Does Artepillin C Have A Putative Role In Defense Against Cancer?

Dias MHLC, Silqueira BG, Vinagre ACB, Campo VL, Zoccal KF and Tefé-Silva C

Published on: 2021-08-14

Abstract

Propolis, also called paste, bee glue, is a compound produced by bees. The Brazilian Propolis, due to its differentiation, has been generating a lot of interest from researchers, which has antioxidant, antimicrobial, anti-inflammatory and even anti-tumor activities, has as main component artepillin C (ARC). We will gather the available articles in order to explore the benefits of Propolis and its components and agents that act against the growth of tumor cells, reduce inflammation and angiogenesis in the control and inhibition of lung, prostate and kidney cancer, and especially melanoma. This is a review article covering some of the literature of the last ten/twenty years, on the scientific research carried out in relation of ARC. Artepillin C demonstrated that its application in malignant, tumor cells cause a cytotoxic effect by inhibiting the growth of tumor cells, highlighting the damage caused by this substance in cancer cells. Animals with renal cell-induced carcinomas were treated with artepillin C and demonstrated a protective effect against lipid peroxidation, preventing the formation of these carcinomas. Recent studies involving artepillin C and colorectal cancer evidenced that after the ARC treatment, there was a reduction in colorectal cancer. ARC demonstrated action against different tumor cells observed in prostate cancer in vitro, affecting cancer cells by inhibiting their cell growth, inducing apoptosis. The studies demonstrated here suggest the ability of propolis to inhibit and proliferate the cell cycle or to induce apoptosis in tumor cells.

Keywords

Cancer therapy; Artepillin C; Lung cancer; Melanoma; Prostate cancer; Colorectal cancer

Background

The Propolis, also called bee paste or bee glue, is a compound produced by the bees based on resins collected from trees and bushes. These combine with the wax produced by the bug and the secretions from their salivary glands, which are rich in enzymes. Tropical propolis samples, especially the Brazilian ones, have shown relevant differences in their chemical compositions in relation to propolis from the temperate zone and has become an object of great interest to researchers. The Brazilian green propolis, produced in São Paulo and Minas Gerais, consists mainly of p-coumaric acid derivatives and has a large number of flavonoids, many of which are not present in propolis from Europe, North America, and Asia [1].

It is formed by a mixture of resinous and balsamic material collected by bees from branches, buds, exudates from trees and flowers; in addition, the bees add salivary secretions to this mixture [2]. Thus, its composition is 50% resin, 30% wax, 10% aromatic oils, 5% pollen and 5% organic waste. Among the organic residues, called flavonoids (bioavailable actives), are phenolic acids, esters, aromatic aldehydes, alcohols, terpenoids, and β-steroids. Baccharis dracunculifolia, brazilian propolis, has as its main component the artepillin C (ARC), in which bees collect the material present in this plant that is extremely rich in antioxidant ARC [3].

Propolis, which has antioxidant, antimicrobial, anti-inflammatory, and especially antitumoral activities, the latter being the objective of the study, since it will be assessed whether this characteristic will help in the intervention against neoplasms, in an attempt of an alternative and effective treatment. artepillin C is an antitumor substance, whose main biologically active phenolic compound is found in Brazilian green propolis, being produced from exudates of the plant Baccharis dracunculifolia by bees [4,5]. This alternative therapy would also be interesting for the treatment of several other cancers, such as renal cell carcinoma, lung carcinoma and colon cancer [6].

The present review aims to gather the available articles and explore the benefits of Propolis and its main components, such as artepillin C, as agents that act against tumor cell growth, reduce inflammation and angiogenesis in the control and inhibition of lung, colon, prostate and kidney cancer, and especially melanoma. Figure 1.

Figure 1: Flowchart of the proposed effects of artepillin C in cancers.

Methodology

This is a review article covering some of the literature of the last ten/twenty years, on the scientific research carried out in relation of artepillin C. The search was based on articles indexed in MedLine Center for Biotechnology information (Pubmed), Scientific Electronic Library Online (Scielo) and EBSCO. The terms used for the search were: Propolis, artepillin C, cancer, melanoma. In total, 60 articles were used, according to a pre-defined inclusion criterion: articles published between 1989 and 2020.

