SCORPION VENOM AND ITS COMPONENTS AS NEW PHARMACEUTICAL APPROACH TO CANCER TREATMENT, A SYSTEMATIC REVIEW

SCORPION VENOM AND ITS COMPONENTS AS NEW PHARMACEUTICAL APPROACH TO CANCER TREATMENT, A SYSTEMATIC REVIEW

Mohammadreza Moradi ¹, Reza Solgi ², Babak Vazirianzadeh ³, Hamid Tanzadehpanah ¹ and Massoud Saidijam ^{* 1}

Molecular Medicine Research Center ¹, Hamadan University of Medical Sciences, Hamadan, Iran.

Legal Medicine Research Center ², Legal Medicine Organization of Iran, Hamadan, Iran.

Department of Parasitology and Mycology ³, College of Medicine Jundi Shapour University of Medical Sciences Ahwaz, Iran.

ABSTRACT: The use of scorpion venom has a very old history in traditional medicine for thousands years ago in China, India and Africa worldwide. The inhibition of cancer progression and induce apoptosis have shown in an increasing number in-vitro and in-vivo studies. We accomplished this systematic review to evaluate the performance of scorpion venom and its components in the growth inhibition of cancer cell lines. To provide a full data for future researches, the in-vitro and in-vivo studies were adopted in this research. The literature search for the published articles from January 1^st, 1968 to January 1^th, 2018 was done in PubMed, ISI Web of Science, Scopus, and Science Direct. All the articles were independently screened by applying some predefined criteria by two reviewers in three consecutive steps. We identified 53 eligible studies from among 1,209 studies. So far, scorpion venom and its components have been discovered to inhibit the growth of 38 various types of cancer cell lines. This was the first systematic review includes some tables that provided some valuable information to the reader on the therapeutic properties of scorpion venom and its components in the sphere of cancer treatment. We found some studies showing that these agents have been able to inhibit the growth of cancer cell lines, while having no effects on the normal cells using the same doses. The findings of this research strongly reinforced the hypothesis that these agents provide a new efficient approach to cancer treatment.

Antineoplastic Agents, Apoptosis, Cancer, Cell Proliferation, Neoplasms, Scorpion Venoms

INTRODUCTION: Scorpions have lived anywhere on the earth since over 400 million years ago. More than 1,500 species have been reported to exist so far ¹. Due to developing such symptoms as pain, swelling, hypertension, cardiac arrhythmia, and other systemic complexities caused by stinging and subsequent envenomation, they have spread a negative reputation among people ^{2, 3}.

Nevertheless, the Chinese, Indian, and African traditional medicines have made a use of scorpions and their venoms for thousands of years ⁴. The direct and indirect functions of these cytotoxic agents broadly involve the ion channels of cell membranes and activation of cellular metabolic pathways, perhaps with the help of secondary messengers, respectively ⁵. Yet, besides their neurotoxic activities, some have antitumor properties. Under in-vitro or in-vivo conditions, cell cycle arrest and apoptosis induction, as well as inhibition of cancer proliferation and metastasis have been demonstrated to be caused by some purified peptides and proteins with the help of crude scorpion venom in an increasing number of pre-clinical and experimental researches ³. In this regard, new potent anticancer drugs with fewer side effects have been continuously searched by oncologists since some drugs have been found to leave adverse effects on the non-involved vital organs like nervous system, heart, liver, bladder, kidney, and lungs ⁶. This approach has led to choosing scorpion venom and its components as good candidates for cancer treatment.

Although there were some review articles collecting some studies about the anti-cancer properties of scorpion venom, there was no study, in which the data had been fully extracted. Thus, we performed a systematic review includes some tables that provide valuable information to the reader.

METHODS:

1.1. The Criteria for Including Studies: Since the purpose of this systematic review was to evaluate a natural venom performance in the treatment of cancer cell lines, we designed some criteria for the selection of studies to help us answer our study question. We selected the studies, in which cancer cell lines had been exclusively used for showing the modulatory effects of scorpion venom on the mentioned cell growth. There were many studies using cell lines because of their immortalities and highly growth rate properties. In such studies, the main objective had been to study the mechanisms of scorpion venom effects, especially on ion channel blockers. Therefore, we excluded these studies regarding the titles and abstracts.

