Scorpion Venom–Toxins that Aid in Drug Development: A Review
Published: 05 June 2018
https://link.springer.com/article/10.1007/s10989-018-9721-x
Abstract
Scorpion venom components have multifaceted orientation against bacterial, viral, fungal infections and other neuronal disorders. They can modulate the ion channels (K+, Na+, Cl-, Ca2+) of our body and this concept has been hypothesized in formulating pharmaceuticals. The triumphant achievement of these venom components as formulated anticancer agent in Phase I and Phase II clinical trials allure researchers to excavate beneficial venom components prohibiting DNA replication in malignant tumor cells. This review brings forth the achievements of Science and Technology in classifying the venom components as therapeutics and further application in drug product development.
Some select paragraphs:
As Antineoplastic Agent
Natural therapy, be it plant or animal derived, is occupying a vast section gradually as antineoplastic or cytotoxic agent due to the increasing uncontrollable adverse effects and ineffectiveness (possibly in metastasis and recurrence conditions) of chemotherapy and radiotherapy. The last three decades have seen attempts at detecting promising anticancer activity of animal venoms and toxins, some of which are presently under clinical trial (Lorenzo et al. 2012). Scorpion venom can be an amazing therapeutic agent against cancer as it inflicts upon cancer cells by arresting cell cycle at the S-phase thereby acting as a proliferative curb (Lorenzo et al. 2012; Ahluwalia and Shah 2014). SVTs are an inducer of apoptosis, aggravates neoplastic cells by amplifying production of nitric oxide, shows caspase-3 activity and depolarizes mitochondrial membrane (Ahluwalia and Shah 2014). Presently, positive results from in-vivo, in-vitro examination and Phase I and II clinical trials have proven SVTs as anticancer therapeutic agent (Kastin 2006). Cuba and Dominican Republic islands dwelling Blue (or Red) Scorpion (Rhopalurus junceus) is steadily gaining fame as an antineoplastic (Podnar 2015; Lorenzo et al. 2012) and is the thrust area for inquisitive researchers as numerous experiments are being executed on this arthropod to evaluate its pharmacological aspects. A protein constituent of this scorpion can abolish cancer cell proliferation (Ahluwalia and Shah 2014). Natives of the Caribbean island have been using this venom as an antitumor agent since 1997 (Podnar 2015). Novel discovery elucidates venom of this scorpion acts as a pain reliever and replenisher of energy in cancer patients (Lorenzo et al. 2012). A recent research work proposed by Díaz-García et al. (2017) on treatment recalcitrant Triple Negative Breast Cancer (TNBC) cell line (MDA-MB-231) demonstrated high cytotoxic activity of this arthropod venom breaking grounds for new therapeutic approaches (Díaz-García et al. 2017).
Traditionally used, venom of BMK scorpion is a possessor of multiple pharmacological activities including cancer and brain tumor (found effective against brain tumor cell line U251-MG) (Gomes et al. 2010; Díaz-García et al. 2013). Antitumor-analgesic peptide (AGAP) obtained by the application of recombinant DNA technology from this scorpion venom and expressed in Escherichia coli have confirmed to have both analgesic and antitumor activity in mice (Hmed et al. 2013). This peptide in a much lower dose compared to other antineoplastic agents has revealed of increasing antitumor activity with very few adverse effects (Oukkache et al. 2013). It can inhibit glioma cell proliferation by regulating their ion channels (Gomes et al. 2010). A peptide isolated from this scorpion has proven to be an anti-thrombotic (Petricevich et al. 2013) and another polypeptide having dose-dependent inhibitory activity arrested cell cycle of prostate cancer cell line DU-145 at G1 phase (Mishal et al. 2013; Zhang et al. 2009). Antiapoptotic role of this polypeptide can be due to highly expressed Bax (proapoptotic) or downregulated Bcl-2 (antiapoptotic) (Zhang et al. 2009). BMHYA1, an enzyme procured by extraction and purification from this scorpion hampers overexpression of CD44 surface marker in cancer cells (Hmed et al. 2013).
