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Journal of Biochemistry International ANTICANCER POTENTIAL OF ANIMAL

TOXINS: A REVIEW

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Journal of Biochemistry International
8(1): 45-61, 2021
ISSN: 2454-4760

ANTICANCER POTENTIAL OF ANIMAL TOXINS:

A REVIEW

SIMRAN SHARMA a AND RAVI KANT UPADHYAY a*

a
Department of Zoology, Deen Dayal Upadhyaya Gorakhpur University, Gorakhpur, 273009 U.P., India.

AUTHORS’ CONTRIBUTIONS
This work was carried out in collaboration between both authors. Both authors read and approved the final
manuscript.

Received: 24 September 2021

Accepted: 29 November 2021
Published: 03 December 2021 Review Article
__________________________________________________________________________________

ABSTRACT

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, PLA2, metalloproteases, phosphatase and
esterase activity showed exhibit antineoplastic activity to various cancer cell lines.

Keywords:Animal toxins; anti-angiogenic activity; apoptosis; ovarian cancer; tumor cells.

1. INTRODUCTION toward tumors this are called angiogenesis. This

Cancer is a highly dreadful disease that is responsible
for millions of deaths worldwide. This is marked by
abnormal and uncontrolled cell growth that infiltrates
to other parts of the body and destroys normal body
tissue and cells. Cancer cells divide continuously for
indefinite times while a normal cell stops dividing
after ageing. In the last, cancer cell dies due to
programmed cell death or apoptosis. Cancer cells
show alterations in the cellular signaling pathways
and invade into nearby areas and spread to other areas
of the body. Cancer cells divide very rapidly, and
become more aggressive or full blooming. Cancer
cells proliferate and form new blood vessels to grow
_____________________________________________________________________________________________________
process involves the migration, growth, and
differentiation of endothelial cells, which line the
inside wall of blood vessels. These blood vessels
supply tumors with oxygen and nutrients and remove
waste products from tumors.
There are several factors which are responsible for
multiple changes in their chromosomes, such as
duplications and deletions of chromosome parts.
Among them are chemical carcinogens, radiation,
steroid drugs, oncogenes, and environmental factors.
The genetic changes occur in cancer cells induce
errors in cell division, and change general shape of
cells from rectangular to ovoid. Carcinogens damage

*Corresponding author: Email: rkupadhya@yahoo.com;


DNA inside cells that are repaired by cells. But
cumulative effect of carcinogens and genetic changes
make cells cancerous. The genetic changes affect
three main types of genes proto-oncogenes, tumor
suppressor genes, and DNA repair genes. These
changes are sometimes called “drivers” of cancer.
Proto-oncogenes are involved in normal cell growth
and division. However, when these genes are altered
in certain ways or are more active than normal, they
may become cancer-causing genes (or oncogenes).
These allow cells to grow and survive when they
should not. Tumor suppressor genes are also involved
in controlling cell growth and division. Cells with
certain alterations in tumor suppressor genes may
divide in an uncontrolled manner. DNA repair genes
are involved in fixing damaged DNA.
Multiple mutations in genes severely make develop
changes in chromosomes, may result in duplications
or deletions of chromosome parts. Together, these
mutations may cause the cells to become cancerous.
For treatment of various methods such as
chemotherapy and or radiation therapy is used.
Various synthetic drugs mainly small molecular
weight chemicals are used to kill cancerous cells.
These chemical lack target specificity, taking and
show undesired side effects, such as bone marrow
toxicity, cardiotoxicity, and immune-suppression
leading to enhanced risks of infection. Antitumor drug
development based on natural animal venoms has
become one of the new strategies to handle these
problems.
Animal toxins are natural therapeutic molecules
which inhibit cancer and tumor cell proliferation.
These successfully control angiogenesis and inhibit
cell proliferation in vitro cell cultures. In animal
kingdom vast majority of venom bearing animal
species exist belong to different phyla. These venom
toxins were evolved during long evolutionary period
and show enormous diversification. More specifically
venomous animals use venom in self-defense or for
paralyzing pray, and deterring predator from territory.
Various animal species contains much diversified
toxins with different biological activity. These toxins
displayed anticancer effects and inhibit line growth
and proliferation of cancerous cells [1]. A number of
toxins purified from fish, toads, fry, snake, bees, or
wasps, hornets, snails, spider and scorpion and sea
anemone has been isolated and screened for their
anticancer effects. These successfully showed
inhibition of cancer cell invasion, cell cycle arrest,
proliferation, migration, induction of apoptotic
activity and neo-vascularization and blocking of
signaling pathways [2].
Animal venom glands are natural depositories of
diverse toxin molecules which possess diversity of the
46
Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021
chemical structures with variety of action on cancer
affected cells. Similarly snake venom toxin
successfully inhibit cell growth at IC50 value 4.5 ry/ml
(Vipera lebetina) snake toxin induced apoptosis in
ovarian cancer cells via inactivation of nuclear factor
kβ and inhibits DNA binding activities of toxin[3].
The signal transducers and STAT3 (Activator of
transcription 3). When snake venom toxin combined
with salicylic acid and stattic 3, these have
significantly increased inhibition of cell growth [4].
Among arthropods bee venom toxin mainly melittin
shows anticancer effects against ovarian cancer
cells.It also acts through induction of death receptors
and inhibition of JAK/STAT3 pathway cell growth
through enhancement of death receptor expressions in
the human ovarian cancer cell at a dose of 0.5.2 µg/ml
[5]. It also induces apoptotic cell death in dose
dependent manner and found highly active against
molestaticharmone induced prostate cancer [6].
Besides this, nano-particle bearing melittin genes are
transferred for prostate cancer therapy it shows no
systemic side effect. These melittin derived nano-
particle formulations effectively target prostatic
cancer cells but its pathway of action is still not clear
[6].
Snake toxins were found effective on human
neuroblastoma cells SK-N-MC and SK-N-5H cells
[7]. These inactivated the apoptosis and disrupted
mitochondrial membrane potential in neuroblastoma
cells [8]. These make significant increase in reactive
oxygen species level [9]. These viper toxins increased
the expression of pro-apoptotic protein Bax and donar
regulate the Bcl-2 anti-apoptotic protein. These small
sized and low molecular weight toxins bound to
various membrane bound receptors/proteins, ion and
gated channels. These highly active toxins make pores
in cell membranes and puncture them. These toxins
facilitate opening of the mitochondrial permeability
transition pore through an apparent bimodal
mechanism of action [10]. These toxins showed time
and dose-dependent anti-neoplastic effects in
cancerous animal cell lines. The present review
explains venom toxins from various species. These
are pharmacologically active molecules which are
capable of protein synthesis inhibition, induction of
angiogenesis and show induction of apoptosis and are
great source of medicines future.
2. SOURCE OF INFORMATION
For writing this comprehensive research review
on animal venom toxins/enzymes/proteins, various
databases were searched. For collection of relevant
information specific terms such as medical subject
headings (MeSH) and key text words, such as “animal