1.2. Study Selection: This systematic review was performed following the recommendations outlined in the PRISMA guidelines. Here include at least the web address (www.prisma-statement.org). After searching in PubMed, ISI Web of Science, Scopus and Science Direct online databases, we manually searched for the reference lists of all the relevant articles for additional studies. The duplicated studies were removed and the first reviewer (M.R) excluded those articles that did not meet the eligibility criteria with regard to the titles and abstracts. The full texts were read when necessary. If the first reviewer could not decide on excluding the article, the second reviewer (M.S) was asked for consultation until both reached a consensus. Furthermore, a single reviewer collected the relevant data from the included articles for the study.

1.3. Data Extraction: To prepare a full extraction from the included studies, we divided the data extraction into two separate parts including the in -vitro and in-vivo studies. For the in-vitro studies, we extracted the author(s), year, cell line, organism, disease, scorpion species, crude venom/component, IC₅₀, and the results (positive or negative).

2. RESULTS:

2.1. Search Results: Our search in PubMed, ISI Web of Science, Scopus, and Science Direct databases provided a total of 1,209 citations. We manually searched the reference lists of all the related articles for additional studies and found 20 studies. After adjusting for the duplicates, 334 articles were remained. Two hundred and fourteen studies were discarded because after reviewing their titles and abstracts, it appeared that the papers did not clearly meet the criteria. The full texts of the remaining 94 citations were examined in detail. Finally, 53 studies were identified to be included in the study. Fig. 1 exhibits the search and study selection processes provided in a flow chart of this systematic review.

Data Extraction: After including the eligible studies based on the goal of this research, we separately extracted the data from the in-vitro and in vivo studies. The number of in-vivo studies was less than that of the in-vitro studies (13 vs. 40 studies). The results revealed that this natural venom and its components had inhibited the growth of 38 various types of cancer cell lines. The in-vitro and in-vivo successes in the growth inhibition were 92% and 100%, respectively. Also, the cell lines of 28 various types of the disease were found to have been defeated by these agents. The venoms of 18 species had been used in the treatment in the two forms of crude venom and component. Their summaries of numerical information are displayed in Tables 1 and 2, respectively.

FIG. 1: PRISM A DIAGRAM OF SCREENING PROCESS AND STUDY SELECTION

TABLE 1: SUMMARY OF NUMERICAL INFORMATION IN VITRO STUDIES

TABLE 2: SUMMARY OF NUMERICAL INFORMATION IN VIVO STUDIES

The in-vitro and in-vivo results of the data extraction and some basic pharmacological data are illustrated in Tables 3, 4 and 5 respectively. In some articles, both in vitro and in vivo studies had been simultaneously performed. These studies are separately exhibited in both tables. The values of IC₅₀ and its unit had been mentioned only based on their articles. However, the amounts of venoms in the articles with negative results had not been mentioned in IC₅₀ column.

TABLE 3: SUMMARY OF INCLUDED ARTICLES ON PERFORMANCE OF SCORPION VENOM AND ITS COMPONENTS IN CANCER CELL LINES GROWTH INHIBITION (IN VITRO STUDIES)

TABLE 4: SUMMARY OF INCLUDED ARTICLES ON PERFORMANCE OF SCORPION VENOM AND ITS COMPONENTS IN CANCER CELL LINES GROWTH INHIBITION (IN-VIVO STUDIES)

TABLE 5: SOME BASIC PHARMACOLOGICAL DATA ABOUT THE SCORPION VENOM AND ITS COMPONENT HAVE BEEN USED IN IN VITRO AND IN VIVO STUDIES

DISCUSSION: Severe deaths occur worldwide due to cancer as a most life-threatening disease. There is still a high rate of mortality related to cancer despite many therapeutic advances. Nowadays, four standard methods are adopted for cancer treatment: surgery, radiation therapy, chemotherapy, and immunotherapy ⁵⁸. To reduce and inhibit cell growth, specific chemical compounds are used through a chemoprevention study. More than 1,000 agents and agent combinations have been selected and accessed via preclinical chemopreventive testing programs since 1987. These activities have included in vitro mechanistic and cell-based transformation assays, as well as carcinogen-induced and transgenic animal models. New agents selected based on their preliminary efficacy, mechanisms, and potentia-lities for improving chemopreventive indices have been continuously regarded to be used in chemopreventive drugs ⁵⁹. Still, more potent anticancer drugs with fewer side effects are being continuously searched by oncologists since some can have adverse effects on other organs, such as nervous system, heart, liver, bladder, lungs, and kidney.

