Introduction
Cervical cancer is very common in women. In terms of prevalence, this cancer ranks second after breast cancer in Iran, and in terms of mortality, it ranks second after ovarian cancer [1]. One of the most common methods of cancer treatment is chemotherapy. Chemotherapy drugs have many toxic effects, including digestive, respiratory, nervous, infertility, etc. These effects lead to a decrease in the quality of life (QoL) [2].
Doxorubicin is one of the most powerful and advanced chemotherapy drugs in the anthracycline group [3]. The anticancer drug doxorubicin is an antibiotic with a wide spectrum of antitumor and anticancer activity [4]. It is used to treat many cancers, such as stomach, breast, lung, ovary, bone, Hodgkin’s disease, and leukemia [5, 6]. Like other chemotherapy drugs, it has many side effects that can lead to fever, cardiac, and pulmonary toxicity, etc. [7, 8]. The destructive effect of doxorubicin is mainly due to the production of reactive oxygen species [9]. Free radicals produced by doxorubicin attack the fatty acids of membrane lipids and lead to lipid peroxidation and ultimately cell death [10]. Doxorubicin leads to lipid peroxidation and oxidative stress [11].
The interrelationships between oxidative stress and cancer are complex [12]. Changes in the level of oxidative stress can play an important role in the occurrence and progression of cancer [13]. Unsaturated fatty acids are very sensitive to oxidative stress changes and their peroxidation leads to the formation of active aldehydes, such as malondialdehyde (MDA) [14]. MDA is used to measure oxidative stress. MDA has been introduced as a mutagenic and carcinogenic agent by creating lesions in macromolecules, enzymes, and DNA [15]. Taking some anticancer drugs and chemotherapy-radiotherapy courses can stimulate lipid peroxidation [16]. Injection of doxorubicin leads to a clear increase in the level of MDA and a decrease in the activity of antioxidants in different tissues [17]. One of the main problems with the use of chemical drugs, such as doxorubicin is its toxicity on host cells and tissues, and this treatment method is not a suitable treatment due to its numerous systemic side effects. It is a substitute for a less dangerous treatment method considered by researchers [18].
Nowadays, all kinds of medicines, serums, and vaccines can be prepared from saliva or poison [19, 20]. Snake venom is acidic and consists of proteins, such as neurotoxins, cardiotoxins, cytotoxins, myotoxins, coagulants, and anticoagulants, and enzymes, such as proteases, oxidases, phospholipases, etc., among all natural poisons. It has the most complexity [21, 22]. Li et al. in 2018 showed the anticancer effect of various snake venoms on the growth and proliferation of cancer cells [23]. Calmet et al. used cobra venom to treat cancer in mice [24].
Naja naja oxiana is a species of cobra in Central Asia. This species belongs to the Elapidae family and affects the nervous system [25]. This poison contains neurotoxin, cytotoxin, and cardiotoxin [26]. Neurotoxin II released from snake venom can induce apoptosis [27]. 
Considering the therapeutic effects of poison as well as the many side effects of chemotherapy drugs, conducting a study on the anti-cancer effects of this poison seems necessary. The present study was conducted to investigate the effects of Caspian cobra venom (Naja naja oxiana) compared to doxorubicin on the proliferation rate and lipid peroxidation rate of human cervical cancer cells (HeLa) and fibroblast cells (HFF). 
Materials and Methods 
Cell culture: To carry out this applied research, human cervical cancer cells (HeLa, ATCC No.: CCL-2) and fibroblast cells (HFF, NCBI code: C163) were purchased from the cell bank of the Pasteur Institute of Iran (2×106 cells) in medium containing 90% FBS and 10% DMSO). These cells were in a medium containing 90% FBS and 10% DMSO. Cells were cultured in sterile conditions, in DMEM (Dulbecco’s modified Eagle’s medium), 10% fetal bovine serum (FBS), potassium bicarbonate buffer, 1% penicillin, and 1% streptomycin at room temperature at 37°C. Then, they were placed inside the incubator (5% CO2 at 37°C). It should be noted that in this research, cell treatments with doxorubicin (Sigma-Aldrich, USA: D1515) and the snake venom Naja naja oxiana (Razi Vaccine and Serum Research Institute, Karaj, Iran) were considered for 24 and 48 hours at the concentrations of 1,10, 50,100, and 500 μg/mL [28].
