An Insight into the Role of Bee Venom and Melittin Against Tumor Cells: A Review of Breast Cancer therapy

Roha Tariq (1), Amna Liaqat (2), Usama Ahmed Khalid (3)
(1) Department of Biotechnology, Lahore College for Women University, Lahore, Pakistan, Pakistan,
(2) Department of Healthcare Biotechnology, Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan, Pakistan,
(3) Department of Biotechnology & Genetic Engineering, Kohat University of Science and Technology, Kohat, Khyber Pakhtunkhwa, Pakistan, Pakistan

Abstract

Background: Breast cancer is the most common and life-threatening cancer in females characterized by the abnormal proliferation of tumor cells in lobules and ducts. For years, many anti-breast cancer drugs have been tested with some of them showing severe health problems and drug resistance. Recently, different biological and pharmacological actions of bee venom have been indicated to play anti-bacterial, anti-viral and anti-inflammatory role against different cancers especially breast cancer.


Methods: This review study is based on PubMed, Google Scholar and PubMed search. Search terms used were Melittin, Breast cancer and Honey Bee Venom.


Results: Many studies have shown that a positively charged C-terminal sequence of mellitin facilitates plasma membrane contact and antitumor action. Precise targeting and selective activity of melittin has been found in recent studies as it suppresses the activation of growth factor receptors in HER2-enriched and triple-negative breast cancer that are generally difficult to treat. Significantly, it leaves healthy cells intact. The most striking feature of melittin is the pore formation property. Monomers of melittin bind to the plasma membrane of cancer cells in a collective manner and start forming pores, ultimately bringing cell lysis. 


Conclusion: Since melittin has a very selective action against the HER-2 related tumors, a combinational therapy of melittin and HER-2 targeted agents could be a very potent strategy in breast cancer. This review reflects the importance of honey bee venom and melittin as a potential therapy for aggressive breast cancer.

Full text article

Generated from XML file

References

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86.

Clegg LX, Reichman ME, Miller BA, Hankey BF, Singh GK, et al. Impact of socioeconomic status on cancer incidence and stage at diagnosis: selected findings from the surveillance, epidemiology, and end results: National Longitudinal Mortality Study. Cancer causes & control. 2009;20(4):417-35.

American cancer society. What is breast cancer? 2009

MA. K. Breast cancer: Merck Manual Consumer Version 2020 [Available from: https://www.merckmanuals.com/home/women-s-health-issues/breast-disorders/breast-cancer ]

Breast Cancer Stages. 2020 [Available from: Breastcancer.org.]

Rahimzadeh M, Baghestani AR, Gohari MR, Pourhoseingholi MA. Estimation of the cure rate in Iranian breast cancer patients. Asian Pac J Cancer Prev. 2014;15(12):4839-42.

Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1(4):505-27.

Eberl MM, Sunga AY, Farrell CD, Mahoney MC. Patients with a family history of cancer: identification and management. The Journal of the American Board of Family Practice. 2005;18(3):211-7.

Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005;353(3):229-37.

Stoppler MC. Breast Cancer. emedicinehealth. 2020.

Wehbe R, Frangieh J, Rima M, El Obeid D, Sabatier JM, et al. Bee Venom: Overview of Main Compounds and Bioactivities for Therapeutic Interests. Molecules. 2019;24(16).

Global Burden of Disease Cancer C, Fitzmaurice C, Akinyemiju TF, Al Lami FH, Alam T, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2018;4(11):1553-68.

Orsolic N. Possible molecular targets of bee venom in the treatment of cancer: application and perspectives. Onco Therapeutics. 2013;4(3-4).

Fidelio GD, Maggio B, Cumar FA. Interaction of myelin basic protein, melittin and bovine serum albumin with gangliosides, sulphatide and neutral glycosphingolipids in mixed monolayers. Chem Phys Lipids. 1984;35(3):231-45.

Jamasbi E, Mularski A, Separovic F. Model Membrane and Cell Studies of Antimicrobial Activity of Melittin Analogues. Curr Top Med Chem. 2016;16(1):40-5.

Polyak K. Breast cancer: origins and evolution. J Clin Invest. 2007;117(11):3155-63.