Cancer cell migration and proliferation may be affected by the specific binding of some isolated peptides or proteins to the cancer cell membrane ⁶. Historically, scorpion venoms have been biochemically studied for a long time. Nevertheless, the great improvements in the technology of peptide / protein isolation and characterization over the past two decades have specifically coincided with the mentioned studies ²⁵. It is nearly a decade that the inhibitive properties of scorpion venom and its components have been specially focused on.

In this research, we collected the results of the anti-proliferation effects of scorpion venom and its components in the form of a systematic review for the first time. As the collected studies were divided into the two parts of in-vitro and in-vivo studies, the discussion was divided into two parts: 1) in-vitro studies; 2) in-vivo studies.

In-vitro Studies: The findings of this study demonstrated that the studies on the anti-cancer effects of scorpion venom have been started since 2006. Before this, many articles were found with the key words of "cancer", "cell line", and "scorpion", but the researches had been focused on the venom cytotoxicity effects on cells to study its toxicity mechanism.

The first available comprehensive study had been done by Das Gupta et al., in 2007. They had made an effort to assess the anti-proliferative and apoptotic efficacy of crude venom extracted from Heterometrus bengalensis C. L. Koch, 1841, against the two human leukemic cell lines of U937 and K562. They had used some experimental methods, such as comet assay, flow cytometry, and scanning electron microscopy.

The mentioned venom had induced cell growth inhibition in U937 and K562 cell lines and their IC₅₀ values had been reported to be 41.5 µg/ml and 88.3 µg/ml, respectively ⁸. In 35 studies, cell lines were found to have been treated with crude venom and 29 various types of components had been applied for inducing apoptosis in them. The variable amount of crude venom ranges between 0.63 mg/ml ²³ and 600 mg/ml ³³.

In some studies, an astonishing subject was observed to strengthen the use of scorpion venom for cancer treatment hypothesis. The scorpion venom and its components had been shown to be able to inhibit the growth of cancer cell lines, while having no effects on the normal cells when using the same doses. For example in 2007, Fu and Yin et al., had produced a recombinant chlorotoxin-like peptide from scorpion Buthus martensii Karsch Karsch, 1879, to treat human glioma (SHG-44) cells with this recombinant peptide. They had shown that rBmK CTa inhibits the growth of glioma cells in a dose-dependent manner with an IC₅₀ value equal to 0.28 µM.

Under the same conditions, the IC₅₀ value for normal astrocytes had increased to 8 µM ⁹. In 2013, Almaaytah and Tarazi et al., had found a synthetic replicate (Mauriporin) to exert potent selective cytotoxic and anti-proliferative activities against prostate cancer cell lines (IC₅₀ 4.4 - 7.8 µM) as compared to non-tumorigenic cells (IC₅₀ = 59.7 - 62.5 µM) ²¹. Also, in 2013, Diaz-Garcia et al., had shown a significant reduction of cancer cell viability to be between a panel of cancer cell lines and normal cells treated with Rhopalurus junceus (Herbst, 1800, venom. This venom had not affected the viability neither in the normal nor in the hematopoietic cell lines at the same concentrations ²³.

Besides the inhibitive effects of scorpion venom on many cancer cell lines, there are some cells that are resistant to scorpion venom ^{22, 23, 25, 28, 32, 34}. The share of such cell lines in this study was 12% out of the total share mainly belonging to HeLa cell ^{22, 32}.

An overview on articles showed that the most of studies have focused on only inhibitory effects of this venom and it’s components on cancer cells lines. It seems that the studies will be more valuable, if the inhibitory effects be assessed simultaneously in cancer cell line and normal cells. Still, there were some scorpions, on which no in vivo studies had been done, for example Hemiscorpius lepturus Peters, 1861, as one of the most dangerous scorpion species.

On the other hand, as it can be seen in the most of articles, their concentration has been on the related apoptotic genes. It seems that the using of some methods such as Western blot in order to detecting of apoptotic genes products is essential.

In-vivo Studies: All the 16 in-vivo treatments were found to be successful leading to reduced tumor size, weight, and volume. In some other researches, some angiogenesis factors were seen to have been reduced ⁵⁰.

