REVIEW ARTICLE


https://doi.org/10.5005/jp-journals-10015-2041
World Journal of Dentistry
Volume 13 | Issue 3 | Year 2022

Venoms and Oral Cancer: A Mini-review


Gargi Sarode1, Urmi Ghone2, Pranali Dhirawani3, Maithili Manohar4, Sachin Sarode5, Namrata Sengupta6, Sourav Sudrania7, Shankargouda Patil8

1-7Department of Oral Pathology and Microbiology, Dr DY Patil Dental College and Hospital, Dr DY Patil Vidyapeeth, Pune, Maharashtra, India

8Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Kingdom of Saudi Arabia

Corresponding Author: Gargi Sarode, Department of Oral Pathology and Microbiology, Dr DY Patil Dental College and Hospital, Dr DY Patil Vidyapeeth, Pune, Maharashtra, India, Phone: +91 9823871462, e-mail: gargi14@gmail.com

ABSTRACT

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies in the world. The commonly employed treatment plan for OSCC is surgery followed by radiotherapy or chemotherapy or both. These conventional therapies are widely accepted but they have certain side effects and perilous consequences. The main drawback of these treatment regimes is nonspecific cell death. Recent advances in oral cancer therapies have shown that some natural compounds, especially animal venoms, offer potentially effective anticancer and cancer-preventive properties. To overcome the harmful effects of conventional therapies, these natural products can be considered as promising safe substitutes for the currently used regimes. This article discusses various potential bioactive animal venoms studied for OSCC therapy. Further extensive research in this field will open new gateways in OSCC therapeutic options.

How to cite this article: Sarode G, Ghone U, Dhirawani P, et al. Venoms and Oral Cancer: A Mini-review. World J Dent 2022;13(3):294-299.

Source of support: Nil

Conflict of interest: None

Keywords: Animal venoms, Bioactive compounds, Conventional cancer therapies, Natural derivatives, Oral cancer, OSCC

INTRODUCTION

Oral cancer is one of the most common malignancies in the world with a high prevalence in developing countries and treating it is the biggest challenge for the oral oncology fraternity.1,2 The main drawback of current oral squamous cell carcinoma (OSCC) therapies like radiotherapy, chemotherapy, photodynamic therapy, surgery, COX-2 inhibitors, and EGFR inhibitors is nonspecific cell death.3 It has been found out that natural products offer potentially effective anticancer and cancer preventive drugs. Some bioactive natural compounds, by targeting different pathways and signaling molecules are capable of preventing and treating cancers.4 It is expected that with the introduction and modification of recent technologies, the medical field will be able to recognize and develop safe and efficacious anticancer and cancer preventive drugs. In this article, various bioactive animal venoms used for OSCC therapy have been discussed.

Conventional therapies to treat OSCC are widely used and well-accepted along with certain risk factors associated with them. Almost all patients encounter serious consequences due to these conventional therapies, sometimes fatal.3 Thus, in recent times, natural compounds4 are being studied thoroughly to make them a safe substitute or an adjunct therapeutic option for conventional therapies of OSCC. Some of the compounds are found to be useful for diagnostic purposes as well. One of such natural compound groups which are being exploited is animal venoms, which are being explored and their effects on oral cancer cell lines are being reported recently in the literature. These natural derivates may prove promising in substituting or adjunct the commonly used therapies with lesser side effects and serious consequences. Different kinds of animal venoms have now become the research hotspots in the quest of finding a safe and cautious therapy for oral cancers. Therefore, this present review highlights and discusses various animal venoms and their mechanisms of action in the treatment of OSCC.

Types of Venoms and Their Mechanisms of Action

Scorpion Venom

Mesobuthus martensii is a scorpion species in the family Buthidae. It is a Chinese scorpion common in Eastern Asian countries. The first aim of the venom is voltage-dependent ion channel among which sodium channels are widely explored. It is also reported to possess antitumor properties.5 BmK venom is composed of carbon (45.58 %) hydrogen (5.83%), oxygen (15.21%), and sulfur (28.8 ~ 29.2%).6,7 The toxins isolated from BmK can be divided in 2 classes: α toxins (BmK I and BmKα IV) and β toxins (BmK IT2 and BmK AEP).8 Studies have shown that the venom causes selective cell death, that is, it destroys only the cancerous cells exclusively by inducing apoptosis through p53 dependent apoptotic pathways.9 Scorpion venoms penetrate the plasma membrane of tumor cells and arrest the cancer cell growth and metastasis in vivo as well as in vitro.10 The mechanism of action of Buthus martensii on KB and HSC4 cell lines is as follows (Flowchart 1 and Fig. 1).