venom toxins”, “anticancer or anti-tumors effects”
published till 2021 were used in MEDLINE. Most
specially for retrieving all articles pertaining to the
use of venom toxins and its nano-formulations for
treatment of cancer, electronic bibliographic databases
were searched and abstracts of published studies with
relevant information on the venom toxins/allergens
were collected. Furthermore, additional references
were included through searching the references cited
by the studies done on the present topic. Relevant
terms were used individually and in combination to
ensure an extensive literature search. For updating the
information about a subject and incorporation of
recent knowledge, relevant research articles, books,
conferences proceedings’ and public health
organization survey reports were selected and collated
based on the broader objective of the review. This was
achieved by searching databases, including SCOPUS,
Web of Science, and EMBASE, Pubmed, Swissprot,
Google searches” From this common methodology,
discoveries and findings were identified and
summarized in this final review.
3. CNIDARIANS
Cniderians are marine animals which secret large
variety of polypeptide and protein toxins. These are
low molecular weight peptides typically having 10–60
amino acids, and folded into well-defined secondary
structures. Few of these peptides are enzymatic in
nature and act as important inhibitors or modulators of
different ion channels and neurotransmitter receptors.
Sea anemone venom toxins posses three receptor sites
Type I and Type III sodium channel inhibitors.
Phospolipase acts as Type I and Type III sodium
inhibitors of both sodium and potassium voltage-gated
channels (Table 1). Cnidarians also secrete non-
proteinaceous compounds purines, quaternary
ammonium compounds, biogenic amines and
Table 1. Showing peptide toxins secreted from various species of cnidarians and its biological effects
S.No. Species name Protein
1. Sea anemone Phospolipase
2. Palythoa caribaeorum PLA2 activity
3. Anemonia viridis Sticholysins I and
II
4. Pelagianoctiluca Phospolipase
5. Nemopilemano murai NnV
6. Chiropsalmus quadrigatus Angiotensin I
converting enzyme
7. Rhizostoma pulmo Phospolipase
47
Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021
betaines. Cnidarians venom contains phopholipase
A2, (EGF)-like toxin (gigantoxin I),Shk,APETx2 that
shows strong hemolytic activity [11]. Cnidarians
toxins mainly sea anemones and jellyfish secrete a
wide variety of polypeptide and protein toxins. These
show pathophysiological effects such as cardiotonic,
cardiotoxic, neurotoxic in man [12]. Cnidarians
venom toxins show multiple biological activity such
as cytotoxic, hemolytic and anti-tumor effects [13,14]
(Table 1) (Fig. 3).
Few important Cnidarians species such as Palythoa
caribaeorum venom contains compounds which show
ant-cancer activity [15]. Palythoa
caribaeorum possess PLA2 activity that shows
specific cytotoxicity against U251 and SKLU-1
cancer cell lines [16]. Sea anemones secrete pore-
forming toxins the actinoporins which bind and
oligomerize in membrane. These cause cell swelling,
impairment of ionic gradients and cell death.
Sticholysins I and II (Sts, StI/II), are actinoporins
which interact with biological cell membranes and
form pores. Sticholysins I and II also show anti-tumor
effects Carlos [17]. Sea anemones Anemonia viridis,
contain Kunitz-type inhibitor, interact with cell
membrane and bind to intigrins due presence of an
Arginine, Glycine, Aspartate (RGD) motif. This
inhibitor stops new blood vessel growth or anti-
angiogenesis effects [18] and stop cancer cell
migration [19] (Table 1) (Fig. 3).
Sea anemone species Anemonia viridis and Pelagia
noctiluca (P. noctiluca) show cytotoxic and anti-
proliferative activities on cancer cell lines [20].
Pelagia noctiluca (P. noctiluca) venom shows nitric
Oxide (NO) inhibition activities. It also showed anti-
proliferative activity on several cell lines such as
human bladder carcinoma (RT112), human
glioblastoma (U87), and human myelogenous
Biological effects References
Type I and Type III sodium [15]
inhibitors, potassium voltage-
gated channels
cytotoxicity [15]
cytotoxic and anti- [64]
proliferative activities
anticancer and nitric Oxide [67]
(NO) inhibition activities
Cytotoxicity [69]
inhibitory activity [71]
cytotoxic and anti- [72]
proliferative activities
 Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021

