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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Analysis of Inhibition Potential of Nimbin and its Analogs against NF-κB Subunits p50 and p65: A Molecular Docking and Molecular Dynamics Study

Author(s): Asiya Khan, Divyam Singh, Kamran Waidha, Sandeep Sisodiya, Pushparathinam Gopinath, Showket Hussian, Pranay Tanwar and Deepshikha Pande Katare*

Volume 24, Issue 4, 2024

Published on: 16 October, 2023

Page: [280 - 287] Pages: 8

DOI: 10.2174/1871520623666230908101204

Price: $65

Abstract

Background: Cancer remains the major cause of morbidity and mortality. The nuclear factor kappa-B (NF- κB) plays an indispensable role in cancer cell proliferation and drug resistance. The role of NF-κB is not only limited to tumor cell proliferation and suppression of apoptotic genes but it also induces EMT transition responsible for metastasis. Inhibition of the NF-κB pathway in cancer cells by herbal derivatives makes it a favorable yet promising target for cancer therapeutics.

Aim: The purpose of the study is to explore the inhibition potential of Nimbin and its analogs against NF-κB subunits p50 and p65.

Methods: In the present study, an herbal compound Nimbin and its derivative analogs were investigated to examine their impact on the p50 and p65 subunits of the NF-κB signaling pathway using in silico tools, namely molecular docking and simulation.

Results: The molecular docking analysis revealed that Nimbin and its analogs may bind to p50 and p65 subunits with dG bind values ranging from -33.23 to -50.49 Kcal/mol. Interestingly, molecular dynamic simulation for the NO5-p65 complex displayed a stable conformation and convergence when compared to the NO4-p50 complex.

Conclusion: These results indicate that NO5 may have a potential inhibitory effect against NF-κB subunit p65, which needs to be further validated in in vitro and in vivo systems. Also, the results obtained emphasize and pave the way for exploring the Nimbin scaffold against NF-κB inhibition for cancer therapeutics.

