AN OVERVIEW OF THE ANTICANCER ACTIVITY OF PROPOLIS

Year 2022, , 122 - 130, 31.12.2022

Nazime Dogan , Farid Nasirli , Naime Nur Bozbeyoğlu Kart , Volkan Kuzucu

https://doi.org/10.55930/jonas.1190050

Abstract

Propolis is one of the most well-known bee products. Honeybees produce propolis by processing the resins they collect from different parts of green plants and trees, such as young buds, leaves and stems, with enzymes they secrete from their glands. This hive product, which has been traditionally used in folk medicine for centuries because of therapeutic properties and pharmacological applications, has a wide variety of types according to plant source, such as Green propolis, Red Propolis, Mediterranean Propolis, Poplar Propolis, Birch Propolis, Clusia Propolis and Pacific Propolis. Propolis, which is hard and brittle when cold, is soft and sticky when heated and can be brown, green and red in color. Honeybees use propolis to seal holes in their hives or honeycombs and to protect themselves against pathogens. Propolis is very important for colony welfare due to its detoxifying properties against various bee pathogens. Especially during the rotting in the hive, the growth of bacteria or mold is prevented with propolis and the health of hive is preserved. Plant resin, wax, pollen and essential oils are major components of propolis. The complex chemical content of propolis is closely related to many factors such as plant source, geographic region, harvest season and type of honeybees. There are many compounds with strong antioxidant activity such as aliphatic and aromatic acids, phenolic esters, fatty acids, alcohols, terpenes, steroids, alkaloids, chrysin, pinocembrin, apigenin, galangin, campherol, quercetin, cinnamic acid, coumaric acid and caffeic acid in the chemical content of propolis. The fact that propolis contains many active ingredients with strong antioxidant effects has also highlighted its tumor inhibitory effect. Today, there is an increase in the death rate due to cancer in the world. For this reason, scientists have focused on searching for new anticancer agents that are effective against cancer. Many scientific reports in the literature showed that propolis plays an important role in suppressing cancer cells. The anticancer activity of propolis on various tumor cells has been proven by in vivo and in vitro experiments by different cell mechanisms such as apoptosis induction, cell cycle inhibition, anti-angiogenesis effect, antiproliferative effect and prevention of metastasis. In particular, the presence of metabolites with high anticancer capacity, especially artepillin C, caffeic acid and caffeic acid phenethyl ester, has significantly affected cancer research in many ways and have helped researchers develop new strategies in the fight against the cancer. With this review, the importance of propolis in the search for anticancer agents was emphasized.

Keywords

Propolis, Anticancer Effect, Chemical compound

PROPOLİSİN ANTİKANSER AKTİVİTESİNE GENEL BİR BAKIŞ

Abstract

Propolis, bilinen en ünlü arı ürünlerinden biridir. Bal arıları propolisi, yeşil bitkilerin ve ağaçların genç tomurcuk, yaprak ve gövde gibi farklı kısımlarından topladıkları reçineleri salgı bezlerinden salgıladıkları enzimlerle işleyerek oluştururlar. Terapötik özellikleri ve farmakolojik uygulamalarından dolayı yüzyıllardır halk hekimliğinde kullanılan bu kovan ürününün, bitki kaynağına göre, Yeşil propolis, Kırmızı Propolis, Akdeniz propolisi, Kavak Propolisi, Huş Propolisi, Clusia Propolisi ve Pasifik Propolisi olmak üzere çok çeşitli türü mevcuttur. Soğukken sert ve kırılgan olan propolis, ısıtıldığında yumuşak ve yapışkan olup, kahverengi, yeşil ve kırmızı renkte olabilir. Bal arıları, propolisi kovanlarındaki ya da peteklerindeki delikleri kapatmak ve patojenlere karşı korumak için kullanırlar. Birçok arı patojenine karşı detoksifikasyon özelliğinden dolayı propolis, koloni refahı için çok önemlidir Özellikle kovandaki çürüme sırasında bakteri veya küf gelişimi propolis ile önlenir ve kovan sağlığı korunmuş olur. Propolisin kimyasal içeriğinde bitki reçinesi, balmumu, polen ve uçucu yağlar baskındır. Propolisin zengin ve karmaşık kimyasal içeriği, bitki kaynağı, coğrafik konum, hasat mevsimi ve bal arısının tipi gibi birçok faktörle yakından ilişkilidir. Propolisin kimyasal içeriğinde, alifatik ve aromatik asitler, fenolik esterler, yağ asitleri, alkoller, terpenler, steroidler, alkaloitler, krisin, pinosembrin, apigenin, galangin, kamferol, kersetin, sinnamik asit, kumarik asit ve kafeik asit gibi güçlü antioksidan aktiviteye sahip bileşikler mevcuttur. Propolisin güçlü antioksidan etkili çok sayıda aktif bileşen içermesi, onun tümör gelişimini durdurucu etkisini de ön plana çıkarmıştır. Günümüzde dünyada kansere bağlı ölüm oranında artış vardır. Bu nedenle bilim insanları kanserle mücadelede etkili yeni antikanser ajanlarını aramaya yoğunlaşmıştır. Literatürdeki bilimsel raporlar, propolisin kanser hücrelerinin baskılanmasında önemli rol oynadığını göstermektedir. Propolisin çeşitli tümör hücreleri üzerine antikanser etkisi apoptoz indüksiyonu, hücre döngüsü inhibisyonu, anti-anjiyogenez etki, antiproliferatif etki ve metastazın önlenmesi gibi çeşitli mekanizmalarla gerçekleştiği birçok araştırmacı tarafından in vivo ve in vitro deneylerle kanıtlanmıştır. Özellikle artepillin C, sinnamik asit, kafeik asit ve kafeik asit fenetil ester gibi yüksek antikanser kapasitesine sahip metabolitlerin varlığı, kanser araştırmalarını birçok yönden önemli ölçüde etkilemiş ve araştırmacıların kanserle mücadelesinde yeni stratejiler geliştirmesine de yardımcı olmuştur. Bu derleme ile antikanser ajan arayışında propolisin önemi vurgulanmıştır.

