Targeting Cancer through NF-Kb Pathway with Selected Natural Products (β-Elemene, Puerarin and Gypenosides)

Introduction

Cancer is the second leading cause of mortality around the world, therefore, its immediate treatment is very necessary [1,2]. Natural products (NPs) are considered more effective and less toxic among all therapies [1]. The vital source of these natural products is medicinal plants. NPs cure cancer via modulation of different molecular pathways, including NF-kB, MEK-ERK, autophagy, PI3K/AKT/mTOR, oxidative stress, inflammation and apoptosis [3]. Sesquiterpene lactones (SLs) are a group of NPs belong to C15 terpenoids group. These SLs possesses a variety of pharmacological and biological activities including anti-cancer and anti-inflammatory [4]. In SLs, ELE possess potent anticancer effect against different cancers [5]. The source of ELE is Rhizoma Zedoaire, which I dry rhizome of Curcuma khangsiensis, Curcuma wenyujin and Curcuma phaeocaulis [1]. The Chinese ministry of health has been approved ELE for the treatment of cancer [1]. ELE induces apoptosis through different mechanisms, including NF-kB pathway.

Next, Puerarin (Pue) is also an NP derive from Pueraria lobata (Wild) ohwi, Pueraria tuberosa (Wild) and Pueraria thomsonii Benthi [3] and approved by the Chinese ministry of health for the treatment of different diseases [3]. The NPs Gypenosides (Gyp) belong to a triterpine saponins group which are derived from Gynostema penthaphyllum (GpM), having an anticancer effect both in vivo and in vitro as well used in different clinical trials [6]. Gyp has been used for the treatment of a number of diseases in China, including hyper-lipoprotenemia [7], cardiovascular diseases [8], and hepatitis [9]. Furthermore, in a number of cancer cell lines including, oral cancer SAS cells, [10] SW620, 2, [11] and cervical epidermoid carcinoma cells have been reported [12]. Gyp inhibits the migration, invasion, metastasis, proliferation and induces apoptosis in a variety of cancers, including lung, hepatocellular, oral, colorectal and leukemic cancer through different mechanisms including NF-kB pathway 2.

NF-kB pathway and Cancer

NF-kB (Nuclear Factor Kapbba B) is a transcription factor complex having homo and heterodimers of five members of a Reticuloenotheliosis oncogene cellular-homolog (Rel) family, including RelB, RelA (p65), c-Rel, NF-kB2 (p52/p100) and NFkB1 (p50/p105) [13]. The functions of NF-kB is dysregulated in tumerogenesis [14]. In different cancers, including prostate, breast, pancreas, liver, colon, lymphoma, leukemia and ovarian cancers the NF-kB has been reported inactive state [15-17]. The DNA damage in lead to activation of NF-kB due to which NF-kB targeted genes are becomes activated, such are cyclooxygenase-2 (COX-2) [18] and iNOS (inducible nitric oxide synthase) [19]. Next, the TNFα binding to TNFR causes homotrimerization of the adopter and receptor proteins, causes cell survival and proliferation through enhancing the expression of NF-kB and activator protein 1 target genes, including vascular cell adhesion molecule 1(VCAM 1) [20-22].

Furthermore, the active NF-kB cause the activation of chemokines and its related receptors such are C-X-C chemokine receptor-4 (CXCR-4) and CCR-7 [23] which are involved in target organs [20]. These genes are involved in the anti-apoptosis and pro-survival. It is very obvious that the NF-kB is a candidate for therapeutic resistance in a variety of cancers. NPs possess potent therapeutic activity against different cancers through regulation of NF-kB pathway [4,24].

Targeting Cancer through NF-kB pathway with NPs (β-Elemene, Puerarin and Gypenosides)

One of the most important and potent NP ELE shows its anticancer activities against different type cancer cells, including RPMI-8226, SGC7901/ADM and HL-60 through modulation of NF-kB pathways. In NF-kB pathway, ELE inhibit NF-kB p65, COX-2, PGE2 and lead to inhibition of cell proliferation [25-27] as depicted in Figure 1.

Figure 1: NPs (ELE, Pue and Gyp) and NF-kN pathway in different cancers. In NF-kB pathway, ELE inhibit NF-kB p65, COX-2, PGE2 and lead to inhibition of cell proliferation. Pue downregulate the expression of TNF-α and IL-6 and Pue inhibits the expression of inflammatory factors TNF-α and IL-6 and reduce the activation of NF-kB through downregulation of p-IkBα/IkBα, IkkappaB and p65 while increasing the expression of miR16. Next, Pue inhibit the nuclear translocation of NF-kB [33] which result in downregulation of COX-2, MMP-2,9, CXCR-4, CCR-7, VCAM, and ICAM, both at mRNA and protein level. Gyp downregulate the SOS, RAS, uPA and FAK, which further reduces the expression of AKT, NF-kB, iNOS and COX-2 while activating p53. Furthermore, they inhibit MMP-2,7,9 which result in inhibition of cell migration, invasion and metastasis.