In 2010, the first available in vivo study had been accomplished by Fan et al., who had reported that proliferation and metastasis of glioma cells had been effectively inhibited by BmKCT due to having a selective affinity to glioma cells. It had been also suggested to be exploited as a potential therapeutic agent for glioma diagnosis ⁴⁷. In that same year, the mechanism and inhibitive effect of a scorpion venom polypeptide (PESV) on H22 tumor cell repopulation during 5-fluorouracil chemo-therapy had been studied by Wang et al., Thus, the inhibition of H22 tumor cell repopulation by PESV, probably through an anti-angiogenesis mechanism, was proved by them during 5-fluorouracil chemotherapy ⁴⁸. In 2011, cyclophosphamide as a tumor growth inhibitor had been used by Sun et al., to establish a cancer model. The polypeptide extracted from scorpion venom (PESV) had been applied to Lewis Lung Carcinomas (LLCs).

In 2013, a replication - defective adenovirus recombinant had been selected by Du et al., to deliver BmK CT gene to the C6 glioma cells. MMP-2 upregulation, which is partially responsible for the enhanced ability of glioma cell migration, can be specifically inhibited by BmKCT enzymatic activity when binding to it. Targeting BmK CT to C6 glioma cells specifically through this delivery system had been developed by them. Thus, the replication-defective recombinant adenovirus Ad-BmK CT could provide a powerful delivery system to treat glioblastoma ⁵². In 2014, Shao et al., had undertaken isolating peptides with analgesic and antitumor activities from scorpion venom. BmK AGAP-SYPU2 as a new analgesic-antitumor peptide had been purified and characterized with bioassay-guided chromatography protocols. It had exhibited analgesic effects and antitumor activities during all the animal tests. The homology model of BmK AGAP-SYPU2 had represented the conservative structures of most scorpion venoms. The variant sites had been considered to be important for the specific pharmaceutical activities of this peptide. This kind of dual-function peptide with pain-relieving and antitumor effects was clinically valuable for improving patient survival without compromising his/her quality of life ⁵⁴.

By conjugating scorpion venom and its components with other agents in some studies, their antitumor effects could be intensified. For example, in 1988, the northern leopard frog Rana Lithobates pipiens Schreber, 1782, oocytes had been first used to isolate Onconase (Onc) as a small RNase ⁶⁰. In 2015, Wang et al. and Guo had prepared Onc conjugated with CTX as a potential anti-glioma drug, in which the recombinant CTX covalently bonded with recombinant Onc via a reversible disulfide linkage. Thus, much higher cytotoxicity to the cultured U251 and SHG-44 glioma cells was obtained by chemically conjugating CTX and Onc compared to their physical mixture (CTX+Onc). Moreover, improved antitumor effects on the subcutaneous U251 or SHG-44 tumors of the nude mouse models had been achieved by the CTX-Onc conjugate compared to the CTX+Onc control. These results were indicative of the promotion of the tumor targeting of Onc through the chemically reversible conjugated CTX. Also, the present CTX-Onc conjugate as a potential drug targeting anti-glioma could be further developed ³⁸.

The in-vivo investigations had not been limited to the evaluation of the antitumor effects of venom components. In a recent study published in 2016, Salem et al. had shown the cytotoxic effects of crude venom extracted from Androctonus amoreuxi Audouin, 1826, as an Egyptian scorpion on the MCF-7 human breast cancer cell line and Ehrlich Ascites Carcinoma (EAC) cells. Interestingly, venom had been shown to restore the altered biochemical and hematological parameters of animals bearing tumors and significantly prolong their lifespan. Consequently, the potential cytotoxic effects of Androctonus amoreuxi Audouin, 1826, on tumor cells through apoptotic, anti-proliferative, and anti-angiogenic activities had been evidenced by them so as to open a new path towards future studies on the anti-cancer effects of the mentioned agent ⁴⁰.

On the whole, scorpion venom and its components were found to have a high rate of success in inducing apoptosis in various types of cancer cell lines. Also scorpion venom and derived molecules have shown their potential as tools for the fight on cancer in directly-acting therapeutic, diagnostic tags, adjuvants or just carriers for other relevant moieties ⁶¹. Interestingly, no effects on the normal cells had been seen when the cancer cell lines and normal cells had been treated at the same time with the same doses. The mentioned agents had represented a novel potentially clinical therapeutic approach for cancer treatment.

CONCLUSION: This was the first systematic review includes some tables that provide valuable information to the reader on the therapeutic anti-cancer properties of scorpion venom and its components. The results demonstrated that this natural venom can induce apoptosis in various types of cancer cell lines.

Some studies were found to show that these agents are able to inhibit the growth of cancer cells, while having no effects on the normal cells with the same doses. Considering the adverse effects of anti-cancer drugs on other vital organs, we need to focus on the development of new drugs with potent anti-cancer and lower side effects. The findings of this research strongly reinforced this hypothesis that these agents provide a new efficient approach to cancer treatment.