Keywords

Propolis, Antikanser Etki, Kimyasal İçerik

References

• 1. Ahn M.R., Kumazawa S., Usui Y., Nakamura J., Matsuka M., Zhu F. & Nakayama T. (2007). Antioxidant activity and constituents of propolis collected in various areas of China. Food Chemistry, 101, 1383–1392.
• 2. Ahn M.R., Kunimasa K., Kumazawa S., Nakayama T., Kaji K., Uto Y., Hori H., Nagasawa H. & Ohta T. (2009). Correlation between antiangiogenic activity and antioxidant activity of various components from propolis. Molecular Nutrition & Food Research, 53(5), 643–651.
• 3. Albini A., Bruno A., Noonan D. M. & Mortara L. (2018). Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy. Frontiers in Immunology, 9, 527.
• 4. Al-Hariri M. (2019). Immune's-boosting agent: Immunomodulation potentials of propolis. Journal of Family & Community Medicine, 26(1), 57–60.
• 5. Amoros M., Sauvager F., Girre L. & Cormier M. (1992). In vitro antiviral activity of propolis. Apidologie,23, 231-240.
• 6. An J.Y., Kim C., Park N.R., Jung H.S., Koo T.S., Yuk S.H., Lee E.H. & Cho S.H. (2022). Clinical Anti-aging Efficacy of Propolis Polymeric Nanoparticles Prepared by a Temperature-induced Phase Transition Method. Journal of Cosmetic Dermatology, 00:1–12.
• 7. Bankova V., Popova M. & Trusheva B. (2018). The phytochemistry of the honeybee. Phytochemistry, 155, 1-11.
• 8. Borawska M.H., Naliwajko S.K., Moskwa J., Markiewicz-Żukowska R., Puścion-Jakubik A. & Soroczyńska J. (2016). Anti-proliferative and anti-migration effects of Polish propolis combined with Hypericum perforatum L. on glioblastoma multiforme cell line U87MG. BMC Complementary and Alternative Medicine, 16, 367.
• 9. Chan G.C., Cheung K.W. & Sze D.M. (2013). The immunomodulatory and anticancer properties of propolis. Clinical Reviews in Allergy & Immunology, 44(3), 262–273.
• 10. Chikaraishi Y., Izuta H., Shimazawa M., Mishima S. & Hara H. (2010). Angiostatic effects of Brazilian green propolis and its chemical constituents. Molecular Nutrition & Food Research, 54(4), 566–575.
• 11. Daikh A., Segueni N., Dogan N.M., Arslan S., Mutlu D., Kivrak I., Akkal S. & Rhouati S. (2020). Comparative study of antibiofilm, cytotoxic activity and chemical composition of Algerian propolis. Journal of Apicultural Research, 59(2), 160–169.
• 12. Dawson M.A. & Kouzarides T. (2012). Cancer epigenetics: from mechanism to therapy. Cell, 150(1), 12–27.
• 13. Demestre M., Messerli S.M., Celli N., Shahhossini M., Kluwe L., Mautner V. & Maruta H. (2009). CAPE (caffeic acid phenethyl ester)-based propolis extract (Bio 30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice. Phytotherapy Research: PTR, 23(2), 226–230.
• 14. Demir S., Aliyazicioglu Y., Turan I., Misir S., Mentese A., Yaman S.O., Akbulut K., Kilinc K. & Deger O. (2016). Antiproliferative and proapoptotic activity of Turkish propolis on human lung cancer cell line. Nutrition and Cancer, 68(1), 165–172.
• 15. De Oliveira Reis J.H., de Abreu Barreto G., Cerqueira J.C., dos Anjos J.P., Andrade L.N., Padilha F. F., Druzian J.I. & MacHado B.A.S. (2019). Evaluation of the antioxidant profile and cytotoxic activity of red propolis extracts from different regions of northeastern Brazil obtained by conventional and ultrasoundassisted extraction. PloS One,14, 0219063.
• 16. Donehower L.A., Soussi T., Korkut A., Liu Y., Schultz A., Cardenas M., Li X., Babur O., Hsu T.K., Lichtarge O., Weinstein J.N., Akbani R. & Wheeler D.A. (2019). Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas. Cell Reports, 28(5), 1370–1384.e5.