Discussion

Some medical studies have demonstrated the beneficial effects of propolis based on experimental evidences. It has been evaluated in several models for its action anticancer, with the identification of a high number of active compounds in these models [7,8]. The potential anticancer effects of the different types of propolis, can be summarized in the following possible mechanisms: suppression of proliferation of precancerous cells through their immunomodulatory effect, decreased cancer stem cell populations, blocking of specific signaling pathways, modulation of the tumor microenvironment and adjuvant or complementary to conventional anticancer therapies [8]. The article will report some of these biological effects of propolis components, especially artepillin C, which contain chemopreventive action against unresolved chronic inflammation, such as cancer.

Propolis have some antitumor properties that vary according to the active components of each species from which propolis is harvested. Propolis has demonstrated efficiency against a diversity of cancers, such as: skin (melanoma), renal carcinoma, prostate, colon, lung and others [9]. Besides the underlying mechanisms such as interruption of the cell cycle and interference in metabolism, there is the antiproliferative action of propolis in avoiding the progression of the tumor. The anti-cancer action of propolis has been proven by high performance instruments such as flow cytometry, mass spectrometry and nuclear magnetic resonance [9]. Among the discoveries of the multifunctions displayed by propolis, the evidence that it inhibits the tumor, has been the most relevant and surprising so far. The main properties of this substance involve increased immunological surveillance [10], suppression of cell proliferation [11], reduction of cancerous stem cells by blocking specific pathways of oncogenes [11], promoting anti-angiogenesis [12] and modulating the tumor microenvironment [13]. Although we are aware of the relevance of conventional therapy, we cannot refuse to recognize the importance of alternative therapies such as propolis, especially because in addition to all these properties that have been cited, it would be an innovative and also low-cost proposal [9].

Effects of ARC in Some Cancers

Melanoma

Skin cancer is a tumor that affects the skin, being the most common neoplasm worldwide, and its most aggressive form, melanoma, affects about 3% of the Brazilian population, responsible for about 90% of cases of this neoplasm [14,15]. In the United States, cutaneous melanoma is the fifth most diagnosed melanoma and is considered the most lethal form of skin cancers [16]. The incidence of melanoma has been increasing in most white populations worldwide and an annual increase of 3% to 7% has been found in many countries. The severity of malignant melanoma is because it can present with metastases at a distance, being the skin, subcutaneous cell tissue, lung, liver and brain the most common sites. Patients who present metastasis at distance have poor prognosis, with an average survival of 6 months [17]. Thus, malignant melanoma represents a socio-economic problem, with worldwide relevance [18].

Exposure to ultraviolet light is a risk factor that affects the skin's defensive response to this damage and increases the danger of developing melanoma. Ultraviolet radiation causes genetic changes in the skin, impairs skin immune function, increases local production of growth factors and induces the formation of DNA damaging reactive oxygen species that affect keratinocytes and melanocytes [19]. Other factors such as skin color, socioeconomic status and behavioral factors also predispose to the development of melanoma [20].

Due to its high metastatic, aggressiveness and low response to conventional therapies, melanoma has elevated mortality rates, thereby it is a serious public health problem [21]. Currently, it has been observed the great advance in tumor treatments through biological therapies, such as the use of monoclonal antibodies, which are more physiological and well tolerated because they induce a memory function of the adaptive immune system and specifically activate the immune system against tumors without causing so many side effects. In addition, there is hormone therapy, in which modulators act by inhibiting the action of hormones that are involved in cell differentiation and proliferation [22]. The treatments for metastatic cancers present a historical difficulty. For this reason, it is required to search for new alternatives to improve these therapies [23].

Another plant worth mentioning is Arctium lappa, also called burdock. It has been widely used as a therapy in Europe, North America, and Asia for many years. Its seeds, leaves and roots have been studied because of their extensive use in Traditional Chinese Medicine to treat some types of cancer [8]. The main active compound of Arctium lappa extract, arctigenin, also demonstrated inhibitory properties on the progression of melanoma [24]. Studies indicate that the use of arctigenin is able to eliminate cancer cells deprived from nutrients, inhibiting tumorigenesis of liver cancer and suppressing melanin synthesis in B16F10 melanoma cells in mice [25].

Lobelia inflata, a herbaceous plant belonging to the Campanulaceae family, native to North America, also showed a therapeutic potential because it showed reduction of tumor activity, chronic inflammation and the angiogenesis process, the latter being one of the main characteristics of melanoma [26]. The potential of this herbal plant was evaluated through an experiment using murine melanoma-derived cells (B16-F10) in mice. The group of mice that did not receive the Lobelia extract showed changes such as ulcerations, while in the group treated with the extract there were no ulcerations, evidencing a better prognosis of melanoma [27].