Fig. 1. Showing various toxin peptides isolated from snake venom toxins

Fig. 2. Showing various toxin peptides isolated from Scolopendra venom toxins

leukemia (K562). P. noctiluca venom toxins do
natural inhibition of cancer cell lines [21].
Nemopilemano murai jellyfish venom (NnV) strongly
induces selective cytotoxicity in HepG2 cells through
apoptotic cell death cells via dual inhibition of the Akt
and mTOR signaling pathways, but not in normal
cells [22] (Fig. 3). ZooanthidAnthopleura
elegantissima palytoxin, was found active against
Ehrlich ascites tumor and P-388 lymphocytic
leukemia in mice (Table 1) (Fig. 3).
Sea Anemone Anemonia viridis contains a low
molecular weight protein that shows anti-angiogenic
activity. It also limits the proliferation of endothelial
cells proliferation and angiogenesis. It shows trypsin
activity inhibition of a Kunitz-type inhibitor, that
interacts with an integrin due to an Arginine, Glycine,
Aspartate (RGD) motif [23]. The anti-angiotensin I
converting enzyme activity of box jellyfish,
Chiropsalmusquadrigatus Haeckel contain venom
hydrolysate. Angiotensin I converting enzyme (ACE)

48

shows inhibitory activity [24] (Fig. 3).The
jellyfish Rhizostomapulmoundergoes possess collagen
peptides have significantly higher AA and possess
greater protective effect against oxidative stress in
HEKa than the hydrolyzed collagen peptides from
vertebrates[25] (Table 1) (Fig. 3).
4. WASP
Polybia-MP1 is a lytic peptide isolated from the
Brazilian wasp venom. Phosphatidylserine lipids and
membrane order precisely regulate the activity of
Polybia-MP1 [26]. It possesses very strong anti-tumor
and anti-cancer activity [27,28]. Similarly, melittin
inhibits tumor cell growth and induces apoptosis [29].
It also acts as a natural detergent with the capacity to
form tetramer aggregates on membranes, which lead
to disorders in the structure of phospholipid bilayers.
It effectively changes membrane potential,
aggregation of membrane proteins, as well as the
induction of hormone secretion [30]. Furthermore,
this membrane disruption directly or indirectly leads
to alterations in enzymatic systems, such as G-protein
[31], protein kinase adenylatecyclase and
phospholipase. Melittin can even inhibit calmodulin, a
calcium-binding protein that plays a crucial role in
cell proliferation [31]. Melittin interacts to anionic
phospholipids, mainly phosphatidyl serine, on the
external leaflet of the plasma membrane of timorous
cells [32] (Fig. 4).
Polybia
-MP1
Melittin wasp
Mastoparan
Fig. 3. Showing biological activity of wasp venom toxins
49
Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021
Melittin displays anti-proliferative activity [33] and
inhibit angiogenesis [34]. Recombinant melittin is
used for making immunotoxins by fusion of genes
that encoded an antibody fragment derived from the
murine monoclonal antibody K121 found effective in
vitro [35]. Melittin also binds to anti-asialo
glycoprotein receptor (ASGPR) a single-chain
variable fragment antibody (Ca) shows anti-invasive
activity in hepatocellular carcinoma cells [36]. More
specifically, CTLA-4-targeted scFv-melittin fusion
protein acts as a potential immunosuppressive agent
showed selective cytotoxicity assist in organ
transplants [37]. Melittin coupled to avidin when
released induces immediate cell lysis [38] and stop
cancer cell latency [39] (Fig. 4).
Small cationic and hydrophobic peptides were found
more toxic to cancer cells than normal cells. These
ACPs kill cancer cells by causing irreparable
membrane damage and cell lysis, or by inducing
apoptosis. Mastoparan functions as an inducer of mast
cell granules exocytosis that is an important cell
function (Table 5). It facilitates opening of the
mitochondrial permeability transition pore through an
apparent bimodal mechanism of action. [40].
Mastoparan is an α-helical and amphipathic
tetradecapeptide obtained from the venom of the wasp
Vespula lewisii. This peptide shows strong tumor cell
cytotoxicity and induces caspase-dependent apoptosis
in melanoma cells through the intrinsic mitochondrial
pathway [41] (Fig. 4).
Phospholipase