AUTHORS' CONTRIBUTION: MS and MM conception, design, collecting data, statistical analysis, writing the article, critical revision of the article and final approval of the article. RS provided information of the scorpion’s venom and re-read articles. HT re-read articles and double-checked the data. BV re-read the articles and provided information of scorpion’s species. All authors approved the final manuscript.

ACKNOWLEDGEMENT: This study is a part of Ph.D thesis of M. R. Moradi and was supported by deputy of research and technology, Hamadan University of Medical Sciences.

CONFLICT OF INTEREST: The authors declared no conflicts of interest.

FUNDING: The study was funded by deputy of research and technology, Hamadan University of Medical Sciences. Hamadan University of Medical Sciences (Grant No. 9412257461).

REFERENCES:

1. Richman DB: Scorpions (Class Arachnida, Order Scorpiones). In: Encyclopedia of Entomology: Springer 2008; 3310-3.
2. Mullen GR and Durden LA: Medical and veterinary entomology. Academic press 2009.
3. Ding J, Chua PJ, Bay BH and Gopalakrishnakone P: Scorpion venoms as a potential source of novel cancer therapeutic compounds. Exp Biol Med (Maywood) 2014; 239(4): 387-93.
4. González JA and Vallejo JR: The scorpion in Spanish folk medicine: a review of traditional remedies for stings and its use as a therapeutic resource. Journal of ethnopharma-cology 2013; 146(1): 62-74.
5. Olvera F, Rosales A, Olvera A, Diaz P, Sevcik C, Salazar V, et al.: An efficient approach to clone and express active Neopladine 2, an anticancer peptide from Tityus discrepans scorpion venom. Process Biochemistry 2016; 51(5): 624-31.
6. Gao R, Zhang Y and Gopalakrishnakone P: Purification and N-terminal sequence of a serine proteinase-like protein (BMK-CBP) from the venom of the Chinese scorpion (Buthus martensii Karsch). Toxicon 2008; 52(2): 348-53.
7. Li JW, Hu J, Zhang GR and Wei ZR: Effects of anti-cancer peptide fraction III from Buthus martensii Karsch on apoptosis of human liver cancer cells. Journal of Jilin University Medicine Edition 2006; 32(4): 625-8.
8. Das Gupta S, Debnath A, Archita S, Giri B, Tripathi G, Vedasiromoni JR, et al.: Indian black scorpion (Heterometrus bengalensis) venom induced antiproliferative and apoptogenic activity against human leukemic cell lines U937 and K562. Leukemia Research 2007; 31(6): 817-25.
9. Fu YJ, Yin LT, Liang AH, Zhang CF, Wang W, Chai BF, et al.: Therapeutic potential of chlorotoxin-like neurotoxin from the Chinese scorpion for human gliomas. Neuroscience Letters 2007; 412(1): 62-7.
10. Das Gupta S, Gomes A, Debnath A, Saha A and Gomes A: Apoptosis induction in human leukemic cells by a novel protein Bengalin, isolated from Indian black scorpion venom: Through mitochondrial pathway and inhibition of heat shock proteins. Chemico-Biological Interactions 2010; 183(2): 293-303.
11. Zhao J, Qiao W, Zhang Y and Shao X: Preparation and in vitro evaluation of 131I-BmK CT as a glioma-targeted agent. Cancer Biotherapy and Radiopharmaceuticals 2010; 25(3): 353-9.
12. D’ Suze G, Rosales A, Salazar V and Sevcik C: Apoptogenic peptides from Tityus discrepans scorpion venom acting against the SKBR3 breast cancer cell line. Toxicon 2010; 56(8): 1497-505.
13. Rjeibi I, Mabrouk K, Mosrati H, Berenguer C, Mejdoub H, Villard C, et al.: Purification, synthesis and characterization of AaCtx, the first chlorotoxin-like peptide from Androctonus australis scorpion venom. Peptides 2011; 32(4): 656-63.
14. Zhao Y, Cai X, Ye T, Huo J, Liu C, Zhang S, et al.: Analgesic-antitumor peptide inhibits proliferation and migration of SHG-44 human malignant glioma cells. Journal of Cellular Biochemistry 2011; 112(9): 2424-34.
