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Kwon, N.;  Sung, S.;  Sung, H.;  Park, J. Anticancer Activity of Bee Venom Components against BC. Encyclopedia. Available online: https://encyclopedia.pub/entry/25564 (accessed on 25 June 2024).
Kwon N,  Sung S,  Sung H,  Park J. Anticancer Activity of Bee Venom Components against BC. Encyclopedia. Available at: https://encyclopedia.pub/entry/25564. Accessed June 25, 2024.
Kwon, Na-Yoen, Soo-Hyun Sung, Hyun-Kyung Sung, Jang-Kyung Park. "Anticancer Activity of Bee Venom Components against BC" Encyclopedia, https://encyclopedia.pub/entry/25564 (accessed June 25, 2024).
Kwon, N.,  Sung, S.,  Sung, H., & Park, J. (2022, July 27). Anticancer Activity of Bee Venom Components against BC. In Encyclopedia. https://encyclopedia.pub/entry/25564
Kwon, Na-Yoen, et al. "Anticancer Activity of Bee Venom Components against BC." Encyclopedia. Web. 27 July, 2022.
Anticancer Activity of Bee Venom Components against BC
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While the survival rate has increased due to treatments for breast cancer, the quality of life has decreased because of the side effects of chemotherapy. Various toxins are being developed as alternative breast cancer treatments, and bee venom is drawing attention as one of them.

bee venom melittin

1. Cytotoxic Activity

As cancer cells are less likely to develop resistance to a membrane pore former, combining a chemotherapeutic medication with melittin could be an effective synergistic treatment [1].
Hematyar et al. [2] showed that all drug formulations, such as melittin, doxorubicin, and doxorubicin/melittin-loaded citric acid-functionalized Fe3O4 magnetic nanoparticles (doxorubicin/melittin-loaded CA-MNPs), decreased the cell growth in a dose-dependent manner and that doxorubicin and melittin delivered together exhibited a synergistic effect on MCF-7 breast cancer (BC) cell proliferation. Because anticancer drugs were more effectively delivered into cells via internalized nanoparticles at the same dose, doxorubicin/melittin-loaded CA-MNPs had better cytotoxic action than free doxorubicin/melittin (1:4).
Niosomes, which are non-ionic surfactant vesicles, have the ability to directly target tumor cells by increasing efficacy and lowering the side effects [3]. The negative effects of drug protection, high stability, and long shelf life are among the most prominent reasons for the delay in drug delivery to target cells in pharmacological research [4]. In order to prevent these side effects, Moghaddam et al. [5] used niosomes as nanocarriers for melittin to enhance the anticancer effects and prevent the hemolytic side effects. They proved that melittin-loaded nanoniosomes had higher anticancer effects and fewer side effects in breast cancer cell treatment.
Because melittin, a peptide found in bee venom, is known to cause nonspecific cytotoxicity and hemolysis, it is important to reduce the dosage of melittin for cancer treatment. Shaw et al. [6] attempted to lower the dosage of melittin by combining melittin with plasma-treated phosphate-buffered saline (PT-PBS), which can induce cancer cell death via oxidative stress-mediated pathways. Melittin alone exerted a dose-dependent cytotoxic effect, apoptosis, and lipid peroxidation in MCF-7 cells. However, when synthesized with PT-PBS, a synergistic effect was observed. As melittin is not oxidized by plasma, this effect is thought to be attributable to the improved potential of melittin through the cell membrane during plasma-induced oxidation of phospholipids.
Cell-based experiments are among the most important studies for confirming the efficacy and mechanism of drugs. Cell culture, which is the most critical part of cell-based experiments, is the basis for cell responses to drugs, compounds, etc. [7]. Several experiments are based on two-dimensional (2D) cell culture. However, because this provides only a uniform environment, the need for three-dimensional (3D) cell culture that can mimic the microenvironment of normal and cancer cells has been raised. A 3D cell culture is different from a 2D cell culture with respect to morphology, proliferation, and stage of cell cycle, and cancer studies using the 3D culture have already been conducted [8][9].
Kamran et al. [10] administered bee venom to MCF-7 cells in proportion to the dose in order to confirm the cytotoxic and apoptotic effects of bee venom. The results regarding the reduction of cell viability and the inhibition of cell growth were confirmed in a 3D culture. Similar to other studies, higher resistance to the cytotoxic effect of bee venom was observed in a 3D culture than in a 2D culture.

