Snake Venom Protein Paralyzes Cancer Cells - Research Paper Example

Snake Venom Protein Paralyzes Cancer Cells Introduction Snake venoms are basically the secretion of poisonous snakes, which are produced, as well as stored in particular regions of their body as the venom glands (Alama et al., 2011). A majority of the venoms are multifaceted mixtures of numerous proteins, toxins, enzymes, peptides and non-protein inclusions (Finn, 2001). A lot of these proteins are harmless, but when mixed together, they can generate toxicity at certain level. Venoms lead to significant morbidity and mortality the world over, and cause fear in humans (Alama et al., 2011). These days, cancer treatment is a huge hurdle to the medical society. Present ways of treatment are awfully expensive and have a lot of side effects to patients; mentally, economically as well as physically (Finn, 2001). A number of the elements of snake venom lead to cancerous cell growth retardation. Snake venom, on the other hand, might be a fundamental nominee for the cure in the future for a lot of diseases and body disorders because of its remedial potency and activity together with its availability. Observing and studying with revolutionary prospectus in pharmaceutical perspectives, snake venom could pay way for fresh age of medicines, as well as the research for treatment of cancer among other illnesses (Alama et al., 2011). Snake venoms are often studied by scientists and researchers for its therapeutically/remedial application (Finn, 2001). Numerous outstanding publications distinguished use of venoms for the healing of a range of therapeutic conditions as inflammation and cancer (Finn, 2001). This article will review recent literature regarding a therapeutic potential of snake venom in an endeavor to develop a scientific basis for use of snake venom for treatment of cancer. Elements of Snake Venom Venoms of snakes are multifaceted mixtures; largely it has proteins that have enzymatic actions. Peptides and proteins formulate 90 to 95% of the dry weight of venom. Besides that, venoms have inorganic cations such as calcium, sodium, magnesium, potassium as well as small amounts of nickel, zinc, cobalt, iron and manganese (Alama et al., 2011). Zinc is vital for anti-cholinesterase action; calcium is needed for activation of enzymes such as phospholipase. A number of snake venoms also comprise of carbohydrate, biogenic amines, lipid plus free amino acids (Finn, 2001). Venoms comprise of at least 25 enzymes, but no venom comprises of all these enzymes. Enzymes are basically protein in nature, but very few of them are reliant on particular non-protein prosthetic cofactors or groups. These elements in summary are Arginine ester hydrolase, Proteolytic enzymes, Thrombin-like enzymes, Thrombin, Hyaluronidase, Collagenase, Phospholipase, Acetylcholinesterase, Phosphodiestsrase, RNase, DNase, L-Amino acid oxidase (L-AAO), 5′-Nucleotidase, Polypeptides and L-Actate dehydrogenase (Alama et al., 2011). These elements catalyze tissue proteins and peptides breakdown. The majority of them have molecular weights that range from 20 000 to 95 000 Da (Finn, 2001). They might, at times, be inactivated by edetic acid along with some reducing agents. Some metal ions assist in catalysis and essentially concerned in the action of various venom proteases, as well as phospholipases. Thrombin like enzymes, for instance, agkistrodon, crotalase, batroxobin and ancrod, can be cleansed from diverse snake venoms (Finn, 2001). They have been applied clinically in different animals for investigative and therapeutic studies (Alama et al., 2011). Cure with ancrod prior to the creation of the experimentally stimulated thrombus in dog, blocked thrombosis and guaranteed vessel patency. Nevertheless, ancrod lacks thrombolytic impact following thrombus formation. Crotalase has been used to assess the part of fibrin deposition in animals in burns (Alama et al., 2011). The function of fibrin deposition has been assessed in cancer metastasis, wherein fibrinogen removed by management with batroxobin and ancrod. Hyaluronidase, in particular, are thought to be associated with the extent of edema generated by the poison. It acts on connective body tissues and hinders their viscosity, hastens the cleavage of glycoside bonds in a number of acid mucopolysaccharides (Alama et al., 2011). Collapse in the hyaluronic blockade permits other fractions of snake venom to infiltrate the tissues. Also, many PLA2 were discovered in snake venoms (Finn, 2001). It has nearly 120 amino acids along with 14 cysteine remains establishing 7 disulfide bonds. Snake venoms are known to be the richest sources of Phospholipase (Egleton et al., 2009). It fastens