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Propolis, a Natural Remedy Against Cancer?
Article written in French by:
• Nicolas Hubin, licenced in chemical sciences;
• Professeur Roch Domerego, Vice-President of the Apitherapy Commission of Apimondia, Co-author of l’Apithérapie” aux éditions Amyris,;
• Liéna Hernandez Orizondo, Doctor in Pharmaceutical Sciences, Member of the Apitherapy Commission of Apimondia.
(Translation by Th. Cherbuliez, MD)
In the last three decades, our understanding of cancers has undergone a fundamental change by the discovery of the genes responsible for the development of these conditions. Nowadays research focuses seriously on the transducers of these genes and more specifically of the PAK1. The PAK 1 is understood to be responsible for the activation of molecules fostering cellular division, the invasion of the body by the tumor, the survival of cancer cells and the development of blood vessels within the tumor.
Current research addresses the development of PAK1 blocking medications.
The medications would decrease the initiation of mitosis of cancer cells, as well as the development of metastases, the angiogenesis, and the cell anti-apoptosis. One can well understand the increasing interest in this type of medication.
PAK1 and cancer
A large number of systematic studies led to the conclusion that the Ser/Thrkinases PAK1 is an essential transducer for more than 70% of the cancers, like cancers of the respiratory tract, of the prostate and of the neurofibromatoses.
These types of tumors depend strongly on the presence of this kinase for their growth, and they are therefore called PAK1-dependant tumors. PAK1 is a Rac/CDC42-dependant kinase that activates numerous effectors by phosphorylation, such as the kinase RAF, the LIM-kinase and the BAD. The PAK1 is therefore involved in all kind of processes in the generation of tumors, including cellular division, the anti-apoptosis, and angiogenesis. [cf fig. 1]
More specifically, the phosphorylation of the BAD (Bcl-xl/Bcl-2-Associated Death Promoter), a pro-apoptotic protein, prevents cellular apoptosis. Activation of the LIM kinase leads to the polymerization of actin, which stimulate cellular migration, and therefore the formation of metastases. Kinase RAF, when phosphorylized, leads through the MEK and ERK metabolic pathways to the passage from the cellular phase GO to phase G1, thereby setting mitosis in motion. Finally, PAK1 activates too the production of VEGF, essential to tumor angiogenesis. [1]
The synthesis of PAK1-blocking substances will take years. This is the reason why research turns more and more towards natural products already available on the market, which will demonstrate this anti PAK1 capacity, with the hope to make this new therapeutic approach available as quickly as possible to patients suffering from cancers and from neurofibromatosis.
Of these natural products, one of the most promising seems to be the green propolis of Brazil, rich in Artepillin C, a PAK1- blocking agent.
Propolis, a PAK1- blocking agent
Propolis is a resinous substance produced by exudation from plants and collected by bees, who use it in the hive.
It includes some 300 components, mainly resin (50%), wax (30%), essential oils (10%), pollen (5%), together with a whole series of other organic components (5%). [2] Amongst these organic components one can identify phenolic components, esters, flavonoids, terpenes, beta-steroids, aldheids and aromatic alcohols. [3]
In traditional medicine, propolis is known for having a large spectrum of biological and therapeutic properties with anti-hepatotoxic, anti-inflammatory and antioxidant activities. [4] And now, one of its most promising medical properties, internationally actively studied, is its anti-cancerous effect. Like any natural substance, its composition is directly dependent on different factors, such as its botanical origin and the environmental conditions of its development. Green propolis of Brazil (GPB) is the only one having in its composition 6 to 8% Artepillin C (ARC).
Scientific literature mentions several rigorously conducted studies of the anti-cancerous property of the active principle of GPB, together with its mechanism of biochemical action. In 2005 a team of Japanese researcher demonstrated the anti-proliferative effect of ARC on human colon cancerous cells. This effect is demonstrated by its ability to stimulate the emergence of Cip1/p21 , which interferes with the passage from phase GO to phase G1 of the cell cycle, in this way blocking mitosis. According to this study, ARC is capable of blocking the chain reaction initiated by PAK1 and responsible for the loss of the P21′s regulating capacity. [5]
The following year this same team published the account of a study based on the oral treatment of mice. Here they picture the properties of ARC and of propolis, both well absorbed by the organism. These compounds trigger an anti-oxidant response by the organism through the production of detoxifying enzymes (glutation S-transferase, NADPH – quinone reductase) which neutralize the damage caused by the free oxidant radicals, an action that is reinforced by the abundance of flavonoids in propolis.