Checking the proliferation rate: The cells were cultured in 96-well plates to check the proliferation rate. After each treatment, cells were washed with PBS and trypsinized, and the cell suspension was prepared from each group. To check the cell proliferation rate, trypan blue staining and cell counting were performed. The number of cells per mL was checked.
Lipid peroxidation assay
MDA is one of the factors that are caused by lipid peroxidation and direct cell damage. Therefore, to measure lipid peroxidation, the concentration of MDA is checked. MDA concentration was measured using the lipid peroxidation assay kit (Kia Bios, Iran) according to the instructions. In this experiment, MDA forms a complex with thiobarbituric acid and is absorbed at the wavelength of 532 nm. The optical absorbance was read by an ELISA reader (ELx808 microplate reader, BioTek, UK). MDA concentration was determined from the standard curve.
Statistical analysis
Statistically, all results were expressed as Mean±Standard error (SEM). Statistical analysis of data was done using SPSS software, version 19. One-way analysis of variance (ANOVA) and Tukey test were performed and the significance level was considered at P≤0.05. Graphs were drawn using Graphpad Prism 5.
Results 
The inhibitory effect of doxorubicin on HeLa cancer cell line and normal fibroblast: 
To investigate the effect of doxorubicin on the proliferation rate of the HeLa cancer cell line and normal fibroblast HFF, five concentrations (1, 10, 50, 100, and 500 µg/mL) of the drug were prepared and evaluated at two different times (24 and 48 hours) (Figures 1 and 2). The results obtained from counting cells per milliliter showed that with the increase in the concentration of doxorubicin, the rate of cell proliferation decreases, which was significant at a concentration of 500 μg/mL at 24 hours. The proliferation rate is the result of dividing the number of cells after treatment by the initial number of cells, which has no unit because they are divided by two numbers.
Inhibitory effects of Naja naja oxiana venom on HeLa cancer cell line and normal fibroblast
To investigate the proliferation rate of HeLa cancer cells and normal fibroblast HFF treated with snake venom, the concentrations of 1, 10, 50, 100, and 500 µg/mL of the snake venom were prepared and two time points of 24 and 48 hours were considered (Figures 3 and 4). The results showed that, with the increase in snake venom concentration, the rate of cell proliferation decreases, which is significant for HeLa cancer cells, but not significant for normal fibroblast cells. In addition, compared to doxorubicin, snake venom reduced the proliferation rate of cancer cells and had no significant effect on normal fibroblast cells. However, the decrease in the proliferation rate of normal fibroblast cells treated with doxorubicin was well observed.
The effect of doxorubicin on HeLa cancer cell line and normal fibroblast in terms of oxidative stress
MDA content was measured as the final product of lipid peroxidation. The shape and amount of MDA in HeLa cancer cell lines and HFF normal fibroblasts treated with different concentrations of doxorubicin for 24 and 48 hours are displayed in Figures 5 and 6. As shown, MDA concentration increased with increasing concentration and time. The level of MDA at the concentration of 500 μg/mL increased significantly at both time points. The MDA level of the treatment group was divided by the control level; thus, it had no unit [29].
The effects of Naja naja oxiana snake venom on HeLa cancer cell line and normal fibroblast in terms of oxidative stress
The results obtained from the tests related to the measurement of MDA in HeLa cancer cell lines and normal fibroblast HFF treated with different concentrations (1, 10, 50, 100, 500 µg/ml) of snake venom are shown in Figures 7 and 8. The results clearly showed that the concentration of MDA in the cancer cell line was higher than in the normal cell line. Also, the amount of MDA in normal cells treated with snake venom was much lower compared to doxorubicin.
Discussion 
Nowadays, there are many treatments for cancer, one of the most common of which is the use of chemical drugs or so-called chemotherapy. One of these drugs is a very effective anthracycline called doxorubicin or adriamycin. This drug is used alone or in combination with other chemical drugs to treat various neoplasms, but, the clinical use of this anticancer drug is limited due to its dose-dependent toxicity [30].