the calcium chemical bond of 2-acyl ester thus creating free fatty acids, as well as lysophospho lipid (Alama et al., 2011). Also, Phospholipase can cause chemical bond of membrane phospholipids, as well as liberation of a number of bioactive products. Phosphodiestsrase, on the other hand, perform as an exonucleotidase and liberate 5-mononucleotide from polynucleotide chains, thus impacting RNA and DNA functions (Egleton et al., 2009). It is seen in every poisonous snake. Acetylcholinesterase is found in sea snakes and cobras but absent in crotalid and viperid venoms (Alama et al., 2011). It fastens the chemical bond of acetylcholine to acetic acid and choline. Finally, 5′-Nucleotidase is the most dynamic phosphatase in venoms that also hydrolyzes phosphate monoesters connected to a 5′ position of DNA and RNA (Alama et al., 2011). Clinical Attempts of Snake Venom Numerous toxins from venom are studied and formulated into vaccines for the treatment of such conditions as cancer, thrombosis and hypertension (Egleton et al., 2009). Generally, rattlesnake venoms and other fresh world crotalids create alterations in opposition of blood vessels, transformation in blood cells, as well as coagulation mechanism, indirect or direct changes in pulmonary and cardiac dynamics. There might be changes in the respiratory system and nervous system (Alama et al., 2011). The strength of venom and its impact on human beings relies on the amount and type of the venom infused and the spot where it is dumped (Finn, 2001). Other factors such as general health, sex, age and size are influencing factors, as well (Alama et al., 2011). History and clinical experiments reveal that the death might happen in less than an hour to a couple of days whereas the majority of the deaths take place from 18 to 32 hours of the poison infusion (Egleton et al., 2009). Snake venoms considerably decrease the blood pressure in human being victims, as well as experimental animals. Shock and hypotension are connected to snake poisoning. Practically, it has been discovered that an intravenous bolus insertion of a Crotalus poison leads to an instant fall in blood pressure along with ranging degree of shock, related to the initial heme absorption followed by a drop in heamatocrit standards (Alama et al., 2011). Captopril was cut off from Bothrops jararaca toxin, which is a therapeutic case, anchored in the snake venoms. Enhanced blood amount in the pulmonary artery and pressure in the lung with related cut in pulmonary artery stream and a rather stable heart stroke volume are witnessed. When Crotalus venom is specified slowly for in a time of 30 minutes, there is hypovolume resultant to a raise in capillary permeability to RBCs and proteins (Alama et al., 2011). The investigational results revealed initial lactacidamiea, lipoprotienamia and haemoconcernatration. Respiration, on the other hand, becomes labored and if time prolongs, then people becomes oliguric, rales develop and then the animal dies (Finn, 2001). According to Finn (2001), the integrins are a group of transmembrane receptor proteins, which attach to extracellular matrix elements. One of their biggest functions is to hold the extracellular matrix, offering traction and permitting cells to travel from one location to another. Scientists in numerous research institutions are centering on one integrin in particular, referred to as αvβ3 (Finn, 2001). This integrin exists on the cancer cell surface and is believed to be vital in metastasis (Finn, 2001). Contortrostatin seems to obstruct cell migration both through attaching to a surface cell protein in the integrin group, stopping it from enthralling the extracellular matrix, and through scrambling signals. Contortrostatin had very efficient inhibitory traits on bond to a number of such extracellular matrix proteins as vitronectin and fibronectin. It is efficient in blocking tumor cell raid (Alama et al., 2011). By utilizing human ovarian cancer cells, as well as human breast cancer cells, in immunodeficient rats provided daily intratumor shots of contortrostatin, it inhibits angiogenesis and tumor dissemination (Egleton et al., 2009). In addition, the side effects are relatively minimal (Finn, 2001). There is some discharge at the region of the injections particularly in breast cancer models. And in ovarian cancer models, scientists have seen some petechiae, also known as hemorrhagic spots, which create an anti-platelet impact. In addition to its on platelets, there have also been least or no side effects, and surely there has been no proof of inner hemorrhaging (Alama et al., 2011). Snake Venom and Cancer Therapy Cancer is typified by unrestrained cell transformation, cell division