For many authors, oxidative damages may cause mutation leading to neoplasic transformation. This receives confirmation by the activity of ARC, which inhibits the resurgence of pre-neoplasic lesions in the colon of the mice. [6]
In addition, another study carried out in 2007 showed accompanying evidence of an anti-angiogenic effect. As a matter of fact the researchers observed a significant decrease in the emergence of new blood vessels within the tumor in mice treated orally with propolis. [7]
Finally, a study published at the beginning of 2009 demonstrates clearly that ARC and BGP are selectively blocking the PAK1 signal, which interferes with phosphorylation of Raf-1, and this limits the mitoses of cancer cells. The authors demonstrate in vitro and in vivo the important therapeutic effect of ARC and GPB on the growth of neurofibromatosis tumors. [8]
All this research demonstrates clearly that Artepillin C present in Brazilian green propolis has anti-cancerous effect by decreasing the frequency of pre-cancerous lesions, by inhibition of mitoses of cancerous cells and of angiogenesis within the tumor.
Conclusion
As their research progresses, scientific researchers seem to discover an ever larger power to Artepillin C. It could be that, taken at an early stage, this molecule might be the remedy for cancer: More than 70% of cancers are PAK1 dependant and Artepillin C appears to be a very efficacious blocking agent of PAK1.
Green propolis of Brazil, very rich in Artepillin C, is therefore expected to be a natural remedy against cancer. As it is PAK1 blocking and easily absorbed by the organism, it seems active when taken orally and might even present an inhibitory effect vis a vis certain cancers, if taken daily.
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[1] H. Maruta, T. Ohta, Signal therapy: propolis and Pepper extracts as cancer therapeutics, In Complementary and Alternative Therapies and the Aging Population, Watson R. Academic Press (2008) : pp 523-539.
[2] A.M. Gómez-Caravaca, M. Gómez-romero, D. Arráez-Román, A. Segura-Carretero, A. Fernández-Gutiérrez, Advances in the analysis of phenolic compounds in products derived from bees, J. Pharmac. Bio. Anal. 41 (2006) : pp 1220-1234.
[3] H. Aga, T. Shibuya, T. Sugimoto, M. Kurimoto, S.H. Nakajima, Isolation and identification of antimicrobial compounds in Brazilian propolis, Biosci. Biotechnol. Biochem. 58 (1994) : pp 945-946.
[4] A. H. Banskota, Y. Tezuka, S. Kadota, Recent Progress in Pharmacological Research of Propolis, Phytotherapy Res. 15 (2001) : pp 561-571.
[5] K. Shimizu, S. K. Das, T. Hashimoto, Y. Sowa, T. Yoshida, T. Sakai, Y. Matsuura, K. Kanazawa, Artepillin C in Brazilian Propolis Induces G0/G1 Arrest via Stimulation of Cip1/p21 Expression in Human Colon Cancer Cells, Mol. Carcinogenesis 44 (2005) : pp 293-299.
[6] K. Shimizu, S. K. Das, M. Baba, Y. Matsuura, K. Kanazawa, Dietary artepillin C suppresses the formation of aberrant crypt foci induced by azoxymethane in mouse colon, Cancer Letters 240 (2006) : pp 135-142.
[7] M. R. Ahn, K. Kunimasa, T. Ohta, S. Kumazawa, M. Kamihira, K. Kaji, Y. Uto, H. Hori, H, Nagasawa, T. Nakayama, Suppression of tumor-induced angiogenesis byBrazilian propolis: Major component artepillin C inhibits in vitro tube formation and endothelial cell proliferation, Cancer Letters 252 (2007) : pp 235-243.
[8] S. M. Messerli, M. R. Ahn, K. Kunimasa, M. Yanagihara, T. Tatefuji, K. Hashimoto, V. Mautner, Y. Uto, H. Hori, S. Kumazawa, K. Kaji, T. Ohta, H. Maruta, Artepillin C(ARC) in Brazilian Green Propolis Selectively Blocks Oncogenic PAK1 Signaling and Suppresses the Growth of NF Tumors in Mice, Phytotherapy Res. 23 (2009) : pp 423-427.
