Anticancer Effects of Royal Jelly: Comparison
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Royal jelly (RJ) is produced by the hypopharyngeal and mandibular salivary glands of young nurse honeybees. RJ contains bioactive substances, such as carbohydrates, protein, lipids, peptides, mineral salts and polyphenols which contribute to the appreciated biological and pharmacological activities. Antioxidant, anticancer, anti-inflammatory, antidiabetic, and antibacterial impacts are among the well-recognized benefits. The combination of RJ or its constituents with anticancer drugs has synergistic effects on cancer disorders, enhancing the drug’s effectiveness or reducing its side effects. 

  • royal jelly
  • cancer
  • anticancer drugs

1. Introduction

Royal jelly (RJ) is one of the honey bee products that has attracted much attention recently [1]. RJ is a hypopharyngeal and mandibular glandular secretion of nurse honey bees. It is known as a “superfood” since it serves as the primary source of nutrition for young worker larvae for the first three days and for the lifetime of the queens [2]. RJ is produced by both the mandibular and hypopharyngeal glands, although only the hypopharyngeal gland is involved in protein synthesis [3,4][3][4]. The mandibular gland is a pair of sacs that can only be found in worker bees and the queen. On the other hand, the hypopharyngeal gland is a pair of long tuberous organs found in the worker bee’s frontal head regions. RJ is partially water soluble and highly acidic, with a gelatinous consistency. It contains proteins, water, and sugar as major components, while the minor components are composed of minerals, amino acids, vitamins, enzymes, and hormones [5]. Naturally occurring bioactive peptides comprise the highest percentage of RJ active ingredients. Bioactive peptides are responsible for most of the unique therapeutic actions of RJ [6]. For generations, fresh RJ has been used as an alternative remedy and an all-natural energy booster. It has been utilized in conventional medicine, particularly in Asia and Ancient Egypt. However, in the last years, the interest in the food industry and natural products has greatly increased, highlighting the importance of RJ and its unique pharmacological and therapeutic properties [3]. RJ has recently shown anticancer, antioxidant, anti-microbial, anti-aging, and anti-inflammatory pharmacological properties, making it a dietary supplement with functional health-enhancing criteria. It is also used in pharmaceutical preparations and as an industrial cosmetic agent [4,7][4][7].

2. Anticancer Effects of Royal Jelly

It is well-known that some bee products have a positive impact on stopping cancer formation [31][8]. The antiproliferative activity of RJ was investigated, and RJ revealed potential anticancer properties owing to the inhibition of tumorigenesis, cancer cell proliferation and/or metastasis, via the inhibition of tumor-induced angiogenesis and/or the activation of immune function [32][9].

RJ exhibited a significant reduction in tumor mass and the serum concentrations of interleukin (IL)-4 and IL10, and cytokines released from type 2 T helper (Th2) cells, whereas the concentrations of IL-2 cytokines produced from type 1 T helper (Th1) cells, interferon (IFN)-α, superoxide dismutase (SOD), as well as total antioxidant machinery showed a significant elevation in an induced breast tumor. IFN-α level elevation manifested the role which RJ plays in immunomodulation. The enhanced release of antioxidant markers in the liver and kidney was another strong indicator of the antioxidant and immunomodulatory activities of RJ, with their possible association in the suppression of tumor growth in animal models [33][10].

However, it is also reported that RJ protein impedes the growth of human breast cancer cell lines induced by bisphenol A (BPA)—through the inhibition of the signaling pathway for cell proliferation induced by E2, and not as believed due to the inhibition of E2 attached to ER5. BPA is an estrogen-like substance used in commercial products such as polycarbonate plastics and synthetic resins, which are applied to coat the inside of beverage cans, and used to manufacture food wrapping paper and dental sealants. BPA has estrogenic activity and binds to estrogen receptors, stimulating the proliferation of human breast cancer MCF-7 cells [34][11] through the activation of the protein kinase/phosphoinositide3 kinase signaling pathway which is induced by estrogen receptor/human epidermal growth factor receptor 2 (HER2)/mitogen [35][12]. The crude RJ stops the damage of bisphenol A, which is a predisposition factor and hazardous insult that induces human breast cancer cell growth [34][11].