In addition, Lobelia chinensis, which is a small perennial herb belonging to the same genus as Lobelia inflata, has been widely used to treat inflammation, as studies have shown its possible pharmacological effect as an anti-inflammatory [28]. Other pharmacological effects have also been demonstrated, such as anti-tumor, anti-inflammatory and inhibitor of vascular smooth muscle cell proliferation [29]. This species has also demonstrated cytotoxicity properties on animal melanoma cells [30]. Thus, in the future, there are possibilities of being an effective therapeutic strategy to combat this neoplasm.

Propolis of Brazilian origin is composed mainly by artepillin C and its constituents are quite different from those of propolis from European origin [31]. ARC has demonstrated several activities, such as anti-viral, anti-bacterial, antioxidant and anti-cancer. It has been studied and documented to inhibit tumor growth in human solid organ transplants and mouse tumors, including mainly malignant melanoma [32]. Artepillin C when applied to human and murine malignant tumor cells in vitro and in vivo shows a cytotoxic effect and clearly inhibits the growth of tumor cells, thus highlighting the significant damage that is caused by this substance on cancer cells [33].

Renal Carcinoma

Renal cell carcinoma (RCC) represents the third most common genitourinary neoplasm and has shown an increase in annual incidence in the last 20 years. It is responsible for 3% of malignant tumors, and it is considered the most lethal of urological cancers, with a mortality rate of 40% [34].

At the same time, despite advances in diagnostic techniques, up to 30% of newly diagnosed patients already have metastases, and a large proportion of patients undergoes surgical treatment experience recurrence of RCC. Therefore, drugs directed against cancer-initiating cells metastases would be of great interest in the future [35]. In the past few decades, the therapeutic landscape of metastatic RCC (mRCC) has changed dramatically. Until 2005, IFN-α (interferon- alpha) and high-dose interleukin-2 (IL-2) were the standard treatment for the treatment of mRCC. However, its impact on immune escape mechanisms was limited and responses to treatments were common, not durable and associated with poor tolerance [36].

Recently, a better understanding of the biological and molecular basis of RCC has led to the development of new targeted agents, most of these drugs being directed against the VEGF (endothelial vascular growth factor) pathway and VEGFRs (VEGF receptor) (bevacizumab, sorafenib, sunitinib, pazopanib, axitinib and cabozantinib); the Mammalian target of rapamycin (mTOR) pathway (everolimus and temsirolimus) and the PD-1 / PD-L1 pathway (nivolumab). After analyzing endothelial cell proliferation, angiogenesis and tumor growth, and by stimulating the immune system, it was evidenced that these medications improved clinical outcomes. Response rates have exceeded 30% and survival is approximately two years, depending on the patient's risk profile, type of treatment, and other clinical variables [36].

Therefore, basic research with careful selection of models to understand their biology is mandatory to define potential new therapeutic targets for all RCC subtypes [35].

ARC was used as an object of study to improve the knowledge about its antitumor effects. As an experiment, rats with ferric nitrilotriacetate (Fe-NTA)-induced renal cell carcinomas were treated with artepillin C and showed a protective effect against lipid peroxidation, preventing the formation of these carcinomas [34]. According to these authors, ARC reduces renal toxicity and consequently the incidence of renal adenocarcinoma by attenuating the formation of lipid peroxidases. The results show that artepillin C inhibits the presence of oxidative radicals. The results showed that Fe-NTA treated mice developed precancerous cysts one year after treatment when compared to the groups receiving artepillin C, which appeared to have no precancerous cysts [34].

Colorectal Cancer

Colorectal cancer (CRC) has been on the rise in recent years and is one of the most common cancers in the world, it is treatable and curable in most cases if detected precociously. Among 90% of these tumors start from polyps (benign lesions that can grow over time) and are very aggressive in later stages, being their incidence closely associated with poor dietary fiber, age, diabetes, physical inactivity and alcoholism [37-41].

The chance of developing CRC can be increased by environmental factors and/or genetic factors. The various risk factors for the development of CRC include age over 50, low socioeconomic class, overweight and obesity, sedentary lifestyle, smoking, high fat diet, consumption of red meat, processed meat and burnt or charred meat, acromegaly, long-term kidney transplantation - long-term immunosuppression, long-term androgen deprivation therapy, personal or family history of CRC or colorectal adenoma, long-term inflammatory bowel disease (IBD), familial adenomatous polyposis (FAP), syndromes of the MMR gene mutated as hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome and Muir-Torre syndrome, hamartomatous polyposis syndromes such as Peutz-Jeghers syndrome, Cowden syndrome and juvenile polyposis syndrome and non-hereditary polyposis syndromes as a syndrome serrated polyposis (SPS) and Cronkhite-Canada syndrome. We are also noting that the incidence of CRC has increased in young adults in the 30s and 40s over the past 25 years in high-income countries (United States, United Kingdom, Denmark, Norway, Canada, Australia and New Zealand) , while it has declined in adults after 50 years [42]. In the tables 1 and 2, listed below, it’s possible to see the risk factors based on the Amsterdam and Amsterdam II and Bethesda (2003) criteria.