A. F. What to know about breast cancer. Medical News Today. 2017.

B. B. Rewari, SUDHIR. Gupta. Radiation Therapy in the Management of Cancer. 50 Years of Cancer Control in India. Ministry of Health and Family Welfare. 2019.

Do N, Weindl G, Grohmann L, Salwiczek M, Koksch B, et al. Cationic membrane-active peptides - anticancer and antifungal activity as well as penetration into human skin. Exp Dermatol. 2014;23(5):326-31.

Forman D, Ferlay J, Stewart B, Wild C. The global and regional burden of cancer. World cancer report. 2014;2014:16-53.

Deng Y, Sriwiriyajan S, Tedasen A, Hiransai P, Graidist P. Anti-cancer effects of Piper nigrum via inducing multiple molecular signaling in vivo and in vitro. J Ethnopharmacol. 2016;188:87-95.

Chaisakul J, Hodgson WC, Kuruppu S, Prasongsook N. Effects of Animal Venoms and Toxins on Hallmarks of Cancer. J Cancer. 2016;7(11):1571-8.

Kim YW, Chaturvedi PK, Chun SN, Lee YG, Ahn WS. Honeybee venom possesses anticancer and antiviral effects by differential inhibition of HPV E6 and E7 expression on cervical cancer cell line. Oncol Rep. 2015;33(4):1675-82.

Liu CC, Hao DJ, Zhang Q, An J, Zhao JJ, et al. Application of bee venom and its main constituent melittin for cancer treatment. Cancer Chemother Pharmacol. 2016;78(6):1113-30.

Liu CC, Yang H, Zhang LL, Zhang Q, Chen B, et al. Biotoxins for cancer therapy. Asian Pac J Cancer Prev. 2014;15(12):4753-8.

Diaz-Garcia A, Morier-Diaz L, Frion-Herrera Y, Rodriguez-Sanchez H, Caballero-Lorenzo Y, 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.

Premratanachai P, Chanchao C. Review of the anticancer activities of bee products. Asian Pac J Trop Biomed. 2014;4(5):337-44.

Soletti RC, de Faria GP, Vernal J, Terenzi H, Anderluh G, et al. Potentiation of anticancer-drug cytotoxicity by sea anemone pore-forming proteins in human glioblastoma cells. Anticancer Drugs. 2008;19(5):517-25.

Al-Sadoon MK, Rabah DM, Badr G. Enhanced anticancer efficacy of snake venom combined with silica nanoparticles in a murine model of human multiple myeloma: molecular targets for cell cycle arrest and apoptosis induction. Cell Immunol. 2013;284(1-2):129-38.

Zhang Y. Why do we study animal toxins? Dongwuxue Yanjiu. 2015;36(4):183-222.

Rady I, Siddiqui IA, Rady M, Mukhtar H. Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy. Cancer Lett. 2017;402:16-31.

Hossen MS, Shapla UM, Gan SH, Khalil MI. Impact of Bee Venom Enzymes on Diseases and Immune Responses. Molecules. 2016;22(1).

Moreno M, Giralt E. Three valuable peptides from bee and wasp venoms for therapeutic and biotechnological use: melittin, apamin and mastoparan. Toxins (Basel). 2015;7(4):1126-50.

Kim DH, Lee HW, Park HW, Lee HW, Chun KH. Bee venom inhibits the proliferation and migration of cervical-cancer cells in an HPV E6/E7-dependent manner. BMB Rep. 2020;53(8):419-24.

Lee JA, Son MJ, Choi J, Jun JH, Kim JI, et al. Bee venom acupuncture for rheumatoid arthritis: a systematic review of randomised clinical trials. BMJ Open. 2014;4(11):e006140.

Jeong YJ, Shin JM, Bae YS, Cho HJ, Park KK, et al. Melittin has a chondroprotective effect by inhibiting MMP-1 and MMP-8 expressions via blocking NF-kappaB and AP-1 signaling pathway in chondrocytes. Int Immunopharmacol. 2015;25(2):400-5.

Son DJ, Lee JW, Lee YH, Song HS, Lee CK, et al. Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacol Ther. 2007; 115(2):246-70.

Ip SW, Liao SS, Lin SY, Lin JP, Yang JS, et al. The role of mitochondria in bee venom-induced apoptosis in human breast cancer MCF7 cells. In Vivo. 2008;22(2):237-45.