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[1]
Ferlay, J.; Colombet, M.; Soerjomataram, I.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Cancer statistics for the year 2020: An overview. Int. J. Cancer, 2021, 149(4), 778-789.
[http://dx.doi.org/10.1002/ijc.33588] [PMID: 33818764]
[2]
Barkett, M.; Gilmore, T.D. Control of apoptosis by Rel/NF-κB transcription factors. Oncogene, 1999, 18(49), 6910-6924.
[http://dx.doi.org/10.1038/sj.onc.1203238] [PMID: 10602466]
[3]
Xia, L.; Tan, S.; Zhou, Y.; Lin, J.; Wang, H.; Oyang, L.; Tian, Y.; Liu, L.; Su, M.; Wang, H.; Cao, D.; Liao, Q. Role of the NFκB-signaling pathway in cancer. OncoTargets Ther., 2018, 11, 2063-2073.
[http://dx.doi.org/10.2147/OTT.S161109] [PMID: 29695914]
[4]
Chuang, S.E.; Yeh, P.Y.; Lu, Y.S.; Lai, G.M.; Liao, C.M.; Gao, M.; Cheng, A.L. Basal levels and patterns of anticancer drug-induced activation of nuclear factor-κB (NF-κB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells. Biochem. Pharmacol., 2002, 63(9), 1709-1716.
[http://dx.doi.org/10.1016/S0006-2952(02)00931-0] [PMID: 12007574]
[5]
Hao, F.; Kumar, S.; Yadav, N.; Chandra, D. Neem components as potential agents for cancer prevention and treatment. Biochim. Biophys. Acta Rev. Cancer, 2014, 1846(1), 247-257.
[http://dx.doi.org/10.1016/j.bbcan.2014.07.002] [PMID: 25016141]
[6]
Elumalai, P.; Gunadharini, D.N.; Senthilkumar, K.; Banudevi, S.; Arunkumar, R.; Benson, C.S.; Sharmila, G.; Arunakaran, J. Ethanolic neem (Azadirachta indica A. Juss) leaf extract induces apoptosis and inhibits the IGF signaling pathway in breast cancer cell lines. Biomedicine & Preventive Nutrition, 2012, 2(1), 59-68.
[http://dx.doi.org/10.1016/j.bionut.2011.12.008]
[7]
Schumacher, M.; Cerella, C.; Reuter, S.; Dicato, M.; Diederich, M. Anti-inflammatory, pro-apoptotic, and anti-proliferative effects of a methanolic neem (Azadirachta indica) leaf extract are mediated via modulation of the nuclear factor-κB pathway. Genes Nutr., 2011, 6(2), 149-160.
[http://dx.doi.org/10.1007/s12263-010-0194-6] [PMID: 21484152]
[8]
Chitta, K.S.; Khan, A.N.H.; Ersing, N.; Swaika, A.; Masood, A.; Paulus, A.; Qadeer, A.; Advani, P.; Sher, T.; Miller, K.C.; Lee, K.; Chanan-Khan, A.A. Neem leaf extract induces cell death by apoptosis and autophagy in B-chronic lymphocytic leukemia cells. Leuk. Lymphoma, 2014, 55(3), 652-661.
[http://dx.doi.org/10.3109/10428194.2013.807927] [PMID: 23721511]
[9]
Kikuchi, T.; Ishii, K.; Noto, T.; Takahashi, A.; Tabata, K.; Suzuki, T.; Akihisa, T. Cytotoxic and apoptosis-inducing activities of limonoids from the seeds of Azadirachta indica (neem). J. Nat. Prod., 2011, 74(4), 866-870.
[http://dx.doi.org/10.1021/np100783k] [PMID: 21381696]
[10]
Priyadarsini, R.V.; Murugan, R.S.; Sripriya, P.; Karunagaran, D.; Nagini, S. The neem limonoids azadirachtin and nimbolide induce cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells. Free Radic. Res., 2010, 44(6), 624-634.
[http://dx.doi.org/10.3109/10715761003692503] [PMID: 20429769]
[11]
Srivastava, P.; Yadav, N.; Lella, R.; Schneider, A.; Jones, A.; Marlowe, T.; Lovett, G.; O’Loughlin, K.; Minderman, H.; Gogada, R.; Chandra, D. Neem oil limonoids induces p53-independent apoptosis and autophagy. Carcinogenesis, 2012, 33(11), 2199-2207.
[http://dx.doi.org/10.1093/carcin/bgs269] [PMID: 22915764]
[12]