5. HONEY BEE AND HORNETS
Bee venom is a complex mixture of natural products
i.e. peptides, enzymes, biologically active amines and
non-peptide components. Melittin is one of the major
amphipathic 26-residue peptide that shows anti-
arthrosclerosis effects [42]. This is a good candidate
for cancer therapy [43]. Melittin induces apoptotic
cell death in cervical cancerous cellsand shows an
inhibitory effect on proliferation of cancer cells [44].
α-mangostin is a major active compound with a
potential anticancer activity in T. laeviceps cerumen
in Thailand [45]. Propolis is a complex resinous
honeybee product. It is reported to display diverse
bioactivities, such as antimicrobial, anti-inflammatory
and anti-tumor properties, which are mainly due to
phenolic compounds, and especially flavonoids.
A.melliferapropolis contains at least two potentially
new compounds (a cardanol and a cardol) with
potential anti-cancer bioactivity. Both could be
alternative anti-proliferative agents for future
development as anti-cancer drugs [46].Overall,
propolis from Thailand may have the potential to
serve as a template for future anticancer-drug
development [47].
Colon carcinogenesis is second important global
human diseases after cardiovascular failures. Bee
venom (BV) possesses in vitro anticancer effects
against several types of cancer cells. Both melittin
(MEL) and phospholipase A2 (PLA2), are bio-
peptides isolated from Apis mellifera, these show
strong anticancer activity. BothMEL and PLA2
inhibit proliferation of human colon carcinoma cells
(HCT116), and synergistic effect [48]. Venom anti-
cancer peptide 1, VACP1 was derived from the wasp
venom of Vespa ducalis SMITHVACP1. It more
potently suppressed cell proliferation and induced the
Table 2. Showing peptide toxins secreted from various species of spider and its biological effects
S.No. Species name Protein
1. Latrodectus tredecim Latroeggtoxin-V
guttatus
2. Lycosa vittata LVTX-8
Table 3. Showing peptide toxins secreted from various species of snake and its biological effects
S.No. Species name Protein
1. Macrovipera lebetina Lebein
2. Crotalus durissusterrificus crotoxin (CrTX),
3. Bothrops alternatus RGD-disintegrin
5. Lebetina transmediterranea Lebetin 2
6. Daboia mauritanica Dabmaurin-1
7. Macroviperalebetina Lebein-1
50
Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021
cell apoptosis of OS cells by inducing the activation
of the p38 MAPK and JNK signaling pathways [49].
6. SPIDER
Spider venom shows anticancer activity in a variety of
human malignancies, including lung cancer. Anti-
cancer peptide toxin LVTX-8, from the spider Lycosa
vittata LVTX-8 shows strong cytotoxicity and anti-
metastasis towards lung cancer. LVTX-8 anticancer
peptide with high efficiency and acceptable
specificity, LVTX-8 may become a potential
precursor of a therapeutic agent for lung cancer in the
future. [50]. A proteinaceous toxin, named
Latroeggtoxin-V isolated form Latrodectus tredecim
guttatus. Black widow spider selectively acts on
breast cancer line MDA-MB-231 cells. It is not only
arresting their cell cycle, inhibiting their proliferation
and migration, but also inducing their apoptosis.
Latroeggtoxin-V belongs to the ATPase inhibitor
protein family and used in the anticancer drug
development [51] (Table 2).
Pancratistatin (PST) is a natural compound that was
isolated from the spider lily Pancratiumlittorale. It
shows anti-neoplastic activity and induces apoptosis
selectively in cancer cells [52]. Some of the spider
peptide toxins produce lethal effects on tumor cells by
regulating the cell cycle, activating caspase pathway
or inactivating mitochondria. Some of them also
target the various types of ion channels (including
voltage-gated calcium channels, voltage-gated sodium
channels, and acid-sensing ion channels) among other
pain-related targets. Herein we review the structure
and pharmacology of spider-venom peptides that are
being used as leads for the development of
therapeutics against the pathophysiological conditions
including cancer and pain [53] (Table 2).
Biological effects References
cytotoxicity [50]
programmed apoptosis of [51]
cancer cells
Biological effects References
anti-angiogenic effects [64]
Neurotoxin, anti-tumor effects, [65]
anti-angiogenic effects
anti-metastatic and anti-angiogenic [66]
anti-platelet activity, anti-tumor [68,69]
effect,
anti-angiogenic agents [71]
anti-angiogenic effects [73]