RJ supplementation decreased the concentrations of TNF-α and transforming growth factor (TGF) -β, thus dramatically reducing the paraneoplastic syndrome in RCC patients. The observed suppression of the malignant invasiveness and the decrease in the tumor weight may be attributed to the presence of 10-hydroxy-2-decenoic acid (10-HDA), which is a remarkable fatty acid among the lipid content of RJ [37][13]. In comparison to other bee products, this fatty acid is exclusively found in RJ at relatively high concentrations, as illustrated in Figure 1 [38,39][14][15].
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Figure 1. Identified anticancer compounds from royal jelly.
Identified anticancer compounds from royal jelly.
An RJ product, fraction RJP30 (RJ protein fraction), was destructive for HeLa human cervicouterine carcinoma cells. An antiproliferative effect of RJ against Lewis lung carcinoma and colorectal adenocarcinoma cells [10,15][16][17] could be related to the effect of 10-HDA, which in previous studies, constrained the initiation of transplantable leukemia in mice AKR and different ascitic tumor cell lines in mice, and showed a neurotrophic effect on murine neuronal cells [40,41][18][19]. 
IL-6 production and nuclear factor kappa (NF-kB) activation induced by lipopolysaccharide (LPS) through either MyD88 or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-b (TRIF) upregulation in murine macrophage cell line RAW264 cells, were inhibited by 10-HAD. In addition, IkB-ζ expression, and IkB-ζ-related gene production induced by LPS were specifically inhibited by 10-HDA [45][20]. It has been shown that the expression of extracellular SOD released by leukemia THP-1 cells is promoted by the inhibition of histone deacetylase activity by both 10-HDA and 4-hydroperoxy-2-decenoic acid ethyl ester promotion [46][21]. It has been reported that the stimulation of human monocyte-derived dendritic cell maturation is catalyzed by another hydroxyl fatty acid, 3,10-dihydroxydecanoic acid, which enhances their Th1 polarizing activity, suggesting a reinforcement of anticancer properties [47][22].

4. Interaction with Anticancer Drugs

Thymoquinone is a bioactive component of the Nigella sativa plant and has been proved effective in treating cancer, explained by its immunoenhancing and anti-oxidative properties [60][23]. Moubarak et al. demonstrated that the administration of RJ at a dose of 5 µg/mL combined with thymoquinone at the concentration 10 µmol/L for 24 h could reveal the remarkable induction of the caspase-3 apoptotic pathway and the death of human breast cancer cells MDA-MB-231. These findings were reproduced in different cell lines with similar effects and without any cytotoxic changes to normal human small intestinal cells [14][24].

Temozolomide is a conventional chemotherapy used against brain cancer, and approved by the Food and Drug Administration (FDA) in 2005 [61][25]. The addition of RJ extract (30 µg/mL) to temozolomide (20 µM) has synergistically elevated the cytotoxicity of the drug on the human glioma cell line U87MG [7].

Interferon alpha is a multi-subtype protein which is used as an antitumor drug. RJ and its active compound 10-HDAA were found to improve the potency of HulFN-αN3 when applied to the human colorectal adenocarcinoma cell line CaCo-2. The same report claimed the mechanism of action to be due to the augmentation of lipid peroxidation, the inhibition of cell proliferation and the depletion of glutathione (GSH) levels in colon cancer cells [16][26].

GE132 plus is a nutraceutical supplement which contains five strong antioxidant compounds, Ganoderma lucidum extract, RJ, resveratrol, sulphraphane and lycopene in one capsule (500 mg) [17][27]. In Traditional Chinese Medicine, it has been utilized for decades as a health-promoting factor for treating various diseases owing to its therapeutic properties, including the anticancer, immunopotentiator, and anti-hypertensive impacts [62][28]. Significant anti-proliferative effects through the potential inhibition of angiogenesis have been recognized upon administration of GE132 plus to breast cancer cell lines (MCF-7), prostate cancer cell line (PC3), and the human colorectal adenocarcinoma cell line (SW48). On the other hand, GE132 plus did not show significant cytotoxicity on mesenchymal stem cells or peripheral blood collected from healthy donors in vitro. The same report revealed that higher concentrations of GE132 plus (500–2000 µg/mL) exhibited a cytotoxic effect to normal human vascular endothelial cell line EA.hy 926. 

Although modern chemotherapeutic drugs have shown an efficient improvement in patient survival, the adverse effects of these drugs represent a great concern for cancer patients as well as physicians. Cisplatin is a well-known drug that is used in many diseases [63][29] and an active drug in anticancer chemotherapy as well, yet its adverse hepatotoxic and nephrotoxic effects are the biggest challenges facing cancer patients [64][30]. Some in vivo and clinical studies have shown that the synergistic interaction of RJ with cisplatin, when both are applied simultaneously, has considerably attenuated the previously observed nephrotoxic and hepatotoxic effects. 

The effect of the synergistic interaction of RJ with the main chemotherapeutic anticancer drugs is summarized in Figure 2, and represents the increase in the apoptosis of cancer cells, as well as the reduced cytotoxicity in normal cells.
/media/item_content/202210/634e0b4d39bd2nutrients-14-04166-g002.png
Figure 2. The effect of the synergistic interaction of royal jelly with anticancer drugs on cancer cells as well as normal cells.
The effect of the synergistic interaction of royal jelly with anticancer drugs on cancer cells as well as normal cells.

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