Another NP Pue has a potent effect against different cancer cell lines including, lipopolysaccharide induced THP1 [28], Z138 [29], T24 [30], MCF-7 [31], MCF-7/Adriamycin (MCF-7/adr) [32], and MDA-MB-231 [31]. In these cells, Pue negates adhesion [31], inhibit migration [31], invasion [31] and proliferation [29] through modulation of NF-kB pathway [28, 29, 31-33]. Furthermore, Pue downregulate the expression of TNF-α and IL-6 and Pue inhibits the expression of inflammatory factors TNF-α and IL-6 [31] and reduce the activation of NF-kB through downregulation of p-IkBα/ IkBα [31,32], [28], IkkappaB [31,32] and p65 while increasing the expression of miR16 [30]. Next, Pue inhibit the nuclear translocation of NF-kB [33] which result in downregulation of COX- 2, MMP-2,9, CXCR-4, CCR-7, VCAM, and ICAM, both at mRNA and protein level [31].

Natural Gyp possesses anticancer effect against SAS and SCC- 4 cells through NF-kB pathway via downregulation of SOS, RAS, uPA and FAK, which further reduces the expression of AKT, NF-kB, iNOS and COX-2 while activating p53. Furthermore, they inhibit MMP-2,7,9 which result in inhibition of cell migration, invasion and metastasis [10,34] as shown in figure (Figure 1).

Conclusions

NPs play pivotal role in cancer therapy. Among these NPs, the ELE, Pue and Gyp possesses the anti-tumor effect through modulation of NF-kB pathways. Further, the mechanisms have been summarized in Figure 1.

Conflict of Interest

The authors declare no conflict of interest.

Consent for Publication

All authors agree to be published.