Table 1: Amsterdam and Amsterdam II criteria for the diagnosis of colorectal cancer heredity [43].

Amsterdam	Colorectal cancer in 3 or more family members
-1991	The family member affected should be a first degree relative
	Two generations presenting colorectal cancer
	At least one family member under the age of 50
Amsterdam II	IG cancer, endometrium and renal pelvis
-1998	The family member affected should be a first degree relative
	Two generations presenting colorectal cancer
	At least one family member under the age of 50

Table 2: Bethesda's (2003) revised criteria [43].

BETHESDA CRITERIA
One more of those criteria must be present:
1. Patients under the age of 50 years diagnosed with colorectal cancer (CRC)
2. Synchronous or metachronous colorectal or other HNPCC-related tumors (for example, stomach, bladder, ureter, renal pelvis, among others) present in patients regardless of age
3. Patients above 60 years old with the presence of CRC tumor with MSI-high (microsatellite instability morphology) histology
4. Patients above 50 years old with the presence of CRC diagnosed with ≥ 1 first-degree relative with an HNPCC-related tumor (in case of adenomas, it must have been diagnosed before 40 years old)
5. Patients diagnosed with CRC in ≥ 2 first or second- degree relatives with an HNPCC-related tumor, regardless of age

Clinical evidence has shown that CRCs often arise from adenomatous polyps that normally acquire dysplastic changes within 10 to 15 years before developing invasive carcinoma, and the early detection and removal of polyps will reduce the incidence of CRC [44]. Recent research involving artepillin C and colon cancer has been done to check if ARC has an antiproliferative effect and to see the growth of these cancer cells and their antioxidant activity. To clarify the effects of artepillin C on tumor cells, human colon tumor cells were used and compared to control cells. After treatment, reduction in cell growth in the cells treated with artepillin C was evident [11,12,31,45].

In addition, the proteins involved in this antiproliferative process were analyzed as CDK4 (a catalytic unit of the protein kinase complex that is important for progression of the G1 phase of the cell cycle) [45]. The results indicated that artepillin C inhibited the growth of colon cancer cells from G1 to S showing a decrease in CDK4 cyclin activity after the start of treatment. In addition, it was observed that there's a relation between CIP 1/p21 proteins (kinase inhibitors) inhibiting progress in the cycle and reporting a cyclic arrest twenty-four hours after treatment, confirming the protective effect of artepillin C [45].

Lung Cancer

Lung cancer is the leading cause of malignant tumor-related deaths in men and women. Although more frequent among males, its incidence in men has stabilized or decreased, while in women it has increased dramatically in recent decades. Only 20% of cases are diagnosed at early stages. Most of the time the diagnosis is late, when the disease is already in advanced stages, which prevents curative treatment [46].

Lung cancer rates are varying around the world, this is due to geographical differences in tobacco use and air quality [47]. The rates of lung cancer in men are considerably higher in developed countries, in comparison with less developed countries, possibly due to smoking [48].

Studies were performed in rats with the administration of FeNTA and artepillin C, to see if propolis extract was a protective factor for lung cancer and kidney cancer. It was observed that in relation to carcinogenesis, the rats that received FeNTA developed adenocarcinoma after one year, unlike the rats that received ARC, which did not develop adenocarcinoma, reaffirming the protective effect of this extract, which prevented tumor progression[46].

Regarding lipid peroxidation, oxidizing agents were observed to induce lung oxidative damage in rats subjected to FeNTa treatment. However, rats that received oral administration of artepillin C demonstrated decreased levels of lipid peroxidation markers. According to the authors, ARC evidenced a protective action and showed antitumor activities. In addition, it has chemopreventive effects and inhibits carcinogenesis in histologically distinct tissues such as lungs and kidneys [46].

Prostate Cancer

Prostate cancer is a neoplasia that occurs mostly in man over 50 years, in which prostatic cells can invade the healthy tissues and spread to other organs via blood or lymphatic. The risk of patient survival is much lower if it is identified at an advanced stage. Therefore, early diagnosis is so important in the control and cure of the disease [10].