Fig. 4. Showing biological activity of Cnidarians venom toxins
7. SCORPION
Scorpion venoms and toxins can decrease cancer
growth, induce apoptosis and inhibit cancer
progression and metastasis in vitro and in vivo. This
activity depends on specific structure of peptides with
biophysical properties (hydrophobicity, hydrogen
bond donor and steric), to penetrate through
membrane and block ion channels successfully and
effect membrane environment due permeability
alteration (sodium, potassium, chloride). Scorpion
venom toxins showed heterogeneous distribution and
interact with the lipid bilayer by using its hydrophobic
side chains; and shift molecules within the lipid
bilayer rather than on the surface. These toxin
polypeptides not only work against cancer cells but
also show good anti-tumor activity and can be used to
treat endometrial cysts. New combinations or
cocktails of venom toxins can assist in fast recovery
of tumor patients.
8. MOLLUSKS
Mollusk-derived metabolites were also found good
anticancer agents. These shows high anti-proliferative
potency against cancer cells in vitro, preferential
inhibition of the proliferation of cancer cells and work
through via non-apoptotic signaling pathways,
circumvention of multidrug resistance phenotype, and
high activity in vivo, among others [54]. Squid ink is
a peptidoglycan shows strong anti-tumor activity [55].
The anti-tumor effect of a novel peptide,
KVEPQDPSEW (AATP), isolated from abalone
51
Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021
(Haliotis discus hannai) shows AATP effectively
inhibited MMPs by blocking MAPKs and NF-κB
pathways, leading to the down regulation of
metastasis of tumor cells. The effect of AATP on anti-
metastatic and anti-vascular in HT1080 cells revealed
that AATP may be a potential lead compound for
treatment of tumors in the future [56].
9. ECHINODERMS
Echinoderms are marine animals having wide
diversity in different environmental conditions.
Echinoderms mainly starfish, produce a huge number
of compounds secondary metabolites that exhibit a
significant anticancer effect against different human
tumor cell lines. A marine-derived compound
PEsaponin displays anti-angiogenesis and anti-tumor
activities. PE saponin possesses anti-angiogenic
activity associated with inhibition of VEGFR2
signaling, and an anti-tumor activity associated with
decreased proliferation of tumor cells and increased
apoptosis of both endothelial cells and tumor cells
[57]. Asterosaponin 1 is isolated from starfish
Culcitanovaeguineae. It was found active against
malignant glioblastoma. It more efficiently
killglioblastoma cells and is used in anti-tumor
chemotherapy [58]. It also shows potential anti-
proliferative and pro-apoptotic activity of in A549
human lung cancer cells. Asterosaponin 1 inhibits the
proliferation of A549 cells through induction of ER
stress-associated apoptosis, making asterosaponin 1 a
candidate new anticancer drug for lung cancer therapy
[59].