Flowchart 1: The mechanism of action of Buthus martensii on KB and HSC4 cell lines

Fig. 1: Effects of BmKn-2 on tumor cells

Chlorotoxin-Indocyanine Green Conjugate–BLZ 100 from another species Leiurus quinquestriatus (deathstalker) is a derivative of chlorotoxin. An experimental study was performed to measure fluorescence produced by BLZ 100. Subcutaneous injection of BLZ 100 was given in the cheek pouch of Golden Syrian hamsters and dysplasia was induced using 7,12-dimethylbenz(a)anthracene, a carcinogen. Measurement of fluorescence uptake was done and it was found that BLZ 100 can be used as a specific and sensitive marker for head and neck squamous cell carcinomas. It is capable of differentiating low from high-risk dysplasia. It can assist as an intraoperational guide for the excision of tumor margin and can also be helpful in premalignant lesion identification.11

  • Advantages of scorpion venoms: The potential therapeutic applications of scorpion venom other than OSCC are: antibacterial, antifungal, analgesic, antiviral, immunosuppressive, and bradykinin potentiating.12

  • Disadvantages of scorpion venoms: Based on the intensity of the symptoms, the amount of venom injected is classified into three levels to avoid severe pathological side-effects and even death. They are classified as mild, moderate, and severe.13,14 Mild amount of injected dose shows local inflammatory reaction while moderate and severe may elucidate life-threatening systemic responses.12

Toad Venom

The desiccated secretions of skin glands of Bufo gargarizans is commonly used as a medicine in the East Asia.15 Telocinobufagin, marinobufagin, bufalin, bufotalin, and resibufogenin are the active components of toad venom. Toad venom binds to and inhibits sodium-potassium ATPase.16-18

The skin from toads secrete antitumor peptides and Bufalin has been tested on CAL-27 cell line. Bufalin reduces CAL-27 cell viability leading to the following sequence causing mitochondria-dependent apoptosis.19 It also increases synthesis of reactive oxygen species, damages DNA, and decreases expression of hTERT.

Bufalin induced cytotoxicity on SCC-4 human tongue cancer cells:

According to earlier experiments, bufalin-induced apoptosis and arrest of cell cycle in several human cancer cells have been observed.20-22 Nonetheless, at present there is no strong evidence present to show that bufalin can induce apoptosis in SCC–4 cell line.19 Along with a dose-dependent drop in the total percentage of viable cells,23-25 bufalin has been found to cause the following changes in the SSC–4 cells.

  • Morphological changes in the cell

  • Reduction in total cell viability

  • M/G2 phase arrest

  • Condensation of chromatin

  • DNA damage and fragmentation

  • Alteration of apoptosis-associated protein expression.

Bufalin and CAL-27:26 Bufalin markedly reduces the cell viability of CAL27 cells, 24 hours after being exposed in a concentration-dependent method. It restrains the multiplication of CAL27 cells by stimulating apoptotic cell death. On staining with DAPI and analyzing using a fluorescence microscope, exposure of CAL27 cells to 125nM of bufalin exhibited elevated levels of activated caspase-3, one of the central controllers of the apoptotic pathway. Bufalin has been found to arrest the growth of CAL27 cells via the AKT signaling pathway.

Toad venom has the following therapeutic advantages:

  • Cardio-tonic effect

  • Antiangiogenesis

  • Analgesic effect of anesthesia

  • Antibacterial effects.

Other than toad venoms, toad skin is also used as a raw material for drugs as it has detoxifying, pain-relieving, and antiviral properties stimulates bone marrow proliferation, boosts immunity, and reversal of multidrug resistance.27

Disadvantages of toad venom: Excess of anything results in side effects. The most common side effect is the addiction due to the psychedelic chemicals in the venom.