2. Apoptosis Activity

Apoptosis is a complex human defense mechanism that occurs under genetic control due to specific stages of occurrence, DNA damage, and viral infection [11]. It plays an important role in removing damaged cells at an individual conservation level and can be the main cause of deviation from the normal cell cycle [12].
Yeo et al. [13] explored the apoptotic effect of bee venom in MCF-7 cells by determining the coefficient of the number of living cells, morphological changes, biochemical changes, and gene expression changes in MCF-7 cells. Taken together, their results indicated that the suppression of human breast cancer cell proliferation caused by bee venom was linked to the induction of apoptosis. Jung et al. [14] attempted to demonstrate the effects of bee venom treatment by conducting a multivariate analysis. Bee venom had an effect on MDA-MB-231 cells in a concentration- and time-dependent manner through cell death-related processes involving protein denaturation and degradation, as well as DNA fragmentation.
Similarly, melittin is amphipathic and capable of disrupting the integrity of the tumor cell membrane bilayer, leading to flaws, disruption, or pore formation. Despite the exceptional anticancer effect of melittin, it is known to be toxic to normal cells, and an appropriate vehicle is required to produce the therapeutic effect. Nevertheless, Sharkawi et al. [1] showed that melittin could be toxic to tumor cells and that the dose worked just before it affected the normal cells. Furthermore, as confirmed by other studies, Sharkawi et al. [1] reported that bee venom and melittin caused cancer cell apoptosis by adjusting the genes related to apoptosis such as p53, Bax, and Bcl-2.

3. Cell Targeting

A previous study confirmed a significantly increased gene expression of fibroblast activation protein-α (FAP) compared with normal cells [15]. LeBeau et al. [16] evaluated FAP, a tumor stromal antigen overexpressed by cancer-associated fibroblasts, as a tumor-specific target [17]. Their study revealed that despite the function of FAP in tumors, the enzyme activity of FAP could be used to selectively activate high-intensity cytotoxins in peritumoral injection. This activation could lead to the death of tumor cells and produce a synergistic effect that causes tumor death within and around the stromal compartment.
While the effectiveness of cell targeting has been confirmed, it has a limitation in that cell targeting should be administered intratumorally and within the organ. Further studies are required to confirm its effectiveness according to the administration method.

4. Regulating Gene Expression

Matrix metalloproteinases (MMPs) are a group of enzymes required for extracellular matrix decomposition for cancer cell growth at metastatic sites [18]. MMP-9 plays a key role in the invasion and spread of human cancer cells [19].
Cho et al. [20] reported that bee venom did not abolish the expression of tissue inhibitors of metalloproteinases-1 and -2 and directly inhibited the ability of MCF-7 cells to invade and move by suppressing the expression of MMP-9. The inhibition of MMP-9 enzyme activity was caused by the inhibition of p39, JNK, and NF-Kb expression; among the components of the bee venom, melittin caused this effect.
Triple-negative breast cancer and human epidermal growth factor receptor-2 (HER2)-positive breast cancer are the most common breast cancers. Anti-HER2 treatment increases the survival rate of patients with early HER2-positive cancer. However, when it has progressed to the end of the stage, it becomes resistant to drugs and is therefore difficult to treat. Therefore, research on alternative methods for aggressive breast cancer treatment is required [21][22].
Duffy et al. [23] showed that bee venom and melittin dynamically regulated the downstream signaling pathway of breast cancer cells by inhibiting the phosphorylation of ligands of the epidermal growth factor receptor (EGFR) and HER2. Furthermore, melittin reacted more specifically to HER2- and EGFR-overexpressing breast cancer cells and showed greater toxicity than bee venom.