10. FISH
Pituitary adenylatecyclase-activating polypeptide
(PACAP) is a regulatory neuropeptide that belongs to
the secretin/glucagon super family is isolated from of
catfish. It shows cytotoxic activity PACAP against
human tumor cells and kill cancer cells
[60].Tetrodotoxin (TTX) isisolated from puffer fish
(Arothronstellatus) that is used asanticancer drug
[61].
11. AMPHIBIA
Amphibians possess toxins in their skin, and poison
glands of toads. Bufobufogargarizans Cantor is
known possess bufadienolides, peptides and alkaloids.
Toad posion glands are reservoir of biologically
active toxin molecules with antitumor activity.
Bufadienolides, such as bufalin, cinobufagin,
resibufogenin, and telocinobufagin, are the major
active compounds derived from the toad skin. Among
all these cinobufacini (e.g. bufalin and cinobufagin)
shows inhibit of cell proliferation, induction of cell
differentiation, induction of apoptosis, disruption of
the cell cycle, and inhibition of cancer angiogenesis.
Cinobufacini have effective anticancer activity with
low toxicity and few side effects [62]. Arenobufagin,
one of the major components of toad venom, is a
traditional Chinese medicine used for cancer therapy.
It inhibits cell growth in several cancer cell lines. It
shows anti-angiogenic activity. Arenobufagin
inhibited vascular endothelial growth factor (VEGF)-
induced viability, migration, invasion and tube
formation in human umbilical vein endothelial cells
(HUVECs) in vitro. More specifically, arenobufagin
is a specific inhibitor of VEGF-mediated angiogenesis
[63].
12. SNAKE
Snake venom based drugs are widely used to treat
various types of cancer. Caspian cobra venom toxins
showed cytotoxic effects against human cancer cell
lines [64]. Lebein is a snake venom disintegrin which
generates anti-angiogenic effects by inhibiting
vascular endothelial growth factors (VEGF) [65] (Fig.
1). These include toxins purified from snake, bee and
scorpion venoms effecting cancer cell proliferation,
migration, invasion, apoptotic activity and
neovascularization .the mechanism behind the
anticancer effect of certain toxins is similar to that of
agents currently used in chemotherapy. CrTX was
found effective against viper Crotalus
durissusterrificus, in human lung adenocarcinoma
A549 cells significant anti-tumor effects by inducing
cell apoptosis probably due to activation of
P38MAPK and caspase-3, and by cell cycle arrest
52
Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021
mediated by increased wt p53 expression. In addition,
CrTX displayed anti-angiogenic effects in vivo [66]
(Tables 3, 4).
Cerivastatin also reduces the proliferation and
invasion of aggressive breast cancer cells. [67] DisBa-
01, is a low molecular weight recombinant protein,
specifically interacted with alpha(v)beta3 integrin. It
shows potent anti-metastatic and anti-
angiogenicproperties. Theinteraction of DisBa-01
with platelet alphaIIbeta3 integrin shows effects on
hemostasis and thrombosis [68]. Lebetin 2 isolated
from Macro viperalebetinaexhibits a potent anti-
angiogenic effect with the integrin [69]. Dabmaurin-1
exhibits in vitro apparent anti-angiogenic effects at
concentrations lower than 30 nM, [70]. Dabmaurin-1
effects are possibly due to some anti-integrin
properties. Contortrostatin (CN), is a disintegrin from
southern copperhead snake venom, it possess anti-
angiogenic activity both in vitro and in vivo [71] (Fig.
1). A cryptic plasminogen-derived domain, kringle 5,
inhibits endothelial cell growth [72]. Phospholipases
type A2 (PLA2s) are the most abundant proteins
found in viper snake venom. It exerts neurotoxicity,
myotoxicity, hemolytic activity, antibacterial,
anticoagulant, and anti-platelet effects, some venom
PLA2s show antitumor and anti-angiogenic activities
by mechanisms independent of their enzymatic
activity [73] (Tables 3, 4).
13. CENTIPEDE TOXINS
Centipede Scolopendra (AECS), venom is a cocktail
of toxins; it shows potential anticancer effects and is
widely used in traditional Chinese medicine. Its
alcohol extract induce expression of epidermal growth
factor receptor (EGFR) (A431 and HEK293/EGFR
cells versus HEK293 cells). AECS binds to EGFR,
induces apoptosis of A431 and HEK293/EGFR cells.
It inhibits high-EGFR expression cell proliferation
and modulates the EGFR pathway [74]. AECS
inhibits A375 cell proliferation in a dose- and time-
dependent manner. Similarly, alcohol extracts of the
centipede Scolopendra subspinipes mutilans (AECS),
shows cell viability, cell cycle and cell apoptosis.
These anticancer effects were associated with Bcl-2
family, whereby decreased Bcl-2 and increased Bak,
Bax and Bad expression levels [75]. From same
species two new isoquinoline alkaloids were isolated
from the ethanol extract. These alkaloids inhibit U87
cell proliferation by arresting cell cycle progress at
G0/G1 phase and inducing apoptosis through loss of
mitochondrial membrane potential (MMP), activation
of caspase 9/3 and down-regulation of the Bcl-2/Bax
protein ratio [76]. Another alkaloid i.e. 1,5-dihydroxy-
4-methoxyisoquinoline, was from this species showed
moderate cytotoxicity on tumour cells with 13 to 26