Sudhakaran, G.; Rajesh, R.; Almutairi, B.O.; Arokiyaraj, S.; Gopinath, P.; Arockiaraj, J. Nimbin analogs stimulate glucose uptake and glycogen storage in the insulin signalling cascade by enhancing the IRTK, PI3K and Glut-4 mechanism in myotubes. Tissue Cell, 2023, 82, 102104.
[http://dx.doi.org/10.1016/j.tice.2023.102104] [PMID: 37207372]
[13]
Oeckinghaus, A.; Ghosh, S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb. Perspect. Biol., 2009, 1(4), a000034.
[http://dx.doi.org/10.1101/cshperspect.a000034] [PMID: 20066092]
[14]
Murwanti, R.; Kholifah, E.; Sudarmanto, B.S.A.; Hermawan, A. Effect of curcumin on NF-κB P105/50 expression on triplenegative breast cancer (TNBC) and its possible mechanism of action. AIP Conf. Proc., 2020, 2260, 040024.
[http://dx.doi.org/10.1063/5.0016423]
[15]
Zhang, T. Ma, C.; Zhang, Z.; Zhang, H.; Hu, H. NF‐κB signaling in inflammation and cancer. MedComm, 2021, 2(4), 618-653.
[http://dx.doi.org/10.1002/mco2.104] [PMID: 34977871]
[16]
Yu, Y.; Wan, Y.; Huang, C. The biological functions of NF-kappaB1 (p50) and its potential as an anti-cancer target. Curr. Cancer Drug Targets, 2009, 9(4), 566-571.
[http://dx.doi.org/10.2174/156800909788486759] [PMID: 19519322]
[17]
Waidha, K.; Anto, N.P.; Jayaram, D.R.; Golan-Goldhirsh, A.; Rajendran, S.; Livneh, E.; Gopas, J. 6,6′-dihydroxythiobinupharidine (DTBN) purified from Nuphar lutea leaves is an inhibitor of protein kinase C catalytic activity. Molecules, 2021, 26(9), 2785.
[http://dx.doi.org/10.3390/molecules26092785] [PMID: 34066895]
[18]
Dadwal, A.; Singh, V.; Sharma, S.; Satyanarayana, T. Structural aspects of β-glucosidase of Myceliophthora thermophila (MtBgl3c) by homology modelling and molecular docking. J. Biomol. Struct. Dyn., 2022, 40(11), 5211-5228.
[http://dx.doi.org/10.1080/07391102.2020.1869095] [PMID: 33413029]
[19]
Giuliani, C.; Bucci, I.; Napolitano, G. The role of the transcription factor nuclear factor-kappa B in thyroid autoimmunity and cancer. Front. Endocrinol. (Lausanne), 2018, 9, 471.
[http://dx.doi.org/10.3389/fendo.2018.00471] [PMID: 30186235]
[20]
Chen, F.E.; Huang, D.B.; Chen, Y.Q.; Ghosh, G. Crystal structure of p50/p65 heterodimer of transcription factor NF-κB bound to DNA. Nature, 1998, 391(6665), 410-413.
[http://dx.doi.org/10.1038/34956] [PMID: 9450761]
[21]
Nakanishi, C.; Toi, M. Nuclear factor-κB inhibitors as sensitizers to anticancer drugs. Nat. Rev. Cancer, 2005, 5(4), 297-309.
[http://dx.doi.org/10.1038/nrc1588] [PMID: 15803156]
[22]
Nelson, D.E.; Ihekwaba, A.E.C.; Elliott, M.; Johnson, J.R.; Gibney, C.A.; Foreman, B.E.; Nelson, G.; See, V.; Horton, C.A.; Spiller, D.G.; Edwards, S.W.; McDowell, H.P.; Unitt, J.F.; Sullivan, E.; Grimley, R.; Benson, N.; Broomhead, D.; Kell, D.B.; White, M.R.H. Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science, 2004, 306(5696), 704-708.
[http://dx.doi.org/10.1126/science.1099962] [PMID: 15499023]
[23]
Brown, M. Cohen, J.; Arun, P.; Chen, Z.; Waes, C.V. NF-κB in carcinoma therapy and prevention. Expert Opin. Ther. Targets, 2008, 12(9), 1109-1122.
[http://dx.doi.org/10.1517/14728222.12.9.1109] [PMID: 18694378]
[24]
Sovak, M.A.; Bellas, R.E.; Kim, D.W.; Zanieski, G.J.; Rogers, A.E.; Traish, A.M.; Sonenshein, G.E. Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. J. Clin. Invest., 1997, 100(12), 2952-2960.
[http://dx.doi.org/10.1172/JCI119848] [PMID: 9399940]
[25]
Nakshatri, H.; Bhat-Nakshatri, P.; Martin, D.A.; Goulet, R.J., Jr; Sledge, G.W. Jr Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol. Cell. Biol., 1997, 17(7), 3629-3639.
[http://dx.doi.org/10.1128/MCB.17.7.3629] [PMID: 9199297]