and release of apoptosis, angiogenesis, invasion and metastasis (Egleton et al., 2009). Introduction of apoptosis is one of the most significant mechanisms of numerous anticancer agents (Alama et al., 2011). Snake venom disintegrins, on the other hand, are the short molecular weight molecules with diverse potency, structure and specificity originally secluded from viperid venoms, typically hold integrin, a cause of growth of remedials for cancer treatment (Alama et al., 2011). Integrins are significant in cell migration, cell adhesion, tissue organization, hemostasis, cell growth, as well as inflammatory responses, thus they are in the research for the creation of drugs for cancer treatment. Alama et al. (2011) removed ACTX-6 from Agkistrodon acutus snake venom. They found out that ACTX-6 could prompt cell apoptosis. The authors argued that ROS - reactive oxygen species - was concerned in apoptosis caused by ACTX-8 through the corrosion of L-amino acid. ACTX-8 has no action on proapoptopic/antiapoptopic BCL2 group. It works by mostly two mechanisms: initially by translocation of Bad and Bax and then the action on Bad to bind to Bcl-xL to replace Bak. The stimulated Bak and Bax played a vital role in the discharge cytochrome C to intercede apoptosis (Alama et al., 2011). The introduction of apoptosis marks the tumor size control and tumor number cells. It establishes the use of apoptotis inducers as fundamental components in the handling of cancer. Tirosh et al. (2013) cleansed an apoptosis-inducing element, apoxin I from rattlesnake venom together with amino-terminal series of the cleansed apoxin-I resembling L-amino acid oxidases. Following formation of the main arrangement of apoxin-I through applying replicated c-DNA, Tirosh et al. (2013) showed that apoxin-I is ready to bind FAD to accelerate L-amino acids oxidative deamination and apoptosis inducing action. Lucena et al. (2011) removed and cleansed L-amino acid oxidases from Bothrops leucurus and accounted for biochemical elements of Bl-LAAO related to its impacts on cytotoxicity and platelet function. Cytotoxicity of Bl-LAAO can be seen in stomach cancer MKN-45, colorectal RKO, adeno carcinoma HUTU, as well as LL-24 cell lines of human fibroblast. Lucena et al. (2011) main point was that venom B. leucurus is cytotoxin performing mainly through the production of high volumes of H2O2 that murders the cells. Vyas et al. (2013) cleansed king cobra venom, Ophiophagus Hannah, and studied the cytotoxic elements in cleansed venom. The elements were mostly reliable of L-amino acid oxidase. Vyas et al. (2013) uncovered cytotoxic impacts of L-amino acid oxidase mainly on murine melanoma, stomach cancer, colorectal cancer, fibrosarcoma as well as Chinese hamster ovary cell lines. It was witnessed that cytotoxic protein leads to inhibition of cell propagation by 74% (Vyas et al., 2013). Mechanism of enzyme action may be connected to the inhibition of thymidine amalgamation and contact with DNA. Alama et al. (2011) also studied both in vivo and in vitro antitumor action of BPB (p-bromophenacyl bromide) customized bothropstoxin-I from BthTX-I (Bothrops jararacussu venom). Diverse tumor cell lines were seen to vulnerable from lytic activities of BPB-BthTX-I plus also from artificial peptide. Vyas et al. (2013) researched pharmacokinetics of cytotoxin from Naja naja atra (Chinese cobra) venom in robents. Plasma heights of the cytotoxin were studied by a biotinavidin enzyme-connected immunosorbent test. Vyas et al. (2013) also cleansed a deadly cardiotoxic-cytotoxic protein from the Naja kaouthia (Indian monocellate cobra) venom through ion-exchange chromatography plus HPLC. Cytotoxicity researched on human leukemic K562 and U937 cells revealed a vital inhibition of cell propagation in a dose and period dependent way. In another study, Egleton et al. (2009) cleansed venom from Indian Naja naja by chromatography (ion exchange) and discovered that fraction 32 formed cytotoxic-cardiotoxic characters. NN-32 revealed cytotoxicity on EAC human cells, enhanced survival period of immunized EAC mice, abridged hard tumor volume as well as weight. Egleton et al. (2009) argued that NN-32 provoked anticancer action in EAC rats mediated by its apoptogenic-antioxidant trait. Spindel (2009) isolated and typified a BJcuL (lectin) from Bothrops jararacussu venom. The author studied in vitro effect of the lectin on bond with human ovarian, as well as breast cancer carcinoma cells and feasibility of such cell lines, together with human bladder carcinoma, human glioblastoma, bovine brain endothelial cells and human leukemia. BJcuL was marked as a strong inhibitor of development of some tumor cell lines plus an endothelial cell