Chinese Blister Beetle Venom

Mylabris phalerata, Mylabris cichorii is a species of blister beetle, belonging to meloid family. Cantharidin is a biotoxin extracted from male blister beetles. Few vital products of CTD transfer are needed to be cancer-specific.28-30

Antitumor activity is exhibited by an active fundamental constituent from the blister beetle Mylabris, species Mylabrisph aleratapallas and the derivative called Norcantharidin, a demethylated form of Cantharidin (an active constituent).31 Cantharidin acts by induction of apoptosis by a p-53 dependent mechanism. Cantharidin breaks double and single-stranded DNA leading to oxidative stress. Thus, DNA damage is aggravated and p-53 dependent apoptosis is seen. The results showed inhibition of protein phosphatases PPP1R13B, 1 and 2A, regulatory subunit 13B pf PP1, and reduced generation of POS and DNA damage.32

Bee Venom

Apis mellifera is a European honeybee and its venom is frequently used in medicine. Melittin, a peptide of 26 amino acids is the important and active constituent of bee venom. It has several toxicological and pharmacological functions, which include hemolytic activity, antibacterial and antifungal activity, surface activity related to cell lipid membrane, and antitumor function.33

Bee venom (apitoxin) has gained the reputation of treating some immune-related diseases and recently, neoplasms also. The derivative is called melittin and has been used on CNE-2 and KB cells. As it is well known that tumors showing the presence of hypoxia are associated with poor prognosis and show resistance to the therapy. Tumor cells are capable of enduring hypoxic microenvironment because of hypoxia-induced factor-1. This favors growth, metabolism, tumor angiogenesis, and related gene transcription. Melittin causes apoptosis of cells, inhibition of cellular growth, and decreased VGF and HIF-1α expression and thus, has been related to hypoxia cell radioresistance. Thus, this melittin contributes to the radiosensitivity of hypoxic cell lines (HNSCC) through its antihypoxic activity and is seen as a capable radiotherapy sensitization agent.

The cell cytotoxic changes because of PLA2 activation by mellitin could be the principal pathway for anticancerous activity. The activation of caspase and matrix metalloproteinases causes apoptosis and hence is necessary for the melittin-induced antineoplastic effects. Melittin stimulates PLA2 which causes cell cytotoxic effects. This has been implied as the most important pathway for anticancerous activity.34

Therapeutic uses:35

  • Antiviral and antibacterial properties

  • Alzheimer’s disease treatment

  • Parkinson’s disease treatment

  • Anti-inflammatory properties.

It should be noted that there are frequent adverse effects of therapeutic bee venom use. Thus, bee venom treatment must be used carefully, and the assurance of the practitioner’s knowledge and practice should be considered.36

Snake Venom

Several snake species are medicinally important like Naja naja. The main components of snake venom are peptides and proteins and additionally have inorganic cations. Zinc is known and required for anticholinesterase property. Calcium is needed for stimulating the activities of enzymes (phospholipase). The venom may have carbohydrate, lipid, biogenic amines etc.37 Various compounds obtained from snake venoms are cytotoxic. They act by causing changes in the cellular metabolism which turns out to be fatal for the cancer cells. According to De Wys et al.,38 a decrease in the weight of the tumor, activated fibrinolysis, and defibrination resulted after the application of Ancrod (Agkistrodon rhodostoma derived polypeptide). Snake venoms comprise a compound named disintegrin. This compound causes inhibition of integrin-dependent platelet aggregation and cell adhesion.34

Najanajaatra venom comprises of a basic polypeptide Cardiotoxin III (CTX III).39 CTX III exerts cytotoxicity as explained in Figure 2. OSCC apoptosis induced by Agkistrodonacutus venom (AAVC-I) comprising component I is given in Flowchart 2.

Fig. 2: The mechanism of cytotoxicity exerted by CTX III

Flowchart 2: OSCC apoptosis by agkistrodon acutus venom (AAVC-I) comprising component I40

Pharmacological actions:

  • Neuroreceptor

  • Antitumoral

  • Cellular signaling

  • Antimicrobial.

Adverse effects:

  • Cytotoxicity

  • Neurotoxicity

  • Myotoxicity

  • Hemorrhage.