[26]
Grivennikov, S.I.; Greten, F.R.; Karin, M. Immunity, inflammation, and cancer. Cell, 2010, 140(6), 883-899.
[http://dx.doi.org/10.1016/j.cell.2010.01.025] [PMID: 20303878]
[27]
Gambhir, S.; Vyas, D.; Hollis, M.; Aekka, A.; Vyas, A. Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies. World J. Gastroenterol., 2015, 21(11), 3174-3183.
[http://dx.doi.org/10.3748/wjg.v21.i11.3174] [PMID: 25805923]
[28]
Lind, D.S.; Hochwald, S.N.; Malaty, J.; Rekkas, S.; Hebig, P.; Mishra, G.; Moldawer, L.L.; Copeland, E.M., III; MacKay, S. Nuclear factor-κB is upregulated in colorectal cancer. Surgery, 2001, 130(2), 363-369.
[http://dx.doi.org/10.1067/msy.2001.116672] [PMID: 11490372]
[29]
Tan, C.; Waldmann, T.A. Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia. Cancer Res., 2002, 62(4), 1083-1086.
[PMID: 11861386]
[30]
Amiri, K.I.; Horton, L.W.; LaFleur, B.J.; Sosman, J.A.; Richmond, A. Augmenting chemosensitivity of malignant melanoma tumors via proteasome inhibition: Implication for bortezomib (VELCADE, PS-341) as a therapeutic agent for malignant melanoma. Cancer Res., 2004, 64(14), 4912-4918.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0673] [PMID: 15256463]
[31]
Yang, J.; Amiri, K.I.; Burke, J.R.; Schmid, J.A.; Richmond, A. BMS-345541 targets inhibitor of kappaB kinase and induces apoptosis in melanoma: Involvement of nuclear factor kappaB and mitochondria pathways. Clin. Cancer Res., 2006, 12(3), 950-960.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-1220] [PMID: 16467110]
[32]
Umezawa, K. Inhibition of tumor growth by NF-?B inhibitors. Cancer Sci., 2006, 97(10), 990-995.
[http://dx.doi.org/10.1111/j.1349-7006.2006.00285.x] [PMID: 16925581]
[33]
Zollo, M.; Di Dato, V.; Spano, D.; De Martino, D.; Liguori, L.; Marino, N.; Vastolo, V.; Navas, L.; Garrone, B.; Mangano, G.; Biondi, G.; Guglielmotti, A. Targeting monocyte chemotactic protein-1 synthesis with bindarit induces tumor regression in prostate and breast cancer animal models. Clin. Exp. Metastasis, 2012, 29(6), 585-601.
[http://dx.doi.org/10.1007/s10585-012-9473-5] [PMID: 22484917]
[34]
Gupta, S.C.; Prasad, S.; Sethumadhavan, D.R.; Nair, M.S.; Mo, Y.Y.; Aggarwal, B.B. Nimbolide, a limonoid triterpene, inhibits growth of human colorectal cancer xenografts by suppressing the proinflammatory microenvironment. Clin. Cancer Res., 2013, 19(16), 4465-4476.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0080] [PMID: 23766363]
[35]
Sudhakaran, G.; Prathap, P.; Guru, A.; Rajesh, R.; Sathish, S.; Madhavan, T.; Arasu, M.V.; Al-Dhabi, N.A.; Choi, K.C.; Gopinath, P.; Arockiaraj, J. Anti‐inflammatory role demonstrated both in vitro and in vivo models using nonsteroidal tetranortriterpenoid, Nimbin (N1) and its analogs (N2 and N3) that alleviate the domestication of alternative medicine. Cell Biol. Int., 2022, 46(5), 771-791.
[http://dx.doi.org/10.1002/cbin.11769] [PMID: 35077598]
[36]
Sudhakaran, G.; Prathap, P.; Guru, A.; Haridevamuthu, B.; Murugan, R.; Almutairi, B.O.; Almutairi, M.H.; Juliet, A.; Gopinath, P.; Arockiaraj, J. Reverse pharmacology of Nimbin-N2 attenuates alcoholic liver injury and promotes the hepatoprotective dual role of improving lipid metabolism and downregulating the levels of inflammatory cytokines in zebrafish larval model. Mol. Cell. Biochem., 2022, 477(10), 2387-2401.
[http://dx.doi.org/10.1007/s11010-022-04448-7] [PMID: 35575874]

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