Current anticancer drugs have various side effects and toxicity. Efforts to produce new anticancer agents are ongoing, especially in screening natural compounds [31]. A major source of a variety of bioactive compounds is animal venom [32]. Some of these toxins induce different medicinal effects [33]. It has been found that snake venom leads to cytotoxicity in different types of tumor cells and the use of snake venom can reduce tumor cells [34, 35, 36]. Ahn et al. showed that king cobra venom inhibits cell proliferation in fibroblastic sarcoma, ovarian cancer, colon cancer, and stomach [37]. Naja naja oxiana snake venom is rich in cytotoxin and cardiotoxin and can induce apoptosis in cancer cells [38, 39]. Feofanov et al. assessed the cytotoxins of Caspian cobra venom and showed that cytotoxins I and II easily penetrate living cancer cells and lead to cell death in these cells [40].
In the present study, the effect of Naja naja oxiana snake venom against HeLa and fibroblast cancer cells was investigated in comparison with doxorubicin. For this purpose, five concentrations (1, 10, 50, 100, 500 µg/mL) of poison and drug and a duration of 24 and 48 hours were considered. The results showed that the proliferation rate of HeLa cancer cells and fibroblasts treated with snake venom and drugs decreased with increasing concentration and time, and this decrease in HeLa cancer cells was more than that of normal fibroblast cells.
In Derakhshani et al.’s study, cytotoxin extracted from snake venom reduced the proliferation rate of breast cancer cells and had anti-proliferative effects, and can be a promising candidate for breast cancer treatment [41]. NN-32 protein from Indian Naja naja snake venom has cytotoxic effects on Ehrlich muscle carcinoma in mice, reduces tumor size, and increases animal survival [42]. Zhang et al. showed that ACTX-6 protein extracted from snake venom can increase the apoptosis of HeLa cells [43]. Cardiotoxic-cytotoxic protein isolated from cobra (Naja kaouthia) can significantly inhibit the growth of human leukemia U937 and K562 cells in a dose- and time-dependent manner [44].
Therefore, due to its chemical and biological properties, snake venom has been used to treat various types of cancer. In addition, reports indicate that snake venoms are capable of inducing apoptosis signaling [45]. Defects in the apoptosis process play an important role in cancer development as well as poor response to treatment, such as chemotherapy. These natural treatment methods aim to stimulate apoptosis signaling in the target cells that play an important role in regulating the evolution and development of cancer treatment. Therefore, the induction of apoptosis is a critical strategy for cancer treatment [46]. Various studies have indicated that snake venom induces apoptosis by increasing reactive oxygen species (ROS) and causing oxidative stress [47]. Oxidative stress plays an important role in its regulation by affecting the internal and external pathways of apoptosis. If oxidative stress continues, oxidative damage is caused affecting vital biomolecules and the accumulation of these damages leads to some biological effects, such as changes in message transmission, changes in gene expression, mutation, and cell death [48]. Cells quickly respond to a series of biological responses, such as cell cycle arrest, gene transcription, oxidation imbalance, and regeneration. Most likely, these initial events will determine the fate of the cell, whether the cell will undergo necrosis, senescence, or apoptosis, or survive and multiply [49]. The level of oxidative stress is very important in regulating the process of apoptosis. The increase in oxidative stress levels in cancer patients is related to the course of the disease, tissue damage, the use of anticancer drugs, and chemo-radiotherapy courses [16]. Some chemotherapy drugs lead to an excessive increase in the level of oxidative stress in tissues, as a result of which healthy tissues are also damaged [50]. It seems that the most important cause of doxorubicin poisoning in the liver and heart tissue is damage caused by free radicals [51]. In other words, treatment with doxorubicin leads to excessive production of free radicals inside the cell and thus causes oxidative stress, which damages the cell by disrupting the balance of oxidants and antioxidants [30]. Hosseini et al. confirmed the negative effects of doxorubicin, such as oxidative stress and tissue damage created in the liver and heart, which were revealed by the imbalance of antioxidant levels and stress proteins in both tissues [52]. Doxorubicin injection leads to a significant increase in MDA levels and a decrease in the activity of antioxidants in different tissues [17]. Hashemi also showed that the MDA index increased in the group treated with doxorubicin [53]. In this regard, Ashrafi et al. showed that DOX induction caused a significant increase in MDA and NO and a significant decrease in SOD activity in the heart and liver tissues [54].
In the present study, an increase in the amount of MDA was observed in HeLa cancer cells and normal fibroblasts treated with doxorubicin compared to the control. The amount of MDA in cancer and normal cell lines that were affected by Naja naja oxiana snake venom also increased, and this increase in MDA was more visible in cancer cells.