Prostate cancer is usually asymptomatic at an early stage and can sometimes require minimal or no treatment. However, when symptoms manifest, the most frequent ones are: difficulty urinating and increased frequency and nocturia, which can be confused with the symptoms of prostatic hypertrophy. In the most advanced stage, the disease can manifest with urinary retention and back pain [49]. Some of the factors that influence the incidence of prostate cancer are diet and physical activity, which undoubtedly influence the development and progression of the disease. Dietary factors are mainly associated with ethnic and global differences observed in prostate cancer incidence rates [50].

In prostate cancer, Brazilian green propolis, rich in artepillin C, demonstrated to sensitizes tumor cells to TRAIL (tumor necrosis factor related apoptosis inducing ligand) induced apoptosis and play a protective autophagy-inducing activity along with LC3-II (LC3-phosphatidylethanolamine conjugate) up-regulation) [10]. Endo identified that ARC rises the formation of LC3-II (an indicator of autophagic activity) dose dependently [51]. This suggests that the responsible compound in green propolis for autophagy induction in prostate cancer cell is the ARC-, and the relationship between protective autophagy in prostate cancer cells and anticancer cytotoxicity (51). Artepillin C demonstrated marked activity against different tumor cells observed in vitro, affecting cancer cells and inhibiting their cell growth, inducing apoptosis [52]. It is also possible to observe suppression of tumor cell growth through the use of artepillin C and two other derivatives [53].

Effects of Artepillin on Angiogenesis

Angiogenesis is the process involving the growth of new blood vessels from preexisting vessels which occurs in both physiologic and pathological settings. It is a complex process controlled by a large number of modulating factors, where the pro-and antiangiogenic factors are fundamental in cancer development and responsible for maintaining a tumor microenvironment, allowing its evolution. Therefore, avoiding this growth is of paramount importance to avoid a worse prognosis [31].

Ahn et al (2007) observed the effects of artepillin C on the formation, proliferation and suppression of angiogenesis and HUVEC (human umbilical vein endothelial cells) endothelial cells [31]. The results showed that artepillin C reduces both the width and length of HUVEC tubes, showing it to be dose dependent, since at lower concentrations it slightly reduced tube width, and at full dose it promoted complete inhibition [31]. In addition, it was also evidenced that ARC and CAPE PAK1, have oncogenic kinase [54]. These kinases transduce signals that lead to cell proliferation or inhibition of programmed cell death by activating transcription factors (AP1, NF kappa B, Myc), inhibiting pro-apoptotic molecules (Bak, Bax). They also participate in the deregulation of cell cycle control. Thus, kinases play a central role in oncogenesis, becoming targets to produce anti-cancer drugs [55].

Brazilian green propolis main phenolic components are ARC, quercetin, kaempferol and p-coumaric acid. Brazilian propolis and its bioactive components markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells (10). Many studies demonstrate the selective antitumor action of acetogenins, inhibiting proliferation and inducing apoptosis cells of the prostate cancer PC-3 lineage, breast cancer MCF-7, lung cancer A-549, HT-29 colon cancer, A-498 of renal carcinoma and PACA-2 of pancreatic carcinoma [56-58]. Relevant findings put together here may contribute for the future steps towards the creation of promising drugs for treatment of these fatal cancers.

Effects of Artepillin C in P53

P53 is a tumor suppressor gene that plays a critical role in inducing apoptosis in response to DNA damage, as well as controlling cell cycle progression [59]. The term “guardian of the genome”, assigned to the p53 protein, is due to its role of monitoring the integrity of the genome. It acts as a DNA damage sensor and assists the repair system, using the moments of checkpoints to stop the cell cycle or inducing apoptosis, thus preventing the proliferation of cells with mutated DNA [59]. During the cell division cycle, p53 checks if there is a possible occurrence of mutations in the genome sequence as a result of faulty DNA replication. In the case of injuries by physical, chemical or biological agents, is a function of p53, through a cascade of reactions, prevent this cell from going into mitosis process and complete cell division.

It was discovered by Bhargava et al (2018) that ARC activates the p53 tumor suppressor by binding to its complex with the mortalin (p53 inactive to protein), thus possessing anticancer activity. ARC docks into and abrogates mortalin-p53 complexes, causing the activation of p53 and the growth arrest of cancer cells. However, its anti-cancer activity proved to be of low effectiveness due to low cytotoxic effectiveness [32].