15. Zargan J, Sajad M, Umar S, Naime M, Ali S and Khan HA: Scorpion (Androctonus crassicauda) venom limits growth of transformed cells (SH-SY5Y and MCF-7) by cytotoxicity and cell cycle arrest. Exp Mol Pathol 2011; 91(1): 447-54.
16. Fu Y, Zheng S, Huang R, An N, Zheng Y, Zhang Z, et al.: A potential strategy for high-grade gliomas: Combination treatment with lithium chloride and BmK CT. Biotechnology Letters 2012; 34(1): 9-17.
17. Graf N, Mokhtari TE, Papayannopoulos IA and Lippard SJ: Platinum (IV)-chlorotoxin (CTX) conjugates for targeting cancer cells. Journal of Inorganic Biochemistry 2012; 110: 58-63.
18. Sarzaeem A, Zare Mirakabadi A, Moradhaseli S, Morovvati H and Lotfi M: Cytotoxic effect of ICD-85 (venom-derived peptides) on HeLa cancer cell line and normal LK cells using MTT Assay. Arch Iran Med 2012; 15(11): 696-701.
19. Song X, Zhang G, Sun A, Guo J, Tian Z, Wang H, et al.: Scorpion venom component III inhibits cell proliferation by modulating NF-κB activation in human leukemia cells. Experimental and Therapeutic Medi. 2012; 4(1): 146-50.
20. Wang Z, Fu WH, Lu XY and Cai GX: Effects of Buthus martensii Karsch Venom on Cell Proliferation and Cytotoxicity in Hela Cells. In: Zhong JL, editor. Smart Materials and Nanotechnology in Engineering 2012; 345: 393-8.
21. Almaaytah A, Tarazi S, Mhaidat N, Al-Balas Q and Mukattash TL: Mauriporin, a Novel Cationic alpha-Helical Peptide with Selective Cytotoxic Activity Against Prostate Cancer Cell Lines from the Venom of the Scorpion Androctonus mauritanicus. International Journal of Peptide Research and Therapeutics 2013; 19(4): 281-93.
22. Contreras-Ortiz JME, Vazquez-Chagoyan JC, Martinez-Castaneda JS, Estrada-Franco JG, Aparicio-Burgos JE, Acosta-Dibarrat J, et al.: Resistance of cervical adenocarcinoma cells (HeLa) to venom from the scorpion Centruroides limpidus. Journal of Venomous Animals and Toxins Including Tropical Diseases 2013; 19.
23. Diaz-Garcia A, Morier-Diaz L, Frion-Herrera Y, Rodriguez-Sanchez H, Caballero-Lorenzo Y, Mendoza-Llanes D, et al.: In vitro anticancer effect of venom from Cuban scorpion Rhopalurus junceus against a panel of human cancer cell lines. J Venom Res 2013; 4: 5-12.
24. Gu Y, Liu SL, Ju WZ, Li CY and Cao P: Analgesic-antitumor peptide induces apoptosis and inhibits the proliferation of SW480 human colon cancer cells. Oncology Letters 2013; 5(2): 483-8.
25. Guo X, Ma C, Du Q, Wei R, Wang L, Zhou M, et al.: Two peptides, TsAP-1 and TsAP-2, from the venom of the Brazilian yellow scorpion, Tityus serrulatus: evaluation of their antimicrobial and anticancer activities. Biochimie 2013; 95(9): 1784-94.
26. Ma J, Hu Y, Guo M, Huang Z, Li W and Wu Y: HERG potassium channel blockage by scorpion toxin BmKKx2 enhances erythroid differentiation of human leukemia cells K562. PLoS ONE 2013; 8(12).
27. Moradhaseli S, Mirakabadi AZ, Sarzaeem A, Kamalzadeh M and Hosseini RH: Cytotoxicity of ICD-85 NPs on human cervical carcinoma hela cells through caspase-8 mediated pathway. Iranian journal of pharmaceutical research: IJPR 2013; 12(1): 155.
28. Qiu YF, Jiang LY, Wang CX, Wang Y, Li T, Xing BQ, et al.: Scorpion venom peptide SPVII promotes irradiated cells proliferation and increases the expression of the IL-3 receptor. Cell and Bioscience 2013; 3.
29. Arpornsuwan T, Sriwai W, Jaresitthikunchai J, Phaonakrop N, Sritanaudomchai H and Roytrakul S: Anticancer activities of antimicrobial BmKn2 peptides against oral and colon cancer cells. International Journal of Peptide Research and Therapeutics 2014; 20(4): 501-9.