Fakhri et al. showed that Naja naja oxiana snake venom increased the level of ROS in the colon cancer cell line, but it was not observed in healthy cell lines [55]. Ibrahim et al. also stated that Naja naja oxiana snake venom is a strong inducer of apoptosis through the oxidative stress cycle in HepG2, MCF7, and DU145 cancer cell lines, which has minimal effects on normal cells [56]. Seydi et al. showed that Naja naja oxiana snake venom increased the level of ROS and caused apoptosis [57]. Angji et al. found that the level of lactate dehydrogenase (LDH) enzyme, which is related to the oxidative cycle, increased after snake venom injection, but this increase was not statistically significant [26].
The results of our research, in line with the results of other studies, confirm the possible anticancer effect of Naja naja oxiana snake venom compared to doxorubicin on the HeLa cancer cell line. Therefore, it can be said that this type of treatment can be useful in inhibiting cancer cells. This method can be used in the treatment of cancer by conducting more extensive research and additional studies on multiple cancer cell lines and also compared to other common chemotherapy drugs, such as cyclophosphamide.
Conclusion
Compared to the common drug doxorubicin, Naja naja oxiana snake venom has the highest inhibitory effect on the cancer cell line and the least effect on the normal cell line. By increasing the concentration and duration of treatment of cancer cells with snake venom, the proliferation rate in cells decreases, and the concentration of MDA increases.

Ethical Considerations
Compliance with ethical guidelines
This research was approved by the ethics committee of the Islamic Azad University, Flavarjan Branch, (IR.IAU.FALA.REC.1398.301).

Funding
This article is taken from the research project of Islamic Azad University, Falawarjan Branch, with project code 301/28367.

Authors' contributions
Statistical analysis: Jaber Zafari; Research: Fatemeh Javani Jouni; Statistical analysis and writing the first version: Elaha Shams; Final review and approval: Ali Asghar Rostagari.

Conflicts of interest
All authors declared no conflict of interest. 

Acknowledgements
The authors of this article thank all the officials who helped us in this research.


References

1. Moradi A, Eivazi Arvanagh N, Chekerzehi A, Hemmati M, Shahmoradi HR. [Melittin inhibit Rac1 expression in cervical cancer cell, hela cell (Persian)]. Journal of Laboratory & Diagnosis. 2014; 6(24):40-5. [Link]
2. Keskar V, Mohanty PS, Gemeinhart EJ, Gemeinhart RA. Cervical cancer treatment with a locally insertable controlled release delivery system. Journal of Controlled Release: Offcial Journal of The Controlled Release Society. 2006; 15(3):280-8. [DOI:10.1016/j.jconrel.2006.08.014] [PMID] [PMCID]
3. Chen C, Lu L, Yan S, Yi H, Yao H, Wu D, et al. Autophagy and doxorubicin resistance in cancer. Anti-Cancer Drugs. 2018; 29(1):1-9. [PMID]
4. Xu M, Sheng L, Zhu X, Zeng S, Chi D, Zhang GJ. Protective effect of tetrandrine on doxorubicininduced cardiotoxicity in rats. Tumori Journal. 2010; 96(3):460-4. [DOI:10.1177/030089161009600314] [PMID]
5. Mohammadi M, Arabi L, Alibolandi M. Doxorubicin-loaded composite nanogels for cancer treatment. Journal of Controlled Release. 2020; 328:171-91. [DOI:10.1016/j.jconrel.2020.08.033] [PMID]
6. Zhao Y, Alakhova DY, Zhao X, Band V, Batrakova EV, Kabanov AV. Eradication of cancer stem cells in triple negative breast cancer using doxorubicin/pluronic polymeric micelles. Nanomedicine: Nanotechnology, Biology and Medicine. 2020; 24:102124. [PMID] [PMCID]