Scorpion venom component III (SVC III) has profound activity on the NF?B signaling pathway (has role on immunocyte generation, lymphocyte development and cell apoptosis) and thus selectively act upon human leukemia Jurkat cell line and THP-1 cells (Mishal et al. 2013). SVC III prevents cyclin D1 production and inhibits cell cycle at G1 phase (Mishal et al. 2013). Venom derived from Odontobuthus doriae is capable of platelet aggregation and possesses proteolytic enzymes (Mishal et al. 2013). It is a cytotoxic and apoptogenic agent as it has lactase dehydrogenase (LDH) (Mishal et al. 2013). This LDH can lower cell viability activating caspase-3 and mitochondrial depolarization (Ahluwalia and Shah 2014). Proteases derived from scorpion Mesobuthus gibbosus are proteolytic and gelatinolytic against human lung adenocarcinoma cell line (A549) (Mishal et al. 2013). An extensive research on venom from Blue Scorpion has drawn a conclusion that it can be an analgesic, anti-inflammatory and antitumor agent (Podnar 2015). To support this research, a drug named Vidatox 30CH has been formulated by Labiofam (a Cuban company) which reports of lessening the spread of cancer cells, increase life expectancy among cancer patients and has negligible side effects on patients (Podnar 2015). This scorpion venom induces apoptosis in HeLa cell line via both extrinsic and intrinsic pathway as p53 upregulation stimulates bax and downregulates bcl-2 (Díaz-García et al. 2013). A549 cell necrosis, as demonstrated by Díaz-García et al. (2013) was noticed along with p53 and bax downregulation when this scorpion venom was further examined (Díaz-García et al. 2013). Demetrio Rodriguez Fajardo, a 17-year-old Mexican has gained enough recognition by discovering a low molecular weight protein from scorpion venom and has developed a prodrug that can be used as a treatment against breast cancer (Takahashi 2014). He has even quoted that this protein has profound inhibitory activity on uterine cancer cells. This protein as a drug substance in the treatment of cancer is efficacious than conventional therapy even for diabetic patients (Takahashi 2014).
Future Prospects in Drug Discovery
The increment in newer techniques in the field of Research and Development (R&D) have led scientists to brood over to find cure from nature be it from plant or animal. A rough estimate brings forth the fact encompassing constant usage (nearly 40%) of Nature in the formulation of pharmaceuticals (Burke 2015). With the evolution of proteomics, genomics and transcriptomics, drug discovery from Nature and her resources has been a splendid approach. Though only a handful of ‘biologically important’ toxins could be derived from toxin-secreting animals still it calls for a revolution to fetch cure from these animals. Thus, it is mandatory to gain a thorough knowledge of the evolutionary history and the ecology of these animals before putting them into practice for the development of future pharmaceuticals (Casewell et al. 2013).
The process of establishing a chemical entity as a clinical candidate is an enormous and time-consuming process. Thousands of potential candidates are screened and only a few with potentialities emerge to face challenges in the pharmaceutical market. Till date, only a few venom peptide derived drugs have been approved by the FDA and furthermore are undergoing clinical trials or at the stage of preclinical development (Henney 2015). Captopril, ziconotide, atracurium, eptifibatide are some of the established drug products formulated from venom toxins (Harvey 2014). The synergistic property exhibited by K+ salt and peptide (scorpion prevenom and venom constituents) indicates the discovery of effective pharmaceuticals in the near future (Inceoglu et al. 2003).
Drugs and pharmaceuticals tend to have an affinity towards the ion channels of our body in conserving human physiology and usually, therapeutic advancement is being made by targeting these channels (Bennett and Guthrie 2003; Kaczorowski et al. 2008). Venom peptides being reservoir of chemical components are the tools to identify or characterize the function and structure of ion channels of our body. The rationale underlying the choice in targeting ion channels lies in their increased accessibility and success in delivering intended pharmacological activity upon being targeted by traditional or novel drug (Kaczorowski et al. 2008; Niemeyer et al. 2001). The failure of a drug candidate or an new drug application (NDA) often lies in the interaction with unrelated targets or channels (Kaczorowski et al. 2008). The key to ion channel drug discovery is embedded in the approaches that include in-vivo, in vitro targeting by the candidate drug product and other traditional drugs. Ziconotide, one such example, was developed to treat pain induced by intrathecal administration and by in vivo methods, was hence confirmed to treat pain as a calcium channel blocker (Kaczorowski et al. 2008).