5. Cell Lysis

Monocyte-derived dendritic cells (moDCs), which are produced in peripheral blood precursor cells filled with tumor lysates or antigen, induce antitumor immune reactions when they are re-injected into patients [24]. In a previous study, it was confirmed that phospholipase A2 causes the maturation of moDCs through enzyme activation and NF-kB, activating protein-1, a nuclear factor of activated T-cells [25]. Putz et al. [26] attempted to determine the synergistic effect between phospholipase A2 (bv-sPLA2) and phosphatidylinositol-(3,4)-bisphosphate (PtdIns (3,4) P2) occurring during maturation of immunostimulatory moDCs mediating tumor cell lysis.
To quantify the amount of cell lysis, data were obtained by measuring [3H] thymidine incorporation. Although the incorporation of [3H] thymidine does not directly measure lytic capacity, it is a sensitive approach for detecting the proliferation of small numbers of unlysed cells that survive combined treatment. Putz et al. [26] identified T-47D cell inhibition and synergistic effects of bv-sPLA2 and PtdIns(3,4)P2, suggesting the possibility of an antitumor vaccine.

References

  1. Sharkawi, F.Z.; Saleh, S.S.; Sayed, A.F.M. Potential anticancer activity of snake venom, bee venom and their components in liver and breast carcinoma. Int. J. Pharm. Sci. Res. 2015, 6, 3224–3235.
  2. Hematyar, M.; Soleimani, M.; Es-Haghi, A.; Rezaei Mokarram, A. Synergistic co-delivery of doxorubicin and melittin using functionalized magnetic nanoparticles for cancer treatment: Loading and in vitro release study by LC-MS/MS. Artif. Cells Nanomed. Biotechnol. 2018, 46, S1226–S1235.
  3. Kanaani, L.; Javadi, I.; Ebrahimifar, M.; Shahmabadi, H.E.; Khiyavi, A.A.; Mehrdiba, T. Effects of cisplatin-loaded niosomal nanoparticles on BT-20 human breast carcinoma cells. Asian Pac. J. Cancer Prev. 2017, 18, 365–368.
  4. Kumar, G.P.; Rajeshwarrao, P. Nonionic surfactant vesicular systems for effective drug delivery—An overview. Acta Pharm. Sin. B 2011, 1, 208–219.
  5. Moghaddam, F.D.; Akbarzadeh, I.; Marzbankia, E.; Farid, M.; Khaledi, L.; Reihani, A.H.; Javidfar, M.; Mortazavi, P. Delivery of melittin-loaded niosomes for breast cancer treatment: An in vitro and in vivo evaluation of anti-cancer effect. Cancer Nanotechnol. 2021, 12, 14.
  6. Shaw, P.; Kumar, N.; Hammerschmid, D.; Privat-Maldonado, A.; Dewilde, S.; Bogaerts, A. Synergistic effects of melittin and plasma treatment: A promising approach for cancer therapy. Cancers 2019, 11, 1109.
  7. Edmondson, R.; Broglie, J.J.; Adcock, A.F.; Yang, L. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev. Technol. 2014, 12, 207–218.
  8. Chitcholtan, K.; Sykes, P.H.; Evans, J.J. The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer. J. Transl. Med. 2012, 10, 38.
  9. Nath, S.; Devi, G.R. Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacol. Ther. 2016, 163, 94–108.
  10. Kamran, M.R.; Zargan, J.; Keshavarzalikhani, H.; Hajinoormohamadi, A. The comparative cytotoxic effects of Apis mellifera crude venom on MCF-7 breast cancer cell line in 2D and 3D cell culture. Int. J. Pept. Res. Ther. 2020, 26, 1819–1828.