7. Ma Z, Xu L, Liu D, Zhang X, Di S, Li W, et al. Utilizing melatonin to alleviate side effects of chemotherapy: A potentially good partner for treating cancer with ageing. Oxidative Medicine and Cellular Longevity. 2020; 2020:6841581. [DOI:10.1155/2020/6841581] [PMID] [PMCID]
8. Zanuso V, Fregoni V, Gervaso L. Side effects of adjuvant chemotherapy and their impact on outcome in elderly breast cancer patients: A cohort study. Future Science OA. 2020; 6(9):FSO617. [DOI:10.2144/fsoa-2020-0076] [PMID] [PMCID]
9. Ertekin MV, Koçer I, Karslioğlu I, Taysi S, Gepdiremen A, Sezen O, et al. Effects of oral Ginkgo biloba supplementation on cataract formation and oxidative stress occurring in lenses of rats exposed to total cranium radiotherapy. Japanese Journal of Ophthalmology. 2004; 48(5):499-502. [PMID]
10. Kumar V, Abbas AK, Aster JC. Robbins & cotran pathologic basis of disease. Philadelphia: Saunders/Elsevier. 2010. [Link]
11. Rezaeyan A, Haddadi G H, Hosseinzadeh M. [Evaluating superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and the histological changes of the lung tissue after γ-Irradiation in Rats (Persian)]. Journal of Advanced Biomedical Sciences. 2016; 6(2):235-45. [Link]
12. Barrera G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncology. 2012; 2012:137289. [PMID] [PMCID]
13. Kruk J. Overweight, obesity, oxidative stress and the risk of breast cancer. Asian Pacific Journal of Cancer Prevention. 2014; 15(22):9579-86. [PMID]
14. Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.Oxidative Medicine and Cellular Longevity. 2014; 2014:360438. [PMID] [PMCID]
15. Gonenc A, Ozkan Y, Torun M, Simsek B. Plasma malondialdehyde (MDA) levels in breast and lung cancer patients. Journal of Clinical Pharmacy and Therapeutics. 2001; 26(2):141-4. [DOI:10.1046/j.1365-2710.2001.00334.x] [PMID]
16. Abdel-Salam O, Youness E, Hafez H. The antioxidant status of the plasma in patients with breast cancer undergoing chemotherapy. Open Journal of Molecular and Integrative Physiology. 2011; 1(3):29-35. [DOI:10.4236/ojmip.2011.13005]
17. Blech DM, Borders CL. Hydroperoxide anion, HO-2, is an affinity reagent for the inactivation of yeast Cu,Zn superoxide dismutase: Modification of one histidine per subunit. Archives of Biochemistry and Biophysics. 1983; 224(2):579-86. [DOI:10.1016/0003-9861(83)90245-X]
18. Hashemipour M, Mehrabizadeh-Honarmand H, Falsafi F, Rajabalian S, Hosseini R. [Cytotoxic effects of Cyclooxygenase enzyme inhibitor drugs (COX1, COX2) on KB cell line: An in-vitro study (Persian)]. Journal of Iranian Dental Association. 2009; 21(3):171-80. [Link]
19. Cruz LS, Vargas R, Lopes AA. Snakebite envenomation and death in the developing world. Ethnicity & Disease. 2009; 19(1 Suppl 1):S1-42-6. [PMID]
20. Haji R. Venomous snakes and snake bite. Gravenhurst: Zoocheck Canada Inc; 2000. [Link]
21. Bailey P, Wilce J. Venom as a source of useful biologically active molecules. Emergency Medicine. 2001; 13(1):28-36. [PMID]
22. Williams D, Welton R. The composition and actions of Papua New Guinean snake venoms. In Williams D, Jensen SD, Winkel KD, editors. Clinical management of snakebite in papua New Guinea. Melbourne: Australian Venom Research Unit; 2000. [Link]
23. Li L, Huang J, Lin Y. Snake venoms in cancer therapy: Past, present and future. Toxins. 2018; 10(9):346. [PMID] [PMCID]
24. Pal SK, Gomes A, Dasgupta SC, Gomes A. Snake venom as therapeutic agents: From toxin to drug development. Indian Journal of Experimental Biology. 2002; 40(12):1353-8. [PMID]