In order to increase the therapeutic potential of ARC in reactivating p53, and thereby stop the growth of cancer cells, extracts of green propolis were prepared to provide a complex mixture of bioactive with multimodular action and protecting the bioactive components from degradation. The supercritical extract of green propolis (GPSE) has high cytotoxicity for cancer cells. In addition, the extract exhibited greater cytotoxicity in vitro (and greater antitumor activity in vivo by the delay of cell migration in wound healing tests, suggesting its potential for metastatic cancer treatment [32].

The anti-cancer mechanism of ART-C seems to involve the activation of p53, an anti-apoptotic protein overexpressed in many tumor cells. In addition, it also involves stopping the growth of cancer cells. Investigating this, Bhargava et all (2018) compared CAPE (caffeic acid phenethyl ester) and ART-C in the capacity to dock into it and abrogates mortalin p-53 complex, activating p-53 and stopping growth of the cancer cells (32). The study shows that ARC fit the mortalin-p53 complex, which can cause the activation of p53, preventing the maturation of the cancer cells. The study shows that ARC fit the mortalin-p53 complex, which can cause the activation of p53, preventing the maturation of the cancer cells abrogation p53-mortalin interaction using small molecule is guaranteed stop cancer cell grow. However, study interaction of p53-mortalin, and its inhibition using small molecule is still difficult because specific site of mortalin that bind to p53, vice versa, is still debatable. The result showed that p53 protein connect to substrate of mortalin[32].

The genetic abnormalities of p53 include powerful changes such as homozygous deletions and abnormally sized messenger RNAs along with a variety of point or small mutations, which map to the p53 open reading structure and change amino acid sequence in a region highly conserved between mouse and man. In addition, very low or absent expression of p53 messenger RNA in lung cancer cell lines compared to normal lung was seen. These findings, combined with the previous demonstration of 17p allele loss in lung cancer, strongly implicate p53 as an anti-oncogene whose disruption is involved in the pathogenesis of human lung cancer [60].

Studies showed that the immuno-histochemical exhibition of p53 in human colon cancer specimens is associated with a greater VEGF expression than in tumors in which p53 is not detectable [54]. Furthermore, the intensity of staining of p53 protein in tumor specimens significantly correlated with expression of VEGF. Additionally, vessel counts in p53-positive tumors were significantly higher than in p53-negative tumors: vessel counts correlated with VEGF expression as well. Although there was no link between p53 positivity and stage of disease, expression of VEGF was huge in metastatic tumors than in non-metastatic tumors. Lastly, an interaction existed between p53 positivity (active in response to mutation in DNA) , VEGF expression, and vessel suggest that the poor prognosis associated with p53 mutations may be due, in part, to the role of mutant p53 in promoting angiogenesis [54].

Table 3: Effects of artepillin C in diverse tumors.

Cancer type	Artepillin C effects	Source
Carcinoma and melanoma	Suppression of tumor growth; increase in the ratio of CD4/CD8 T cells and the total number of helper T cells. Apoptosis, abortive mitosis and massive necroses.	[33]
Renal cell carcinoma (RCC)	Prevention of an oxidative renal damage and carcinogenesis by inhibition of renal lipid peroxidation	[34]
Pulmonary carcinoma	Inhibition of lipid peroxidation and the development of pulmonary cancers; adenomas did not progress to carcinomas due to proliferation of macrophages and local anti-oxidant activity	[46]
Colon Cancer	Inhibition of cell growth; induction of cell-cycle arrest by stimulating the expression of Clip 1/p21	[3]
Prostate cancer	Sensitization of prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis	[10]
	Autophagy-inducing activity accompanying LC3-II upregulation and induced apoptosis	[51]
Tumor-induced angiogenesis	Reduction in the number of newly formed vessels	[31]

Conclusion

With the increase in the incidence of cancer worldwide, it is essential to think about new methods to combat the disease. The studies demonstrated in this review that propolis and its compounds can inhibit cell cycle proliferation or induce apoptosis in tumor cells.

Based on this it is perfectly possible to conclude that propolis and its components of many active substances, such as ARC have anticancer properties, displaying beneficial factors such as antiproliferative and anti-apoptotic activities. So, these compounds could potentially be useful as anticancer drugs, as it was demonstrated in studies with propolis and lung, prostate and renal cancer, as well as complementing radiotherapy and chemotherapy treatments. However, Additional studies are necessary for fully understanding about the mechanisms correlated with antitumor properties of propolis derived substances.

Journal of Biomedical Science and Research