• 17. Dornelas C.A., Fechine-Jamacaru F.V., Albuquerque I.L., Magalhães H.I.F., Dias T.A., Faria M.H.G., Alves M.K.S., Rabenhorst S.H.B., de Almeida P.R.C., de Lemos T.L.G., de Castro J.D.V., Moraes M.E.A. & Moraes M.O. (2012). Angiogenesis inhibition by green propolis and the angiogenic effect of L-lysine on bladder cancer in rats. Acta Cirúrgica Brasileira, 27(8), 529.
• 18. Duan J., Xiaokaiti Y., Fan S., Pan Y., Li X. & Li X. (2017). Direct interaction between caffeic acid phenethyl ester and human neutrophil elastase inhibits the growth and migration of PANC-1 cells. Oncology Reports, 37(5), 3019–3025.
• 19. El-Guendouz S., Lyoussi B. & Miguel M.G. (2019). Insight on Propolis from Mediterranean Countries: Chemical Composition, Biological Activities and Application Fields. Chemical & Biodiversity, 16(7):e1900094. doi: 10.1002/cbdv.201900094.
• 20. Forma E. & Bry´s M. (2021). Anticancer Activity of Propolis and Its Compounds. Nutrients, 13, 2594. https://doi.org/10.3390/nu13082594.
• 21. Ghisalberti E. L. (1979). Propolis: A review. Bee World, 60, 59-84.
• 22. Gülçin I., Bursal E., Sehitoğlu M.H., Bilsel M. & Gören A.C. (2010). Polyphenol contents and antioxidant activity of lyophilized aqueous extract of propolis from Erzurum, Turkey. Food and Chemical Toxicology, 48, 2227–2238.
• 23. Hosoya T., Tsuchiya I., Ohta T., Benhanifia M. & Kumazawa S. (2021). Composition of Algerian Propolis, Plant Origin, and Its Antiangiogenic Activity In Vitro. Molecules (Basel, Switzerland), 26(21), 6510.
• 24. Huang S., Zhang C. P., Wang K., Li G.Q. & Hu F.L. (2014). Recent Advances in the Chemical Composition of Propolis. Molecules, 19, 19610-19632.
• 25. Inoue K., Saito M., Kanai T., Kawata T., Shigematsu N., Uno T., Isobe K., Liu C.H. & Ito H. (2008). Anti-Tumor Effects of Water-SolublePropolis on a Mouse Sarcoma Cell Line In Vivo and In Vitro. The American Journal of Chinese Medicine, 36(3), 625–634.
• 26. Keshavarz M., Mostafaie A., Mansouri K., Shakiba Y. & Motlagh H.R. (2009). Inhibition of corneal neovascularization with propolis extract. Archives of Medical Research, 40(1), 59–61.
• 27. Keskin S., Yatanaslan L. & Karlidağ S. (2020). Chemical characterization of propolis samples collected from different provinces of Anatolia. Uludağ. Arıcılık Dergisi. 20, 81–88.
• 28. Kim J.H., Lee B.J., Kim J.H., Yu Y.S. & Kim K.W. (2009). Anti-angiogenic effect of caffeic acid on retinal neovascularization. Vascular Pharmacology, 51(4), 262-267.
• 29. Klopell F.C., Lemos M., Sousa J.P., Comunello E., Maistro E.L., Bastos J.K. & de Andrade S.F. (2007). Nerolidol, an antiulcer constituent from the essential oil of Baccharis dracunculifolia DC (Asteraceae). Zeitschrift fur Naturforschung. C, Journal of Biosciences, 62(7-8), 537–542.
• 30. Kocot J., Kiełczykowska M., Luchowska-Kocot D., Kurzepa J. & Musik I. (2018). Antioxidant potential of propolis, bee pollen, and royal jelly: Possible medical application. Oxidative Medicine And Cellular Longevity, 2018, 7074209.
• 31. Kumazawa S., Hamasaka T. & Nakayama T. (2004). Antioxidant activity of propolis of various geographic origins. Food Chemistry, 84, 329–339.
• 32. Lee K.W., Kang N.J., Kim J.H., Lee K.M., Lee D.E., Hur H.J. & Lee H.J. (2008). Caffeic acid phenethyl ester inhibits invasion and expression of matrix metalloproteinase in SK-Hep1 human hepatocellular carcinoma cells by targeting nuclear factor kappa B. Genes & Nutrition, 2(4), 319–322.