30. Du Q, Hou X, Ge L, Li R, Zhou M, Wang H, et al.: Cationicity-enhanced analogues of the antimicrobial peptides, AcrAP1 and AcrAP2, from the venom of the scorpion, Androctonus crassicauda, display potent growth modulation effects on human cancer cell lines. International Journal of Biological Sciences 2014; 10(10): 1097-107.
31. Fu Y, Jiao Y, Zheng S, Liang A and Hu F: Combination of lithium chloride and pEGFP-N1-BmK CT effectively decreases proliferation and migration of C6 glioma cells. Cytotechnology 2014.
32. Li W, Xin Y, Chen Y, Li X, Zhang C, Bai J, et al.: The anti-proliferative effects and mechanisms of low molecular weight scorpion BmK venom peptides on human hepatoma and cervical carcinoma cells in vitro. Oncology Letters 2014; 8(4): 1581-4.
33. Li WL, Li Y, Zhao YW, Yuan JL and Mao WF: Inhibition effects of scorpion venom extracts (Buthus matensii karsch) on the growth of human breast cancer MCF-7 cells. African Journal of Traditional Complementary and Alternative Medicines 2014; 11(5): 105-10.
34. Song Y, Gong K, Yan H, Hong W, Wang L, Wu Y, et al.: Sj7170, a unique dual-Function peptide with a specific α-Chymotrypsin inhibitory activity and a potent tumor activating effect from scorpion venom. Journal of Biological Chemistry 2014; 289(17): 11667-80.
35. Wang H, Gu W, Xiao N, Ye L and Xu Q: Chlorotoxin-conjugated graphene oxide for targeted delivery of an anticancer drug. International Journal of Nanomedicine 2014; 9(1): 1433-42.
36. Li Q, Xiao K and Wang Z: Cytotoxic and Apoptotic Effects of the Venom of the Scorpion Heterometrus liangi in Human KYSE-510 Cells (Esophageal cancer). In: 2015 International Conference on Mechatronics, Electronic, Industrial and Control Engineering (MEIC-15): Atlantis Press 2015.
37. Tong-ngam P, Roytrakul S and Sritanaudomchai H: BmKn-2 scorpion venom peptide for killing oral cancer cells by apoptosis. Asian Pacific Journal of Cancer Prevention 2015; 16(7): 2807-11.
38. Wang X and Guo Z: Chlorotoxin-conjugated onconase as a potential anti-glioma drug. Oncology Letters 2015; 9(3): 1337-42.
39. Al-Asmari AK, Islam M and Al-Zahrani AM: In vitro analysis of the anticancer properties of scorpion venom in colorectal and breast cancer cell lines. Oncol Lett 2016; 11(2): 1256-62.
40. Salem ML, Shoukry NM, Teleb WK, Abdel-Daim MM and Abdel-Rahman MA: In vitro and in vivo antitumor effects of the Egyptian scorpion Androctonus amoreuxi venom in an Ehrlich ascites tumor model. SpringerPlus 2016; 5(1): 1.
41. Xu T, Fan Z, Li W, Dietel B, Wu Y, Beckmann MW, et al.: Identification of two novel Chlorotoxin derivatives CA4 and CTX-23 with chemotherapeutic and anti-angiogenic potential. Scientific reports 2016; 6.
42. Pedron CN, Andrade GP, Sato RH, Torres MDT, Cerchiaro G, Ribeiro AO, et al.: Anticancer activity of VmCT1 analogs against MCF-7 cells. Chemical Biology and Drug Design 2017.
43. Akef H, Kotb N, Abo-Elmatty D and Salem S: Anti-proliferative Effects of Androctonus amoreuxi Scorpion and Cerastes cerastes Snake Venoms on Human Prostate Cancer Cells. J Cancer Prev 2017; 22(1): 40-6.
44. Al-Asmari AK, Ullah Z, Al Balowi A and Islam M: In vitro determination of the efficacy of scorpion venoms as anti-cancer agents against colorectal cancer cells: a nano-liposomal delivery approach. Int J Nanomedicine 2017; 12: 559-74.
45. Diaz-Garcia A, Ruiz-Fuentes JL, Rodriguez-Sanchez H and Fraga Castro JA: Rhopalurus junceus scorpion venom induces apoptosis in the triple negative human breast cancer cell line MDA-MB-231. J Venom Res 2017; 8: 9-13.
46. Al-Asmari AK, Riyasdeen A and Islam M: Scorpion Venom Causes Upregulation of p53 and Downregulation of Bcl-xL and BID Protein Expression by Modulating Signaling Proteins Erk(1/2) and STAT3, and DNA Damage in Breast and Colorectal Cancer Cell Lines. Biopolymers 2017:1534735417704949.