line. Spindel (2009) also separated ACTX-6 from Agkistrodon acutus venom and revealed cytotoxic activity to a range of cancer cells in vitro. The authors investigated the exact mechanism (induce cell apoptosis) of ACTX-6. Spindel (2009) reported that the ACTX-6-provoked cell death by manufacture of hydrogen peroxide (ROS). Egleton et al. (2009) removed particular protein OHAP-1 (Okinawa Habu apoxin protein-1) from Okinawa Habu venom that is well recognized for its poisonous effects. In this research, it was studied how OHAP-1 could encourage apoptosis in a number of glioma cells and clarified the probable mechanism concerned. Introduction of apoptosis was decided by using gel electrophoresis of the DNA, TUNEL assay and DNA flow cytometry. It was accounted that apoptotic impact of OHAP-1 on glioma cells might be via the cohort of p53 protein expression and intracellular ROS. Lucena et al. (2011) assessed antitumor action of the Lapemis curtus (sea snake venom) against EAC (Ehrlichs ascites carcinoma) in Hep2 and HeLa tumor cell cultures and Swiss albino mice. Drop in tumor volume and feasible tumor cell count was seen in these traits were regarded as a vital indicator of reduction of tumor weight. Egleton et al. (2009) assessed snake venom and RGD arginine-glycine-aspartic acid-controlling disintegrins (for instance, rhodostomin), which reserved the bond of prostate and breast carcinoma cells to bone extracellular surroundings, devoid of impacting the practicability of tumor cells. It was accounted that direction of a disintegrin with tumor cells reserved tumor development in bone by the cut of migration, cell adhesion plus osteolysis in bone. Alama et al. (2011) cleansed and crystallized heat steady protein toxin (drCT-I) from Daboia russelli snake venom. drCT-I was assessed for anticancer action against EAC cells in vitro human leukemic cells (K562, U937) and in vivo. drCT-I considerably dropped EAC cell count. Alama et al. (2013) established introduction of apoptosis. It was seen that drCT-I created apoptosis through G1 phase seizes of the cell sequence. Vyas et al. (2013) separated cardiotoxin III, from Naja atra snake venom, and accounted for its anticancer action. It was witnessed by buildup of sub-G1 populace, phosphatidylserine externalization, cytochrome C release, as well as activation of both caspase-3 and -9, which CTX III-provoked cell apoptosis. Conclusions Venoms of snakes are complex mixtures of numerous physically active proteins, enzymes, peptides and organic, as well as inorganic compounds. Venom is a significant agent for healing many forms of cancers. A lot of the research publications listed in this paper revealed an entire remission of tumor cells following healing with molecules founded on snake venoms. It has been assessed in many articles, which argue that snake venom acts through inhibiting cell proliferation plus promoting cell death by diverse means: introduction of apoptosis in a cancerous cell, rising Ca2+ invasion; encouraging cytochrome C release; increasing or decreasing the expression of proteins, which manage cell cycle, and causing harm to cell membranes. Snake venoms have many components, most which act upon the minor nervous system for immobilizing or murdering prey. We can expect the progress of a fresh agent from venoms in the future that will be helpful in cancer therapy. References Alama, A., Bruzzo, C., Cavalieri, Z., Forlani, A., Utkin, Y., Casciano, I., & Romani, M. (2011). Inhibition of the nicotinic acetylcholine receptors by cobra venom α-neurotoxins: Is there a perspective in lung cancer treatment? Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113800/ Egleton, R. D., Brown, K. C., & Dasgupta, P. (2009). Angiogenic activity of nicotinic acetylcholine receptors: implications in tobacco-related vascular diseases. Pharmaceutical Therapy, 12(1), 205–223. Finn, R. (2001). Snake venom protein paralyzes cancer cells. Retrieved from http://jnci.oxfordjournals.org/content/93/4/261.full Lucena, S., Sanchez, E. E., & Pereza, J. C. (2011). Anti-metastatic activity of the recombinant disintegrin, r-mojastin 1, from the Mohave rattlesnake. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293478/ Spindel, E. R. (2009). Is nicotine the estrogen of lung cancer? American Journal of Respiratory and Critical Care, 179(3), 1081–1082. Tirosh, Y., Ofer, D., Eliyahu, T., & Linial, M. (2013). Short toxin-like proteins attack the defense line of innate immunity. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737499/ Vyas, V., Brahmbhatt, K., Bhatt, H., Parmar, U., & Patidar, R. (2013). Therapeutic potential of snake venom in cancer therapy. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627178/ Read More