• 33. Li Q.Q., Wang K., Marcucci M.C., Sawaya A.C.H.F., Hu L, Xue X.F., Wu L.M. & Hu F.L. (2018). Nutrient-rich bee pollen: A treasure trove of active natural metabolites. Journal of Functional Foods, 49, 472–484.
• 34. Mercan N., Kıvrak İ., Duru M.E., Katircioglu H., Gulcan S., Malcı S., Acar G. & Salih B. (2006). Chemical composition effects onto antimicrobial and antioxidant activities of propolis collected from different regions of Turkey. Annals of Microbiology, 56(4), 373-378.
• 35. Misir S., Aliyazicioglu Y., Demir S., Turan I. & Hepokur C. (2020). Effect of Turkish Propolis on miRNA Expression, Cell Cycle, and Apoptosis in Human Breast Cancer (MCF-7) Cells. Nutrition and Cancer, 72(1), 133–145.
• 36. Mora D.P.P., Santiago K.B., Conti B.J., de Oliveira Cardoso E., Conte F.L., Oliveira L.P.G., de Assis Golim M., Uribe J.F.C., Gutiérrez R.M., Buitrago M.R., Popova M., Trusheva B., Bankova V., García O.T. & Sforcin J.M. (2019). The chemical composition and events related to the cytotoxic effects of propolis on osteosarcoma cells: A comparative assessment of Colombian samples. Phytotherapy Research, 33(3), 591-601.
• 37. Mouse H.A., Tilaoui M., Jaafari A., M’barek L.A., Aboufatima R., Chait A. & Zyad A. (2012). Evaluation of the in vitro and in vivo anticancer properties of Moroccan propolis extracts. Revista Brasileira de Farmacognosia Brazilian Journal of Pharmacognosy, 22(3), 558-567.
• 38. Murray T.J., Yang X. & Sherr D.H. (2006). Growth of a human mammary tumor cell line is blocked by galangin, a naturally occurring bioflavonoid, and is accompanied by down-regulation of cyclins D3, E, and A. Breast Cancer Research: BCR, 8(2), R17.
• 39. Nasirli F. (2020). Propolis Alt Fraksiyonlarının Antibiyofilm ve Antikanser Etkilerinin Aydınlatılması. Yüksek Lisans Tezi. Pamukkale University Fen Bilimleri Enstitüsü, Denizli, 109.
• 40. Orsolić N. & Basić I. (2003). Immunomodulation by water-soluble derivative of propolis: a factor of antitumor reactivity. Journal of Ethnopharmacology. 84(2-3):265-273. doi: 10.1016/s0378-8741(02)00329-x.
• 41. Orsolić N., Knezević A.H., Sver L., Terzić S. & Basić I. (2004). Immunomodulatory and antimetastatic action of propolis and related polyphenolic compounds. Journal of Ethnopharmacology, 94(2-3), 307–315.
• 42. Ozdal T., Ceylan F.D., Eroglu N., Kaplan M., Olgun E.O. & Capanoglu E. (2019). Investigation of antioxidant capacity, bioaccessibility and LC-MS/MS phenolic profile of Turkish propolis. Food Research International (Ottawa, Ont.), 122, 528–536.
• 43. Özkök A., Keskin M., Samancı A.E.T., Önder E.Y. & Takma Ç. (2021). Determination of antioxidant activity and phenolic compounds for basic standardization of Turkish propolis. Applied Biological Chemistry, 64, 37.
• 44. Park S.I., Ohta T., Kumazawa S., Jun M. & Ahn M.R. (2014). Korean propolis suppresses angiogenesis through inhibition of tube formation and endothelial cell proliferation. Natural Product Communications, 9(4), 555–560.
• 45. Patel S. (2016). Emerging Adjuvant Therapy for Cancer: Propolis and its Constituents. Journal of Dietary Supplements, 13(3), 245–268.
• 46. Perna A., Simonetti A., Intaglietta I., Sofo A. & Gambacorta E. (2012). Metal content of southern Italy honey of different botanical origins and its correlation with polyphenol content and antioxidant activity. International Journal of Food Science and Technology, 1909–1917.
• 47. Pilyugin M. & Irminger-Finger I. (2014). Long non-coding RNA and microRNAs might act in regulating the expression of BARD1 mRNAs. The International Journal of Biochemistry & Cell Biology, 54, 356-367.