47. Fan SZ, Sun ZB, Jiang DH, Dai C, Ma YB, Zhao ZH, et al.: BmKCT toxin inhibits glioma proliferation and tumor metastasis. Cancer Letters 2010; 291(2): 158-66.
48. Wang Z, Zhang W, Jia Q, Wang Z, Zhang Y and Wang Y: Inhibitive effect of polypeptide extract from scorpion venom on repopulation in H22 tumor cell during chemotherapy. Zhongguo Zhongyao Zazhi 2010; 35(1): 108-13.
49. Sun X, Zhang Y, Jia Q, Wang Z, Wang Z and Zhang W: Effect of polypeptide extract from scorpion venom (PESV) with chemotherapy inhibited angiogenesis of lewis lung carcinomas. Zhongguo Zhongyao Zazhi 2011; 36(12): 1644-9.
50. Wang Z, Zhang W, Wu L, Jia Q, Wang Z, Zhang Y, et al.: [Effect of polypeptide extract from scorpion venom (PESV) on expression of HIF-1alpha and SDF-1/CXCR4 in repopulating H22 tumour tissue during chemotherapy treatment]. Zhongguo Zhong Yao Za Zhi 2011; 36(13): 1803-7.
51. Ning YN, Zhang WD and Wu LC:[Study on the mechanism of polypeptide extract from scorpion venom to promote the restraint of cyclophosphamide on Lewis lung cancer]. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine / Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban 2012; 32(4): 537-42.
52. Du J, Fu Y, Wang J and Liang A: Adenovirus-mediated expression of BmK CT suppresses growth and invasion of rat C6 glioma cells. Biotechnology Letters 2013; 35(6): 861-70.
53. Zheng AH, Zhang WD, Wang ZP, Wang ZX, Wu LC, Jia Q, et al.: [Research on the effect and mechanism of polypeptide extract from scorpion venom combined with 5-fluorouracil on vasculogenic mimicry of H22 hepatoma]. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine / Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban 2013; 33(4): 492-6.
54. Shao JH, Cui Y, Zhao MY, Wu CF, Liu YF and Zhang JH: Purification, characterization, and bioactivity of a new analgesic-antitumor peptide from Chinese scorpion Buthus martensii Peptides 2014; 53: 89-96.
55. Sui WW, Zhang WD, Wu LC, Wang ZP, Zhang YY, Wang ZX, et al.: Inhibitory mechanism of polypeptide from scorpion venom combined with 5-fluorouacil on angiogenesis of H22 hepatoma. Chinese Traditional and Herbal Drugs 2014; 45(3): 392-7.
56. Liu CH, Sui WW, Wang ZP, Zhang YY and Zhang WD: Study on inhibitory mechanism of polypeptide extract from scorpion venom on ovarian cancer. Chinese Traditional and Herbal Drugs 2015; 46(7): 1018-22.
57. Wang X and Guo Z: Anti-gliomas Effect of Chlorotoxin-Conjugated Onconase at High Dose. Cell Biochemistry and Biophysics 2015.
58. Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson B, et al.: Annual Report to the Nation on the Status of Cancer, 1975-2014, Featuring Survival. J Natl Cancer Inst 2017; 109(9).
59. Mirakabadi ZA, Mahdavi S, Koohi M and Taghavian M: Cytotoxic effect of ICD-85 (venom-derived peptides) on MDA-MB-231 cell line. Journal of Venomous Animals and Toxins including Tropical Diseases 2008; 14(4): 619-27.
60. Darzynkiewicz Z, Carter S, Mikulski S, Ardelt W and Shogen K: Cytostatic and Cytotoxic Effects of Pannon (P-30 Protein), A Novel Anticancer Agent. Cell Proliferation 1988; 21(3): 169-82.
61. Ortiz E, Gurrola GB, Schwartz EF and ossani LD: Scorpion venom components as potential candidates for drug development. Toxicon 2015; 93: 125-35.
    

    ---

    How to cite this article:

    Moradi M, Solgi R, Vazirianzadeh B, Tanzadehpanah H and Saidijam M: Scorpion venom and its components as new pharmaceutical approach to cancer treatment, a systematic review. Int J Pharm Sci Res 2018; 9(7): 2604-15. doi: 10.13040/IJPSR.0975-8232.9(7).2604-15.

    ---

    All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---