25. Jamunaa A, Vejayan J, Halijah I, Sharifah S, Ambu S. Cytotoxicity of Southeast Asian snake venoms. Journal of Venomous Animals and Toxins including Tropical Diseases. 2012; 18(2):150-6. [DOI:10.1590/S1678-91992012000200004]
26. Ebrahim K, Vatanpour H, Zare A, Shirazi FH, Nakhjavani M. Anticancer activity a of caspian cobra (Naja naja Oxiana) snake venom in human cancer cell lines via induction of apoptosis. Iranian Journal of Pharmaceutical Research. 2016; 15(Suppl):101-12. [PMID]
27. Strizhkov BN, Blishchenko EY, Satpaev DK, Karelin AA. Both neurotoxin II from venom of Naja naja oxiana and its endogeneous analogue induce apoptosis in tumor cells. FEBS letters. 1994; 340(1-2):22-4. [DOI:10.1016/0014-5793(94)80165-7]
28. Soleimani S, Azarnia M, Sharifi Z, Soleimani H, Zamanian M. [Evaluation of the Hemiscorpius lepturus scorpion venom on cell viability of K-562 cell line (Persian)]. Complementary Medicine Journal. 2016; 5(4):1364-74. [Link]
29. Tajvidi E, Nahavandizadeh N, Pournaderi M, Pourrashid AZ, Bossaghzadeh F, Khoshnood Z. Study the antioxidant effects of blue-green algae Spirulina extract on ROS and MDA production in human lung cancer cells. Biochemistry and Biophysics Reports. 2021; 28:101139. [PMID]

30. Nagai K, Fukuno S, Oda A, Konishi H. Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. Anticancer. Drugs. 2016; 27(1):17-23. [PMID]
31. Liu CC, Yang H, Zhang LL. Biotoxins for cancer therapy. Asian Pacific Journal of Cancer Prevention. 2014; 15(12):4753-8. [PMID]
32. Andreotti N, Jouirou B, Mouhat S, Mouhat L, Sabatier JM. Therapeutic value of peptides from animal venoms. Comprehensive Natural Products II. 2010; 5:287-303. [DOI:10.1016/B978-008045382-8.00114-3]
33. Kini RM, Doley R. Structure, function and evolution of three-finger toxins: Mini proteins with multiple targets. Toxicon. 2010; 56(6):855-67. [PMID]
34. Chaim-Matyas A, Borkow G, Ovadia M. Isolation and characterization of a cytotoxin P4 from the venom of Naja nigricollis nigricollis preferentially active on tumor cells. Biochemistry International. 1991; 24(3):415-21. [PMID]
35. Stevens-Truss R, Messer WS Jr, Hinman CL. Heart and T-lymphocyte cell surfaces both exhibit positive cooperativity in binding a membrane-lytic toxin. The Journal of Membrane Biology. 1996; 150(1):113-22. [DOI:10.1007/s002329900035] [PMID]
36. Chen YH, Hu CT, Yang JT. Membrane disintegration and hemolysis of human erythrocytes by snake venom cardiotoxin (a membrane-disruptive polypeptide). Biochemistry International. 1984; 8(2):329-38. [PMID]
37. Ahn MY, Lee BM, Kim YS. Characterization and cytotoxicity of L-amino acid oxidase from the venom of king cobra (Ophiophagus hannah). The International Journal of Biochemistry & Cell Biology. 1997; 29(6):911-9. [DOI:10.1016/S1357-2725(97)00024-1]
38. Son DJ, Park MH, Chae SJ, Moon SO, Lee JW, Song HS, et al. Inhibitory effect of snake venom toxin from Vipera lebetina turanica on hormone-refractory human prostate cancer cell growth: Induction of apoptosis through inactivation of nuclear factor kappaB. Molecular Cancer Therapeutics. 2007; 6(2):675-83. [PMID]
39. Thangam R, Gunasekaran P, Kaveri K, Sridevi G, Sundarraj S, Paulpandi M, et al. A novel disintegrin protein from Naja naja venom induces cytotoxicity and apoptosis in human cancer cell lines in-vitro. Process Biochemistry. 2012; 47(8):1243-9. [DOI:10.1016/j.procbio.2012.04.020]
40. Feofanov AV, Sharonov GV, Astapova MV, Rodionov DI, Utkin YN, Arseniev AS. Cancer cell injury by cytotoxins from cobra venom is mediated through lysosomal damage. The Biochemical Journal. 2005; 390(Pt 1):11-8. [PMID]
