SNAKE VENOM - THERAPEUTIC ROLE IN CANCER

World Health Organization has placed bite envenoming on its list of prime twenty priority neglected tropical diseases, that kills quite 100,000 people and maims 400,000 people annually.

Snake venom toxins contributed considerably to the treatment of the many medical conditions. 

Snake venoms are complicated mixtures containing totally different peptides, proteins, enzymes, carbohydrates and alternative bioactive molecules, that are secreted by the snake within the predation or defensive against threats. 

Some of these proteins or peptides and enzymes from venom once isolated and evaluated might bind specifically to neoplastic cell membranes, moving the migration and proliferation of those cells. a number of substances found within the venom present a good potential as anti-tumor agent. 

• There are several revealed studies describing and elucidating the anti-cancer potential of venom. 

Figure 1

WHAT IS CANCER? 

Cancer could be a group of diseases that arises from the uncontrollable proliferation of malignant cells. 

It's a multigenic and multistage sickness because of multifactorial etiology. 

Briefly, high levels of exposure to carcinogens corresponding to radiation, tobacco,and oncogenic viruses increase the danger of DNA injury within the cells. 

The DNA-repair mechanism will be initiated at this stage. 

However, once the injury is just too extensive, the repair of lesions fails.

This gives rise to changes within the expression of genes (such as tumor-suppressor genes) in the Cells,which additional alter the signalling pathways leading to unrestricted cell growth

SNAKE VENOM 

• Snake venom is harmless if ingested in liquid or crystal kind once drying through mouth and it'll be excreted unchanged; it contains anti-clotting proteins. It produces toxicity as long as contacted with blood. venom is obvious, viscous and clear liquid, which might be dried to solid crystal kind.

• The constituents of venom will be preserved for extended amount, if dried solid crystal kind is hold on properly. 

• The crystal mass will dissolves readily in blood and water. 

• There are essentially 3 sorts of venom consistent with its effects. 

• Hemotoxic venoms, that affects circulatory system and blood functions, cytotoxic venoms targets specific cellular sites or muscles and neurotoxic venoms harms systema nervosum of human body. 

• Snake venom has in the main 2 functions; 

• Paralyzes the prey and 

• Starts the digestive process. 

• Enzymes present in venom hydrolyze proteins and membrane parts, that result in tissue death and coagulation. 

• Components of venom are answerable for dysfunction attack on nerve membrane and branches and neuro-muscular junctions. supported mode of action, venom will be classified into totally different classes. Some parts of venom bind to cholinergic receptors without inflicting any biological activity. 

• Prey typically dies as respiratory muscles not perform. 

• A group of poisons inhibits or just will increase unleash of neurotransmitter, therefore the muscle fiber can't react to nerve stimuli and ends up in spasm or relaxation of muscle. 

• Some toxins are answerable for injury to the skin and connective tissues of the body, their precise mode of action are unknown. 

• Cytotoxins and cardiotoxins within the venom causes injury to the semipermeable membrane or interfere with the transport of drugs or the transduction of signals across the membranes. 

HISTORY OF SNAKE VENOM IN THE FIELD OF MEDICINE

COMPOSITION OF SNAKE VENOM

• Snake venoms are advanced mixtures; principally it's proteins, that have protein activities. 

• Protein and peptides create ninety to ninety five % of the dry weight of venom. 

• In addition to that snake venoms contain inorganic cations like Na, calcium, potassium, Mg and little amounts of Zn, nickel, cobalt, iron, manganese. 

• Zinc is important for anti-cholinesterase activity; Ca is needed for activation of accelerator like phospholipase. 

• Some snake venoms conjointly contain carbohydrate, lipid, biogenic amines, and free amino acids. 

• Snake venoms contain a minimum of twenty five enzymes, however no single venom contains all of them. 

• Enzymes are protein in nature, however few are depends on bound nonprotein prosthetic teams or cofactors.

 

Photo credit: Snake Venoms in Drug Discovery: Valuable Therapeutic Tools for Life Saving - Scientific Figure on ResearchGate. [accessed 12 Jun, 2020]

FAD APPROVED DRUGS BY SNAKE VENOM 

[accessed 13 Jun, 2020]

MECHANISM OF SNAKE VENOM IN ROLE OF CANCER

• ANTI-ANGIOGENESIS 

Human neoplasm growth is among neovascularization to supply essential nutrition and oxygen. development supports neoplasm cell extension and invasion into close normal tissue and is needed to distant metastasis.

Leucurogin, a disintegrin cloned from Bothrops leucurus (white-tailed-jararaca), showed important malignant tumor activities was assessed and confirmed by the sponge implant model in mice.

Adinbitor may be a disintegrin cloned from Agkistrodon halys brevicaudus stejneger with seventy three organic compound residues as well as twelve cysteines and a RGD motif. 

Contortrostatin may be a homodimeric amide isolated from the venom of agkistrodon contortrix contortrix showed anti-angiogenic activity against the primary neoplasm of human carcinoma MDA-MB-435 carried in mice.

Salmosin was pure from the venom of agkistrodon halys brevicaudus in 1998. 

Salmosin considerably suppressed the expansion of each the pathological process and solid neoplasm in mouse xenografts of Lewis lung cancer cells, and also the neoplasm specific antiangiogenic activity of 

salmosin was thought-about concerning the blockade of αvβ3 integrin

• CYTOTOXICITY 

Cytotoxic snake venoms target specific cellular sites. 

