A review on signaling pathways of Propolis as a nutrition adjuvant in cancer therapy
A review on signaling pathways of Propolis as a nutrition adjuvant in cancer therapy
Sara Aravand,1Hajie Lotfi,2,*Nassim Valivand,3Nematollah Gheibi,4
1. Department of Advanced Technologies in Medicine, department of Medical Biotechnology, School of Paramedical Sciences, Qazvin University of Medical Sciences, Qazvin, Iran 2. Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran. 3. Department of Advanced Technologies in Medicine, department of Medical Biotechnology, School of Paramedical Sciences, Qazvin University of Medical Sciences, Qazvin, Iran. 4. Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
Introduction: Introduction:Cancer is still a global complication which is a major burden for societies. Propolis, is a promising plant-based substance with diverse chemical compounds. Recently, it has been noticed by medical researchers due to extensive therapeutic capacities,. Nowadays, the low side effect therapeutic strategies are necessary in order to alleviate the complications of conventional therapies like surgery, : chemotherapy, and radiotherapy. Therefore, clinical application of propolis as an adjuvant, is hopeful. Anti cancer compounds of propolis trigger different signaling cascades leading to apoptosis and cancer cells death.
Methods: Method: In this review, during the last 10 years, anti-cancer and adjuvant potential of propolis, is well-established based on extensive studies.
Results: Result: One of the major mechanisms which is failed in cancer, is programmed cell death (apoptosis). Propolis, can regulate both intrinsic and extrinsic pathways in apoptosis. It was found that ethanolic extract of propolis (EEP) might induce various cascades, including the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway, Bcl-2 associated X protein (Bax) and p53 pathway, and downregulate extracellular signal regulated kinases (ERK1/2) signaling pathway. The epithelial mesenchymal transition (EMT) plays a crucial role in metastasis. Key pathways such as Wnt, Hedgehog, and Notch are involved in cell motility, invasion, and migration. Additionally, overexpression of Mortalin, a highly conserved heat shock chaperone, in cancer cells contributes to metastasis. CAPE(caffeic acid phenethyl ester) as a well-known anticancer constituent of propolis, can reduce the expression of mortalin, vimentin, MMP2, MMP9, β-catenin, Wnt3α, and TGFβ in breast cancer cells (MDA-MB-231 and MCF-7). Angiogenesis inhibitors impede the formation of blood vessels by targeting proteins known as angiogenesis activators, such as vascular endothelial growth factor (VEGF). In tumors, the balance between activators and inhibitors is skewed due to the dominance of pro angiogenic factors. Propolis and some of its components have shown anti angiogenic activity. Caffeic acid (CA) acts as an anti angiogenic compound by inhibiting HIF-1 (hypoxia-inducible factor 1), leading to a reduction in phosphorylated JNK-1 (c-Jun N-terminal kinases). CAPE also inhibits the production of VEGF, MMP-2, and MMP-9. One of the main characteristics of tumor cells is their failure to regulate the cell cycle, resulting in uncontrolled cell proliferation. Mechanisms such as Cyclins, which bind and activate cyclin-dependent kinases (CDKs), control cell division at the appropriate time. CDKs phosphorylate specific targets/molecules that are properly activated during the cell cycle. Propolis and its components regulate cyclin D, CDK2/4/6, and their inhibitors, and upregulate p21 and p27, thereby arresting the cell cycle in the G2/M or G0/G1 phases. In U937-a leukemia cell line- it was found that a methanol extract of propolis increased cell accumulation to 32.8% and 37.7% in the G2/M phase due to the downregula¬tion of cyclin A, B, CDK2, and high levels of p21 and p27 proteins. Another important protein in cell cycle arrest is p53, which is activated after DNA damage. P21, activated by p53, is responsible for the p53 dependent checkpoint and G1 arrest. CAPE and Art C (artepillin C) disinte¬grate the mortalin-P53 complex, leading to P53 activation. In addition to anticancer characteristics of propolis, Synergistic effects with anti cancer drugs reduces the required doses of drugs and their associated side effects. The use of doxorubicin and epirubicin in chemotherapy presents side effects such as liver damage due to oxidative stress via ROS. During oxidative stress, ALT and AST, two key hepatic enzymes, are increased. The antioxidant effects of propolis prevents hepatocyte damage secondary to lipid peroxidation induced by doxorubicin and epirubicin.
Conclusion: Conclusion: The various effective components of propolis are involved in the different biological pathways including critical cell signaling pathways in the onset, progression, and metastasis of cancer cells. The pathways affected by propolis are apoptosis, PI3k / AKT / mTOR, NF-κB, JAK-STAT, TLR4, VEGF, and TGFβ path¬ways. The majority of the studies demonstrated the cytotoxicity activity of propolis and its bioactive compounds against various cancer cells. Some studies also investigated the potential synergistic activity of propolis with other therapeutics. Numerous in vitro and in vivo studies, have verified anticancer and adjuvant potential of propolis as a promising drug for further investigation in clinical trials.