Jang MH, Shin MC, Lim S, Han SM, Park HJ, et al. Bee venom induces apoptosis and inhibits expression of cyclooxygenase-2 mRNA in human lung cancer cell line NCI-H1299. J Pharmacol Sci. 2003; 91(2):95-104.

Jo M, Park MH, Kollipara PS, An BJ, Song HS, et al. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway. Toxicol Appl Pharmacol. 2012;258(1):72-81.

Tu WC, Wu CC, Hsieh HL, Chen CY, Hsu SL. Honeybee venom induces calcium-dependent but caspase-independent apoptotic cell death in human melanoma A2058 cells. Toxicon. 2008;52(2):318-29.

Ip SW, Chu YL, Yu CS, Chen PY, Ho HC, et al. Bee venom induces apoptosis through intracellular Ca2+ -modulated intrinsic death pathway in human bladder cancer cells. Int J Urol. 2012;19(1):61-70.

Moon DO, Park SY, Heo MS, Kim KC, Park C, et al. Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. Int Immunopharmacol. 2006;6(12):1796-807.

Hussein AA, Nabil ZI, Zalat SM, Rakha MK. Comparative study of the venoms from three species of bees: effects on heart activity and blood. J Nat Toxins. 2001;10(4):343-57.

Orlov B, Romanova E, Omarov S. Immunological properties of bee venom 28th Int. Congr. Apicult. Acapulco. Mexico, Apimondia Publishing House, Bucharest; 1981.

Shaposhnikova VV, Egorova MV, Kudryavtsev AA, Levitman M, Korystov Yu N. The effect of melittin on proliferation and death of thymocytes. FEBS Lett. 1997;410(2-3):285-8.

Dotimas E, Hider R. Honeybee venom. Bee world. 1987;68(2):51-70.

Habermann E. Bee and wasp venoms. Science. 1972;177(4046):314-22.

Shi W, Li C, Li M, Zong X, Han D, et al. Antimicrobial peptide melittin against Xanthomonas oryzae pv. oryzae, the bacterial leaf blight pathogen in rice. Appl Microbiol Biotechnol. 2016;100(11):5059-67.

Skalickova S, Heger Z, Krejcova L, Pekarik V, Bastl K, et al. Perspective of Use of Antiviral Peptides against Influenza Virus. Viruses. 2015;7(10):5428-42.

Adade CM, Oliveira IR, Pais JA, Souto-Padron T. Melittin peptide kills Trypanosoma cruzi parasites by inducing different cell death pathways. Toxicon. 2013;69:227-39.

Pereira AV, de Barros G, Pinto EG, Tempone AG, Orsi Rde O, et al. Melittin induces in vitro death of Leishmania (Leishmania) infantum by triggering the cellular innate immune response. J Venom Anim Toxins Incl Trop Dis. 2016;22:1.

Sisakht M, Mashkani B, Bazi A, Ostadi H, Zare M, et al. Bee venom induces apoptosis and suppresses matrix metaloprotease-2 expression in human glioblastoma cells. Rev Bras Farmacogn. 2017;27:324-8.

Killion JJ, Dunn JD. Differential cytolysis of murine spleen, bone-marrow and leukemia cells by melittin reveals differences in membrane topography. Biochem Biophys Res Commun. 1986;139(1):222-7.

Zarrinnahad H, Mahmoodzadeh A, Hamidi MP, Mahdavi M, Moradi A, et al. Apoptotic Effect of Melittin Purified from Iranian Honey Bee Venom on Human Cervical Cancer HeLa Cell Line. Int J Pept Res Ther. 2018;24(4):563-70.

Gao D, Zhang J, Bai L, Li F, Dong Y, et al. Melittin induces NSCLC apoptosis via inhibition of miR-183. Onco Targets Ther. 2018;11:4511-23.

Wang X, Li H, Lu X, Wen C, Huo Z, et al. Melittin-induced long non-coding RNA NONHSAT105177 inhibits proliferation and migration of pancreatic ductal adenocarcinoma. Cell Death Dis. 2018;9(10):940.

Duffy C, Sorolla A, Wang E, Golden E, Woodward E, 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.

