52
A
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
2þ
activated
K
þ
(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.
53
Another experiment showed that blockade of the BK chan-
nels by IbTX inhibited K
þ
currents and growth of PC-3
prostate cancer cells.
54
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.
55
Charybdotoxin (ChTX), another peptide isolated from
Leiurus quinquestriatus scorpion venom, is structurally
similar to IbTX and MgTX and acts as an inhibitor of
Ca
2þ
-activated K
þ
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
2þ
entry,
which is important in the cell migration process.
56
However,
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
þ
channel
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-
ject.
57
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.
58
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.
59
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.
60
These
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.
61
Immunohistochemistry
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.
62,63
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.
64
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
131
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
imaging.
52,65,66
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.
67
Conclusion
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
23–27
BmKCT Buthus martensii Karsch SHG-44 glioma cells, glioma/SD rat Inhibit chloride current and selectively
target glioma
28–30
Chlorotoxin Leiurus quinquestriatus Glioma cells, animal models and clin-
ical trials
Inhibit chloride current, bind to matrix
metalloproteinase-2 (MMP-2)
48–52
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
55
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
submission.
ACKNOWLEDGEMENT
This work was supported by Grant NMRC/EDG/1013/2010.
JD is a recipient of the National University of Singapore
Research Scholarship.
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