  11. Evans, V.G. Multiple pathways to apoptosis. Cell. Biol. Int. 1993, 17, 461–476.
  12. Shi, L.; Nishioka, W.K.; Th’ng, J.; Bradbury, E.M.; Litchfield, D.W.; Greenberg, A.H. Premature p34cdc2 activation required for apoptosis. Science 1994, 263, 1143–1145.
  13. Yeo, S.W.; Seo, J.C.; Choi, Y.H.; Jang, K.J. Induction of the growth inhibition and apoptosis by beevenom in human breast carcinoma MCF-7 Cells. J. Korean Acupunct. Mox. Med. Sci. 2003, 20, 45–62.
  14. Jung, G.B.; Huh, J.E.; Lee, H.J.; Kim, D.; Lee, G.J.; Park, H.K.; Lee, J.D. Anti-cancer effect of bee venom on human MDA-MB-231 breast cancer cells using Raman spectroscopy. Biomed. Opt. Express 2018, 9, 5703–5718.
  15. Ghilardi, C.; Chiorino, G.; Dossi, R.; Nagy, Z.; Giavazzi, R.; Bani, M. Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. BMC Genom. 2008, 9, 201.
  16. LeBeau, A.M.; Brennen, W.N.; Aggarwal, S.; Denmeade, S.R. Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol. Cancer Ther. 2009, 8, 1378–1386.
  17. Xia, Q.; Zhang, F.F.; Geng, F.; Liu, C.L.; Xu, P.; Lu, Z.Z.; Yu, B.; Wu, H.; Wu, J.X.; Zhang, H.H.; et al. Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model. Cancer Immunol. Immunother. 2016, 65, 613–624.
  18. Rahman, K.M.; Sarkar, F.H.; Banerjee, S.; Wang, Z.; Liao, D.J.; Hong, X.; Sarkar, N.H. Therapeutic intervention of experimental breast cancer bone metastasis by indole-3-carbinol in SCID-human mouse model. Mol. Cancer Ther. 2006, 5, 2747–2756.
  19. Mondal, S.; Adhikari, N.; Banerjee, S.; Amin, S.A.; Jha, T. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur. J. Med. Chem. 2020, 194, 112260.
  20. Cho, H.J.; Jeong, Y.J.; Park, K.K.; Park, Y.Y.; Chung, I.K.; Lee, K.G.; Yeo, J.H.; Han, S.M.; Bae, Y.S.; Chang, Y.C. Bee venom suppresses PMA-mediated MMP-9 gene activation via JNK/p38 and NF-kappaB-dependent mechanisms. J. Ethnopharmacol. 2010, 127, 662–668.
  21. de Melo Gagliato, D.; Jardim, D.L.; Marchesi, M.S.; Hortobagyi, G.N. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget 2016, 7, 64431–64446.
  22. Shah, S.P.; Roth, A.; Goya, R.; Oloumi, A.; Ha, G.; Zhao, Y.; Turashvili, G.; Ding, J.; Tse, K.; Haffari, G.; et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012, 486, 395–399.
  23. Duffy, C.; Sorolla, A.; Wang, E.; Golden, E.; Woodward, E.; Davern, K.; Ho, D.; Johnstone, E.; Pfleger, K.; Redfern, A.; et al. Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer. NPJ Precis. Oncol. 2020, 4, 24.
  24. Den Brok, M.H.; Nierkens, S.; Figdor, C.G.; Ruers, T.J.; Adema, G.J. Dendritic cells: Tools and targets for antitumor vaccination. Expert Rev. Vaccines 2005, 4, 699–710.
  25. Perrin-Cocon, L.; Agaugué, S.; Coutant, F.; Masurel, A.; Bezzine, S.; Lambeau, G.; André, P.; Lotteau, V. Secretory phospholipase A2 induces dendritic cell maturation. Eur. J. Immunol. 2004, 34, 2293–2302.
  26. Putz, T.; Ramoner, R.; Gander, H.; Rahm, A.; Bartsch, G.; Thurnher, M. Antitumor action and immune activation through cooperation of bee venom secretory phospholipase A2 and phosphatidylinositol-(3,4)-bisphosphate. Cancer Immunol. Immunother. 2006, 55, 1374–1383.
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