• 48. Saini K.S., Loi S., de Azambuja E., Metzger-Filho O., Saini M.L., Ignatiadis M., Dancey J.E. & Piccart-Gebhart M.J. (2013). Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. Cancer Treatment Reviews, 39(8), 935–946.
• 49. Santos L.M., Fonseca M.S., Sokolonski A.R., Deegan K.R., Araújo R.P., Umsza-Guez M.A., Barbosa J.D., Portela R.D. & Machado B.A. (2020). Propolis: types, composition, biological activities, and veterinary product patent prospecting. Journal of the Science of Food and Agriculture, 100(4), 1369–1382.
• 50. Sforcin J.M. & Bankova V. (2011). Propolis: Is there a potential for the development of new drugs? Journal of Ethnopharmacology, 133, 253-260.
• 51. Silva-Carvalho R., Baltazar F. & Almeida-Aguiar C. (2015). Propolis: A Complex Natural Product with a Plethora of Biological Activities That Can Be Explored for Drug Development. Evidence-based Complementary and Alternative Medicine. 1-29.
• 52. Silva J.C., Rodrigues S., Feás X. & Estevinho L.M. (2012). Antimicrobial activity, phenolic profile and role in the inflammation of propolis. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association, 50(5), 1790–1795.
• 53. Simone M., Borba R.S., Wilson M. & Spivak M. (2017). Propolis Counteracts Some Threats to Honey Bee Health. Insects, 8(2), 2-20.
• 54. Simone M., Evans J.D. & Spivak M. (2009). Resin Collection and Social Immunity in Honey Bees. The Society for the Study of Evolution, 3 (11), 3016-3022.
• 55. Stojanović S.T., Najman S.J., Bogdanova‐Popov B. & Najman S.S. (2020). Propolis: Chemical composition, biological and pharmacological activity—A Review. Acta Medica Medianae, 59, 108–113.
• 56. Taciak B., Pruszynska I., Kiraga L., Bialasek M. & Krol M. (2018). Wnt signaling pathway in development and cancer. Journal of physiology and pharmacology: an official journal of the Polish Physiological Society, 69(2), 10.26402/jpp.2018.2.07.
• 57. Tsai Y.C., Wang Y.H., Liou C.C., Lin Y.C., Huang H. & Liu, Y.C. (2012). Induction of oxidative DNA damage by flavonoids of propolis: its mechanism and implication about antioxidant capacity. Chemical Research in Toxicology, 25(1), 191–196.
• 58. Tseng J.C., Lin C.Y., Su L.C., Fu H.H., Yang S.D. & Chuu C.P. (2016). CAPE suppresses migration and invasion of prostate cancer cells via activation of non-canonical Wnt signaling. Oncotarget, 7(25), 38010–38024.
• 59. Wang H.X. & Tang C. (2017). Galangin suppresses human laryngeal carcinoma via modulation of caspase-3 and AKT signaling pathways. Oncology Reports, 38(2), 703–714.
• 60. Wang M. & Jiang X. (2020). SUMOylation of vascular endothelial growth factor receptor 2 inhibits the proliferation, migration, and angiogenesis signaling pathway in non-small cell lung cancer. Anti-cancer Drugs, 31(5), 492–499.
• 61. Watanabe M.A., Amarante M.K., Conti B.J. & Sforcin J.M. (2011). Cytotoxic constituents of propolis inducing anticancer effects: a review. The Journal of Pharmacy and Pharmacology, 63(11), 1378–1386.
• 62. Zabaiou N., Fouache A., Trousson A., Baron S., Zellagui A., Lahouel M. & Lobaccaro J.A. (2017). Biological properties of propolis extracts: Something new from an ancient product. Chemistry And Physics of Lipids, 207(Pt B), 214–222.
• 63. Zhao L., Pu L., Wei J., Li J., Wu J., Xin Z., Gao W. & Guo C. (2016). Brazilian Green Propolis Improves Antioxidant Function in Patients with Type 2 Diabetes Mellitus. International Journal of Environmental Research and Public Health, 13(5), 498.