Park MH, Choi MS, Kwak DH, Oh KW, Yoon DY, et al. Anti-cancer effect of bee venom in prostate cancer cells through activation of caspase pathway via inactivation of NF-kappaB. Prostate. 2011;71(8):801-12.

Alizadehnohi M, Nabiuni M, Nazari Z, Safaeinejad Z, Irian S. The synergistic cytotoxic effect of cisplatin and honey bee venom on human ovarian cancer cell line A2780cp. J Venom Res. 2012;3:22-7.

Kondratskyi A, Kondratska K, Skryma R, Prevarskaya N. Ion channels in the regulation of apoptosis. Biochim Biophys Acta. 2015;1848(10 Pt B):2532-46.

Orsolic N. Potentiation of bleomycin lethality in HeLa and V79 cells by bee venom. Arh Hig Rada Toksikol. 2009;60(3):317-26.

Chu ST, Cheng HH, Huang CJ, Chang HC, Chi CC, et al. Phospholipase A2-independent Ca2+ entry and subsequent apoptosis induced by melittin in human MG63 osteosarcoma cells. Life Sci. 2007;80(4):364-9.

Liu S, Yu M, He Y, Xiao L, Wang F, et al. Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway. Hepatology. 2008;47(6):1964-73.

Jeong YJ, Choi Y, Shin JM, Cho HJ, Kang JH, et al. Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K/Akt/mTOR signaling pathway in breast cancer cells. Food Chem Toxicol. 2014;68:218-25.

Park JH, Jeong Y-J, Park K-K, Cho H-J, Chung I-K, et al. Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-κB and AP-1-dependent MMP-9 expression. Mol Cells. 2010;29(2):209-15.

Zhu H, Yang X, Liu J, Ge Y, Qin Q, et al. Melittin radiosensitizes esophageal squamous cell carcinoma with induction of apoptosis in vitro and in vivo. Tumour Biol. 2014;35(9):8699-705.

Vento R, D'Alessandro N, Giuliano M, Lauricella M, Carabillo M, et al. Induction of apoptosis by arachidonic acid in human retinoblastoma Y79 cells: involvement of oxidative stress. Exp Eye Res. 2000;70(4):503-17.

Anders C, Carey LA. Understanding and treating triple-negative breast cancer. Oncology (Williston Park). 2008;22(11):1233-9; discussion 9-40, 43.

Yao H, He G, Yan S, Chen C, Song L, et al. Triple-negative breast cancer: is there a treatment on the horizon? Oncotarget. 2017;8(1):1913-24.

Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 2006;24(36):5652-7.

Lee MT, Sun TL, Hung WC, Huang HW. Process of inducing pores in membranes by melittin. Proc Natl Acad Sci U S A. 2013;110(35):14243-8.

Lee MT, Hung WC, Chen FY, Huang HW. Mechanism and kinetics of pore formation in membranes by water-soluble amphipathic peptides. Proc Natl Acad Sci U S A. 2008;105(13):5087-92.

van den Bogaart G, Guzman JV, Mika JT, Poolman B. On the mechanism of pore formation by melittin. J Biol Chem. 2008;283(49):33854-7.

Fisusi FA, Akala EO. Drug Combinations in Breast Cancer Therapy. Pharm Nanotechnol. 2019;7(1):3-23.

Lee C, Bae SS, Joo H, Bae H. Melittin suppresses tumor progression by regulating tumor-associated macrophages in a Lewis lung carcinoma mouse model. Oncotarget. 2017;8(33):54951-65.

Pan H, Soman NR, Schlesinger PH, Lanza GM, Wickline SA. Cytolytic peptide nanoparticles ('NanoBees') for cancer therapy. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2011;3(3):318-27.

Authors

Roha Tariq
Amna Liaqat
Usama Ahmed Khalid
usama.ahmed.khalid@gmail.com (Primary Contact)
1.
Tariq R, Liaqat A, Khalid UA. An Insight into the Role of Bee Venom and Melittin Against Tumor Cells: A Review of Breast Cancer therapy. Arch Breast Cancer [Internet]. 2021 Oct. 31 [cited 2024 Jul. 27];:267-76. Available from: https://archbreastcancer.com/index.php/abc/article/view/374

Article Details