Spider Venoms

Most of the spiders have neurotoxin venoms. Latarcins from Lachesana tarabaevi (Mierenjagers, Zodariidae) central Asian spider venom, demonstrate antineoplastic property.8 There are four possible mechanisms as follows: absence of angiogenesis, invasion or metastasis, cell cycle arrest, and apoptosis leading to abrupt growth stoppage or blocking of specific transmembrane channel (Fig. 3). Moreover, membrane perturbing peptides found in certain ant venoms are promising candidates for serving as potential novel anticancer drugs.

Fig. 3: Mechanisms of action of spider venoms

Advantages of spider venoms:41

  • Antiarrhythmia

  • Antimicrobial, analgesic, antiparasitic, cytolytic, hemolytic

  • Inhibitory activity towards enzymes

  • Treatment of erectile dysfunction

  • Antimalarial

Commercially available venom toxins: There are a lot of other animals secreting venoms (cone snails, sea anemones, octopuses, sea stars, frogs, caterpillars, etc.) which might have therapeutic as well as pharmacological benefits which are yet to be explored. The table below mentions the approved toxin-based molecules from the animal venoms. Maximum approved toxin-based drugs are extracted from snakes due to large amount of venom produced by them and thus the availability42 (Table 1).

Table 1: Commercially available toxin-based therapeutic molecules
Brand name (molecules) Species (venom toxin origin) Binomial name Mechanism of action (MOA) Clinical use/ Cell lines used
Batroxobin (De fibrase) Brazilian lancehead snake Bathrops moojeni Cleaves Aα-chain of fibrinogen Defibrinogenating agent for thrombosis
Batroxobin (Plateltex-Act) Common lancehead snake Bathrops atrox Gelification of blood Human mesenchymal stem cells
Batroxobin- Fibrin sealant (Vivostat) Brazilian lancehead snake Bathrops moojen Cleaves Aα-chain of fibrinogen Tumor cell lines
Bee venom therapy (Apitox) Honeybee Apis mellifera Anti-inflammatory action, alteration of immune response Human hepatocellular carcinoma (HCC) cell lines
Cobratide (Ketongning, cobrotoxin) Chinese cobra Naja naja atra Blockage of nicotinic receptors Human embryonic kidney (293T) Mouse myoblast (C2C12) cell lines

From the above-discussed species and their secreted venom toxins the various mechanisms of action and their targets in cancer cells are as follows (Flowchart 3):

Flowchart 3: Various mechanisms of action of various venoms and their targets in cancer cells

  • Inhibiting cell proliferation

  • Increasing the expression of proapoptotic protein

  • Causing damage to cell membrane

  • Inhibition of P-53 gene

  • Increasing calcium influx

  • Disorganization of actin filament

  • Hypoxia

  • Hemostasis deregulation and caspase activation.

Thus, these compounds are difficult to isolate from the animals and expensive to make them available. Most of these animals are endangered or on the verge of extinction. Also, there is very little knowledge and awareness about the existence of their therapeutic benefits. Therefore, they are not yet implemented in routine practice for the desired treatment.

Drug Delivery

Toxins from bee venom are used as creams, liniments, ointments, injections, acupuncture, or also through live bee stings.43 Peptides derived from Naja species cobra venom is administered orally and is sanctioned by Europe and South America.44 Toxins from spider venoms are administered as subcutaneous or intravenous injections in rats and have shown modulation of voltage-gated sodium. A scorpion species, T. serrulatus venom has shown a promising intranuclear drug delivery tool to target cancerous cells.45,46

CONCLUSION

Great potential is shown by compounds derived from a natural source in treatment of oral cancer. Usually, traditionally used anticancer agents have unwanted side effects. Venomous animals secrete venoms from certain specialized parts of their body. Due to their selective anticancer activities, these naturally derived compounds would be of great significance in the field of cancer. A few natural compounds are also capable of preventing the formation of cancer by proactive measures like green tea catechins, panax ginseng, polygonum cuspidatum etc.47 Thus, the chemopreventive role of the mentioned venoms should also be studied explicitly. As described above, various compounds derived from the venom are still being studied under clinical trials and they can well be used to therapeutically treat cancer. One of the most exciting approaches for cancer treatment has been the combined usage of nanoparticles with venom. The various mechanisms of action through which these venoms act have been explained in detail in this article. Extensive exploration in this field is of utmost importance. These natural derivatives, especially the animal venoms, should be the limelight of future studies to open new gateways in cancer therapies.

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