μm IC50 values esophageal squamous cancer cells.
This compound also showed potent inhibitory effect
(inhibition rate > 50% at 13 μm) on cell migration in
human umbilical vein endothelial cells [77]. A
polysaccharide-protein complex isolated from
Scolopendrasubspinipesmutilans L. Koch (SPPC) on
the tumor growth and immune function were assessed
in sarcoma S180 and hepatoma H22 bearing mice.
SPPC inhibits tumor growth in vivo by improving
antitumor immune responses at least partly via down
regulating AA-metabolic pathways in TAMs. It also
acts as an anti-tumor agent with immunomodulatory
activity [78]. These inhibitory effects of Scolopendra
subspinipes mutilans (SSM) toxin play a protective
role during the development of AP and pancreatitis
associated lung injury via deactivating c-Jun NH2-
terminal kinase, p38 and NF-κB. SSM inhibited the
cerulein-induced acinar cell death, cytokine, and
HMGB-1 release. SSM also inhibited the activation of
c-Jun NH2-terminal kinase, p38 and nuclear factor
(NF)-κB[79] (Table 5) (Fig. 2).
14. MODE OF ACTION
Animal toxins are a complex mixture of polypeptides,
enzymes and chemicals which cause cellular injury.
The unique molecules act by using several
mechanisms and put targeted physiological effect.
Most of the animal venom toxins block ion channels
and exert potent physiological effects [80]. This effect
is equally noted in cancer cells and normal cells.
Animal venom toxins block function of potassium
channels within mammalian nerve cells [81]. Animal
toxins stop cancer cell proliferation, induce apostosis
and repair genomic damage. There are toxins
targeting voltage-gated sodium and calcium channels
as well as potassium channels. Animal venoms cause
occasionally serious complications arising from
human envenomations [82]. PLA2 binds to membrane
hydrolyseglycerophospholipids at the sn-2 position to
release lysophospholipids and fatty acids such as
arachidonic acid, that may puncture cancer cells and
cause cell lysis [83].
Cniderians toxins peptides acts on ligand-gated ion
channels, including acid-sensing ion channel (ASIC)
toxins. These small size enzymatic toxins break
glycerophospholipds and control a variety of cellular
functions, including dietary lipid catabolism, in cell
membrane metabolism and inflammatory diseases
[83]. These toxins mainly act on voltage-gated sodium
and potassium channel toxins and form pores within
membranes. Ions also pass using the electrochemical
gradient across the membrane itself [84]. By
controlling the opening and closing of the sodium
channel, the toxins control the electrical signals that
encode and propagate vital information across long
53
Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021
distances. Heteractiscrispa contain sodium channel
inhibitors and act as pain blockers. Bunodosoma
caissarumBcsTx1 and BcsTx2 secreted by sea
anemone type 1 potassium channel toxins interact
with voltage-gated K+ channels (KV) mainly rKv1.2
over rKv1.6, hKv1.3, Shaker IR and
rKv1.1.(Cnidaria, Anthozoa) (Fig. 3). Sea anemones
Heteractis crispa contain peptide toxins APETx-2. It
also contains APETx-like peptides, Hcr 1b-2 and Hcr
1b-4 which interfaces with the rASIC1a channel
[85].The nematocysts of the sea anemone Actinia
bermudensis contains peptide toxinsAbeTx1. It
possesses a ring of basic amino acids that shows
multipoint interaction for the binding of the toxin to
the channel. Sea anemone Anthopleura dowii Verrill
venom, contain proteases, neurotoxins,
phospholipases A2, and other polypeptides, that act as
either potassium (K+) or sodium (Na+) channels
inhibitors [86] (Fig. 3). Moreover, these low
molecular weight diverse animal toxins inhibit
membrane function in cancer cells and lead to their
mass death (Fig. 4).
Animal toxins are unique natural molecules which
show diverse biological activity. These show potent
cytotoxic and lyse cancerous cells via modulation of
the apoptosis response pathway. These inhibit enzyme
activity, slow down cell cycle and stop proliferation
of cancer cells. Snake venom toxins are very strong
cytolysins and suppress oncogene activity [87-91].
Animal toxin molecules may alter abnormal
expression of ion channels on the surface of cells
which are involved in cancer processes and pathology.
Animal venom toxins target Na+, K+, Ca2+, and Cl−)
ion channels and show selective activities against
cancer cells. These animal venoms were found in
several species, and may target ion channels in
different cancer types. For example, AGAP peptide
from BmK scorpion venom acts as the selective
inhibitor of a voltage-gated sodium channel. 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]. Moreover,
venom components from other animal species, like
family Bufonidae, bees, and spiders, are also found
antitumor activities [94-95] (Fig. 5).
All molecular changes mainly mutations that lead to
cancer, may silent or inactive by using animal toxin
based drug combinations, These anticancer drugs
might more strongly target gene mutations and revert
back to normal state by inducing repairing.
Angiogenesis plays a critical role in the growth of
 Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021

cancer because solid tumors need a blood supply if
they are to grow beyond a few millimeters in size.
Tumors can actually cause this blood supply to form
by giving off chemical signals that stimulate
angiogenesis [73]. So far researches animal toxins
were found strong inhibitors of angiogenesis. These
inhibitors might help to reduce both morbidity and
mortality from carcinomas. Further, animal toxins
from marine animals could be used treatment and
prevention of cancer recurrence and metastasis.
Moreover, combination of anti-angiogenic agents with
conventional cytoreductive treatments could provide
much better control of cancer (Fig. 5).

Table 4. Showing peptide toxins secreted from various species of animals and its biological effects

S.N. Species name Protein Biological effects References

1. Palythoa caribaeorum phospholipase PLA2 activity [15]
2. Chiropsal musquadrigatus hydrolysate. Angiotensin I inhibitory activity [71]
converting enzyme
3. Rhizostoma pulmo Kunitz-type inhibitor mitochondrial [72]
permeability
transition and tumor
cell cytotoxicity
4. Vespula lewisii Mastoparan caspase-dependent [40]
apoptosis
6. Tetragonula laeviceps α-mangostin anticancer activity, [40]
anti-proliferative
activity
7. Vespa ducalis venom anti-cancer peptide 1, cell apoptosis of OS [41]
VACP1 cells
8. Latrodectus tredecim Latroeggtoxin-V anticancer activity [51]
guttatus
9. Lycosa vittata LVTX-8 cytotoxicity and [52]
anti-metastasis
10. Pancratium littorale Pancratistatin antineoplastic [52]
activity
11. Arothron stellatus tetrodotoxin (TTX), cytotoxic effects [61]
12. Murraya koenigii girinimbine apoptosis [61]
13. Bufo bufog argarizans bufadienolides antitumor activity [62]