References

• Bashir Ahmad, Pengyu S, Lijuan Z (2018) Natural β-Elemene: Advances in Targeting Cancer Through Different Molecular Pathways. North American Journal of Acedamic Research 1(4): 27.
• B Ahmad, S Khan, G Nabi, Y Gamallat, P Su (2019) Natural gypenosides: targeting cancer through different molecular pathways. Cancer management and research 11: 2287-2297.
• B Ahmad, S Khan, Y Liu, M Xue, G Nabi, et al. (2020) Molecular Mechanisms of Anticancer Activities of Puerarin, Cancer management and research 12: 79-90.
• S Jalal, B Ahmad, T Zhang, L Guo, L Huang, et al. (2020) SANTAMARINE: Mechanistic Studies on Multiple Diseases. Chemical Biology & Drug Design.
• Z Jiang, J A Jacob, DS Loganathachetti, P Nainangu, B Chen, et al. (2017) Beta-Elemene: Mechanistic Studies on Cancer Cell Interaction and Its Chemosensitization Effect. Frontiers in pharmacology 8: 105.
• Y Li, W Lin, J Huang, Y Xie, W Ma, et al. (2016) Anti-cancer effects of Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan), Chinese medicine 11: 43.
• YH Yang, J Yang, QH Jiang (2013) Hypolipidemic effect of gypenosides in experimentally induced hypercholesterolemic rats. Lipids Health Dis 12: 154.
• H Yu, Q Guan, L Guo, H Zhang, X Pang, et al. (2016) Gypenosides alleviate myocardial ischemia-reperfusion injury via attenuation of oxidative stress and preservation of mitochondrial function in rat heart. Cell stress & chaperones 21(3): 429-437.
• MH Chen, QF Wang, LG Chen, JJ Shee, JC Chen, et al. (2009) The inhibitory effect of Gynostemma pentaphyllum on MCP-1 and type I procollagen expression in rat hepatic stellate cells. Journal of Ethnopharmacology 126(1): 42-49.
• KW Lu, JC Chen, TY Lai, J Yang, SW Weng, et al. (2011) Gypenosides inhibits migration and invasion of human oral cancer SAS cells through the inhibition of matrix metalloproteinase-2 -9 and urokinase-plasminogen by ERK1/2 and NF-kappa B signaling pathways. Human & experimental toxicology 30(5): 406-415.
• H Yan, X Wang, Y Wang, P Wang, Y Xiao, et al. (2014) Antiproliferation and anti-migration induced by gypenosides in human colon cancer SW620 and esophageal cancer Eca-109 cells. Hum Exp Toxicol 33(5): 522-533.
• TH Chiu, JC Chen, JG Chung (2003) N-acetyltransferase is involved in gypenosides-induced N-acetylation of 2-aminofluorene and DNA adduct formation in human cervix epidermoid carcinoma cells (Ca Ski). In vivo (Athens, Greece) 17(3): 281-288.
• R Sen, D Baltimore (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46(5): 705-716.
• ND Perkins (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function Nat Rev Mol Cell Biol 8(1): 49-62.
• MC Arkan, FR Greten, (2011) IKK-NF-kB-mediated functions in carcinogenesis. Current topics in microbiology and immunology 349: 159-169.
• DS Basseres, AS Baldwin (2006) Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene 25(51): 6817-6830.
• SPrasad, J Ravindran, B B Aggarwal (2010) NF-kB and cancer: how intimate is this relationship. Molecular and cellular biochemistry 336(1-2): 25-37.
• K Yamamoto, T Arakawa, N Ueda, S Yamamoto (1995) Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells. The Journal of biological chemistry 270(52): 31315-31320.
• JH Park, YJ Jeong, HK Won, SY Choi, JH Park, et al. (2014) Activation of TOPK by lipopolysaccharide promotes induction of inducible nitric oxide synthase through NF-kappa B activity in leukemia cells. Cellular signalling 26(5): 849-856.
• A Müller, B Homey, H Soto, N Ge, D Catron, et al. (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824): 50-56.
• GD Kalliolias, LB Ivashkiv (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nature reviews. Rheumatology 12(1): 49-62.
• D Brenner, H Blaser, TW Mak (2015) Regulation of tumour necrosis factor signalling: live or let die, Nat Rev Immunol 15(6): 362-374.
• UE Hopken, HD Foss, D Meyer, M Hinz, K Leder, et al. (2002) Up-regulation of the chemokine receptor CCR7 in classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs. Blood 99(4): 1109-1116.
• T Nabekura, T Hiroi, T Kawasaki, Y Uwai (2015) Effects of natural nuclear factor-kappaB inhibitors on anticancer drug efflux transporter human P-glycoprotein. Biomed Pharmacother 70: 140-145.
• CP Zheng, XM Tong, HP Yao, J Yang, J Xu, et al. (2009) [Beta-elemene enhances aclarubicin-induced apoptotic effect in HL-60 cells and its mechanism]. Zhonghua Xue Ye Xue Za Zhi 30(12): 821-824.
• TH Fu, J Y Li, YY Jing, PJ Sun, X Bai, et al. (2013) [Effect of elemene on reversing chemoresistance to adriamycin in human stomach cancer cell line]. Zhong Yao Cai 36(4): 601-603.
• H Chen, L Shi, ZY Cheng, L Yao, YY Yang, et al. (2010) [Effects of beta-elemene on proliferation and apoptosis of human multiple myeloma cell RPMI-8226]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 18(2): 368-371.
• H Zhang, Z Zhai, H Zhou, Y Li, X Li, et al. (2015) Puerarin Inhibits oxLDL-Induced Macrophage Activation and Foam Cell Formation in Human THP1 Macrophage. BioMed research international 403616.
• M Gan, X Yin (2015) Puerarin induced in mantle cell lymphoma apoptosis and its possible mechanisms involving multi-signaling pathway, Cell biochemistry and biophys 71(1): 367-373.
• X Liu, S Li, YLi, B Cheng, B Tan, et al. (2018) Puerarin Inhibits Proliferation and Induces Apoptosis by Upregulation of miR-16 in Bladder Cancer Cell Line T24. Oncol Res 26(8): 1227-1234.
• X Liu, W Zhao, W Wang, S Lin, L Yang (2017) Puerarin suppresses LPS-induced breast cancer cell migration, invasion and adhesion by blockage NF-kappaB and Erk pathway. Biomed Pharmacother 92: 429-436.
• TT Hien, HG Kim, EH Han, KW Kang, HG Jeong (2010) Molecular mechanism of suppression of MDR1 by puerarin from Pueraria lobata via NF-kappaB pathway and cAMP-responsive element transcriptional activity-dependent up-regulation of AMP-activated protein kinase in breast cancer MCF-7/adr cells. Mol Nutr Food Res 54(7): 918-928.
• X Liu, S Li, Y Li, B Cheng, B Tan, et al. (2018) Puerarin inhibits proliferation and induces apoptosis by up-regulation of miR-16 in bladder cancer cell line T24. Oncol Res 26(8):1227-1234.
• KW Lu, ML Tsai, JC Chen, SC Hsu, TC Hsia, et al. (2008) Gypenosides inhibited invasion and migration of human tongue cancer SCC4 cells through down-regulation of NFkappaB and matrix metalloproteinase-9. Anticancer Res 28(2A): 1093-1099.