41. Derakhshani A, Silvestris N, Haji-Asgarzadeh K, Mahmoudzadeh S, Fereidouni M, Paradiso AV, et al. Expression and Characterization of a novel recombinant cytotoxin II from Naja naja oxiana venom: A potential treatment for breast cancer. International Journal of Biological Macromolecules. 2020, 162:1283-92. [DOI:10.20944/preprints202005.0098.v1]
42. Das T, Bhattacharya S, Halder B, Biswas A, Das Gupta S, Gomes A, et al. Cytotoxic and antioxidant property of a purified fraction (NN-32) of Indian Naja naja venom on Ehrlich ascites carcinoma in BALB/c mice. Toxicon. 2011. 57(7-8):1065-72. [PMID]
43. Zhang L, Wei LJ. ACTX-8, a cytotoxic L-amino acid oxidase isolated from Agkistrodon acutus snake venom, induces apoptosis in Hela cervical cancer cells.Life Sciences. 2007; 80(13):1189-97. [PMID]
44. Debnath A, Saha A, Gomes A, Biswas S, Chakrabarti P, Giri B, et al. A lethal cardiotoxic-cytotoxic protein from the Indian monocellate cobra (Naja kaouthia) venom. Toxicon. 2010; 56(4):569-79. [PMID]
45. Shanbhag VKL. Applications of snake venoms in treatment of cancer. Asian Pacific Journal of Tropical Biomedicine. 2015; 5(4):275-76. [DOI:10.1016/S2221-1691(15)30344-0]
46. De Rosa M, Pace U, Rega D, Costabile V, Duraturo F, Izzo P, et al. Genetics, diagnosis and management of colorectal cancer (review). Oncology Reports. 2015; 34(3):1087-96. [PMID]
47. Sharifi I, Tabatabaie F, Nikpour S, Mostafavi M, Tavakoli Oliaee R, Sharifi F, et al. The effect of Naja naja oxiana snake venom against leishmania tropica confirmed by advanced assays. Acta Parasitologica. 2021; 66(2):475-86. [PMID]
48. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Current Biology: CB. 2014; 24(10):453-62. [PMID] [PMCID]
49. Khoshtabiat L, Mahdavi M. [The role of oxidative stress in proliferation and cell death (Persian)]. Journal of Mazandaran University of Medical Sciences. 2015; 25(127):130-45. [Link]
50. Marques-Aleixo I, Santos-Alves E, Mariani D, Rizo-Roca D, Padrão AI, Rocha-Rodrigues S, et al. Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress. Mitochondrion. 2015; 20:22-33. [PMID]
51. Yap MY, Lo YL, Talbot K, Ong WY. Oxidative stress reduces levels of dysbindin-1A via its PEST domain. Neurochemistry International. 2014; 79:65-9. [DOI:10.1016/j.neuint.2014.10.001] [PMID]
52. Sadat Hoseini SK, Dabidi Roshan V. [The effect of six weeks of voluntary wheel running exercise on hepatic superoxide dismutase levels and apoptosis-inducing factor after doxorubicin administration in aging model rats (Persian)]. Feyz. 2018; 22(3):267-73. [Link]
53. Hashemi-Chashmi SZ, Dabidiroshan V. [The effect of pretreatment of aerobic training on some of the pulmonary stress indices against the toxicity of doxorubicin (Persian)]. Journal of Isfahan Medical School . 2019; 37(559):1422-7. [Link]
54. Ashrafi J, Dabidi Roshan V, Mahjoub S. Cardioprotective effects of aerobic regular exercise against doxorubicin-induced oxidative stress in rat. African Journal of Pharmacy and Pharmacology. 2012; 6(31):2380-8. [Link]
55. Fakhri A, Omranipour R, Fakhri S, Mirshamsi M, Zangeneh F, Vatanpour H, et al. Naja naja oxiana venom fraction selectively induces ros-mediated apoptosis in human colorectal tumor cells by directly targeting mitochondria. Asian Pacific Journal of Cancer Prevention. 2017; 18(8):2201-8. [PMID]
56. Seydi E, Babaei S, Fakhri A, Pourahmad J. Selective toxicity of Caspian cobra (Naja oxiana) venom on liver cancer cell mitochondria. Asian Pacific Journal of Tropical Biomedicine. 2017; 7(5):460-5. [DOI:10.1016/j.apjtb.2017.01.021]
57. Angajia SA, Houshmandia A, Zare Mirakabadib A. Acute effects of the Iranian snake (Naja naja oxiana) venom on heart. Biomacromolecular Journal. 2016: 2(2):97-101. [Link]