14. Caspian cobra Lebein anti-angiogenic [65]

effects
15. Crotalus durissus terrificus crotoxin (CrTX), anti-tumor effects [66]
by inducing cell
apoptosis
16. Bothrops alternatus DisBa-01 anti-metastatic and [68]
anti-angiogenic
properties
17. Cerastes cerastes CC5 and CC8, disintegrin anti-angiogenic [69]
effect
18. Macro viperalebetina Lebetin 2, α5β1 and αv anti-platelet activity [65]
integrins
19. Daboia mauritanica Dabmaurin-1 hemotoxic venom [70]
20. copperhead snake Contortrostatin (CN), anti-angiogenic [71]
activity
21. Viperidae snake Phospholipases type neurotoxicity, [72]
A2,kringle 5 myotoxicity,
hemolytic activity,
antibacterial,
anticoagulant, and
antiplatelet effects
22. Scolopendra subspinipes Spooky Toxin (SsTx) neurotoxic [74]

54
 Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021

S.N. Species name Protein Biological effects References

mutilans)
23. Scolopendra polymorpha SsTx acute hypertension, [75]
myocardial
ischemia
24. S. subspinipes SsTx acute hypertension, [76]
myocardial
ischemia
25. Henia vesuviana Glycoside Hydrolases [77]
26. Aphilodonan gustatus Glycoside Hydrolases antibacterial agent [77]
27. Scutigeromorpha γ-Glutamyltranspeptidases antibacterial agent [78]
28. Scolopendra morsitans Phospholipase A2 PLA2 activity [78]
29. Thereuopoda longicornis astacin-like myonecrosis and [78]
metalloendoproteases inflammation
30. Scolopendra viridis Metalloproteases myonecrosis and [79]
inflammation
31. Scolopendra subspinipes Metalloproteases cardiotoxic and [79]
dehaani neurotoxic
properties
32. Anemonia viridis Sticholysins I and II cytotoxic and anti- [79]
proliferative
activities

Table 5. Showing peptide toxins secreted from various species of Scolopendraand its biological effects

S.No. Species name Protein Biological effects References

1. Scolopendra morsitans Metalloproteases phosphatase and [74]
esterase activity
2. Thereuopoda longicornis astacin-like myonecrosis and [74]
metalloendoproteases inflammation
3. Scolopendra viridis astacin-like myonecrosis and [75]
metalloendoproteases inflammation
4. Scolopendra subspinipesde astacin-like myonecrosis and [75]
haani metalloendoproteases inflammation
5. Scolopendridae S1 and S8 type protease serine protease [76]
activity
6. Scolopendrine γ-Glutamyltranspeptidases aggregation of [76]
human platelets and
hemolysis of red
blood cells
7. Ethmo stigma glycoside hydrolase antibacterial agent [76]
8. T. longicornis Phospholipase A2 protein neo [77]
functionalisation.
9. Scolopendra viridis γ-Glutamyltranspeptidases aggregation of [77]
human platelets and
hemolysis of red
blood cells
10. Otostigmus pradoi Phospholipase A2 protein neo [77]
functionalisation.
11. Scolopendra viridicornis γ-Glutamyltranspeptidases aggregation of [76]
human platelets and
hemolysis of red
blood cells
12. Cormocephalu swestwoodi Phospholipase A2 protein neo [77]
functionalisation.

55

Fig. 5. Showing biological activity of animal venom toxins
15. CONCLUSION
Venomous animals synthesize and secrete a diverse
arsenal of peptides and proteins. Animal toxins as
natural molecules are highly active molecules and
show diverse biological activity. These exhibit much
potent cytotoxic effects to cancer cells via induction
of the apoptosis response pathway. These cause
impairment of cancer cell proliferation, and inhibit
enzymatic activity. These inhibit cyclin activity in
cancer cells and suppress cell division and oncogenes.
Coelenterates mainly Sea anemone venom toxins
show diverse biological activity such as anti-
angiogenesis effects and cytolytic activity against
human myelogenous leukemia and cancer cell lines.
These act like actinoporins and form pores and cause
cell hemolysis. Sea anemone B. verrucosa toxins
show Kunitz-type protease and pancreatic α-amylase
inhibition activity. Wasp, honey bee, scorpion and
snakes possess 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.
These specially show cytotoxic effects in tumor and
cancer cells and degrade/destroy. These toxin
polypeptides not only work against cancer cells but
also show good anti-tumor activity and can be used to
treat endometrial cysts. Animal toxins can be
converted into potential drugs candidates for the
treatment of various cancer types. New combinations
or cocktails of venom toxins can assist in fast
56
Sharma and Upadhyay; JOBI, 8(1): 45-61, 2021
recovery of tumor patients. Animal toxin derived
nano-particles could assist in various types of cancers
and can be used in targeted chemotherapy and
immunotherapy of timorous growths. Further,
transcriptomic and proteomic studies may resolve
molecular and ionic interactions of venom peptides
with cancer cells from various animal groups. This
will alternatively help in unique modeling of peptides,
its use in inhibition of important molecular and
cellular pathways to target specific cancer types.
ACKNOWLEDGEMENT
I thank HOD department of Zoology, Deen Dayal
Upadhyaya Gorakhpur University, Gorakhpur for
facilities.
COMPETING INTERESTS
Authors have declared that no competing interests
exist.
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