These cytotoxins will act with lipoproteins present within the cytomembrane of cells to cause shrinkage. Thus, the cytotoxic effects of venom elements have the potential to degrade/destroy growth cells. 

Elapid venoms is possessed considerably cytotoxicity towards each B16F10 malignant melanoma and sarcoma cell lines than that of viperid or crotalid venoms. serpent venoms noncontinuous the cytomembrane resulting in death. 

Currently, cancers are one in all the main public health issues round the world and finding new cancer treatments may be a major analysis focus worldwide. 
Many excellent publications characterised the utilization of venom compounds from 

• bothrops newweidii
• Naja naja
• Naja nigricollis
• Naja naja atra
• Bothrops leucurus
• Laticauda semifasciata Opiophagus hannah
• Bothrops jararacussu
• Daboia russelli russelli
• Lapemis curtus
• Bungarus multicinctus
• Walterinessia aegyptia
• Crotalus durissus terrificus
• Agkistrodon acutus
• Macrovipera lebentina 
• Bungarus fasciatus
• Lachesis muta muta
• Agkistrodon rhodostoma 

for the treatment of varied conditions to incorporate cancer and inflammation. 

Accessed [13 june 2020]

• APOPTOSIS 

Apoptosis could be a method of programmed cell death to delete unnecessary cells in normal tissues and to stay cellular equilibrium.

In 1993, Araki et al. found that some haemorrhagic snake venoms evoked programmed cell death of vascular  epithelial tissue cells.

Zhang et al. isolated ACTX-6 (98 kDa proteins containing 2 subunits) from Agkistrodon acutus venom. 

The Zhang et al. found that ACTX-6 may induce cell programmed cell death and conjointly rumored that reactive O species (ROS) was concerned in apoptosis generated by oxidization of L-amino acid by ACTX-8. ACTX-8 has no activity on antiapoptopic /proapoptopic BCL2 members of the family. 

It works by principally 2 mechanisms: 

• Firstly by translocation of Bax and bad 
• second action was on bad bound to Bcl-xL to substitute Bak. 

The activated Bax and Bak compete a vital role within the unleash cytochrome to mediate programmed cell death. 

The induction of the programmed cell death manifests the management on the neoplasm size and range of tumour cells thence establishing the applying of apoptotis inducers as important parts within the treatment of cancer. Torii et al. refined an apoptosis-inducing issue, apoxin I from pit viper venom and amino-terminal sequences of the refined apoxin-I kind of like L-amino acid oxidases (LAAO). 

LAAOs from snake venoms have progressively been shown to induce programmed cell death.
Suhr et al. prompt that the activity of apoptosis induction of LAAO wasn't alone because of the assembly of H2O2 within the reaction of LAAO

After creation of the first structure of apoxin-I by exploitation cloned c-DNA, the authors incontestible that apoxin-I doubtless to bind furore to catalyse oxidative deaminization of L-amino acids and programmed cell death causing activity. 

NEWER DRUG DELIVERY SYSTEM

One of the plausible ways to develop clinical anti-cancer versions of cytotoxins is to conjugate the medication with monoclonal antibodies that acknowledge and bind to specific epitopes on malignant cancer cells.

Zhao et al. used an anti-nasopharyngeal cancer antibody BAC5 conjugated with the venom of the Chinese cobra, that showed sturdy effects against nasopharyngeal cancer cells in vitro

Al-Sadoon et al. incontestable  that the venom extracted from Walterinnesia aegyptia (WEV) combined with silica nanoparticles (NP) will inhibit the proliferation of human breast cancer cell lines and powerfully induced  cell death without vital effects on normal breast epithelial MCF-10A cells.

OTHER MEDICINAL PROPERTIES OF SNAKE VENOM

Accessed [12 June 2020]

CONCLUSION 

Venom from snakes is a vital agent for curing many varieties of cancers. 

Combination of snake venoms with different technologies like nanoparticles continues to be at its early stage for cancer therapy and it are often expected that a lot of combinatory treatment can emerge. 

Snake venom acts by inhibiting cell proliferation and promoting cell death by totally different means: 

• Induction of programmed cell death in neoplastic cell
• Increasing Ca2+ influx
• Inducement cytochrome c release
• Decreasing or increasing the expression of proteins that management cell cycle; causing harm to cell membranes.

Snake venoms aren't any doubt valuable resources for antineoplastic development.

REFERENCE 

• Vivek Kumar Vyas,Keyur Brahmbhatt,Hardik Bhatt,and Utsav Parmar.Therapeutic potential of snake venom in cancer therapy: current. 2013 Feb; 3(2): 156–162. Available  at URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627178/#__ffn_sectitle
• ABD EL AZIZ, Tarek & Soares, Garcia & Stockand,. (2019). Snake Venoms in Drug Discovery: Valuable Therapeutic Tools for Life Saving. Toxins. 11. 564. 10.3390/toxins11100564 
• Li, L.; Huang, J.; Lin, Y. Snake Venoms in Cancer Therapy: Past, Present and Future. Toxins 2018, 10, 346. Available at URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162746/ [cited at 12 June 2020]
• Figure 1 photos taken from 
• https://www.cancercenter.com
• https://www.medicaldaily.com