Abstract
Background: Fruits like berries are known not only for their taste and nutritional value but also for the potential health benefits of their bioactive components. Stilbenes, a group of phenolic metabolites found in berries, demonstrate significant pharmacological activities. Its derivatives also have been investigated for their biological functions, including as anticancer agents. Bcl-2 antiapoptotic proteins are highly involved in regulating cancer progression by promoting apoptosis evasion. Hence, Bcl-2 is a promising therapeutic target in drug development.
Objective: This study aimed to determine the stilbene derivatives with the best potential as Bcl-2 inhibitors.
Methods: The method used was molecular docking of several stilbene derivatives to Bcl-2 receptors using AutoDock 4.2, followed by an ADMET study.
Results: Based on the docking score and ligand-receptor interactions, oxyresveratol and pterostilbene had the best docking findings for the Bcl-2 antiapoptotic proteins. Among these eleven substances, pterostilbene significantly inhibited Bcl-w and Mcl-1, whereas oxresveratrol could inhibit Bcl-2. Although the findings from the two ADMET profiles were varied, further in vitro and in vivo studies are required to explore the potential of the compounds.
Conclusion: In conclusion, the study identified the potential chemopreventive agents, such as pterostilbene and oxyresveratrol might serve as potential lead compounds for developing new Bcl-2 inhibitors.
Keywords: Bcl-2, anticancer, molecular docking, stilbene, ADMET, antiapoptotic, apoptotis, AutoDock 4.2.
[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Bennett, J.E.; Stevens, G.A.; Mathers, C.D.; Bonita, R.; Rehm, J.; Kruk, M.E.; Riley, L.M.; Dain, K.; Kengne, A.P.; Chalkidou, K.; Beagley, J.; Kishore, S.P.; Chen, W.; Saxena, S.; Bettcher, D.W.; Grove, J.T.; Beaglehole, R.; Ezzati, M. NCD Countdown 2030: Worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet, 2018, 392(10152), 1072-1088.
[http://dx.doi.org/10.1016/S0140-6736(18)31992-5] [PMID: 30264707]
[http://dx.doi.org/10.1016/S0140-6736(18)31992-5] [PMID: 30264707]
[3]
Kalkavan, H.; Green, D.R. MOMP, cell suicide as a BCL-2 family business. Cell Death Differ., 2018, 25(1), 46-55.
[http://dx.doi.org/10.1038/cdd.2017.179] [PMID: 29053143]
[http://dx.doi.org/10.1038/cdd.2017.179] [PMID: 29053143]
[4]
Skrovankova, S.; Sumczynski, D.; Mlcek, J.; Jurikova, T.; Sochor, J. Bioactive compounds and antioxidant activity in different types of berries. Int. J. Mol. Sci., 2015, 16(10), 24673-24706.
[http://dx.doi.org/10.3390/ijms161024673] [PMID: 26501271]
[http://dx.doi.org/10.3390/ijms161024673] [PMID: 26501271]
[5]
World Health Organization. Fruit and vegetable promotion initiative/a meeting report. 2003. Available from: https://apps.who.int/iris/handle/10665/68395
[6]
Afrin, S.; Giampieri, F.; Gasparrini, M.; Forbes-Hernandez, T.; Varela-López, A.; Quiles, J.; Mezzetti, B.; Battino, M. Chemopreventive and therapeutic effects of edible berries: A focus on colon cancer prevention and treatment. Molecules, 2016, 21(2), 169.
[http://dx.doi.org/10.3390/molecules21020169] [PMID: 26840292]
[http://dx.doi.org/10.3390/molecules21020169] [PMID: 26840292]
[7]
Folmer, F.; Basavaraju, U.; Jaspars, M.; Hold, G.; El-Omar, E.; Dicato, M.; Diederich, M. Anticancer effects of bioactive berry compounds. Phytochem. Rev., 2014, 13(1), 295-322.
[http://dx.doi.org/10.1007/s11101-013-9319-z]
[http://dx.doi.org/10.1007/s11101-013-9319-z]
[8]
Baby, B.; Antony, P.; Vijayan, R. Antioxidant and anticancer properties of berries. Crit. Rev. Food Sci. Nutr., 2018, 58(15), 2491-2507.
[http://dx.doi.org/10.1080/10408398.2017.1329198] [PMID: 28609132]
[http://dx.doi.org/10.1080/10408398.2017.1329198] [PMID: 28609132]
[9]
Golovinskaia, O.; Wang, C.K. Review of functional and pharmacological activities of berries. Molecules, 2021, 26(13), 3904.
[http://dx.doi.org/10.3390/molecules26133904] [PMID: 34202412]
[http://dx.doi.org/10.3390/molecules26133904] [PMID: 34202412]
[10]
Castro, D.; Teodoro, A. Anticancer properties of bioactive compounds of berry fruits - A review. Br. J. Med. Med. Res., 2015, 6(8), 771-794.
[http://dx.doi.org/10.9734/BJMMR/2015/15289]
[http://dx.doi.org/10.9734/BJMMR/2015/15289]
[11]
Sosa, V.; Moliné, T.; Somoza, R.; Paciucci, R.; Kondoh, H. LLeonart, M.E. Oxidative stress and cancer: An overview. Ageing Res. Rev., 2013, 12(1), 376-390.
[http://dx.doi.org/10.1016/j.arr.2012.10.004] [PMID: 23123177]
[http://dx.doi.org/10.1016/j.arr.2012.10.004] [PMID: 23123177]
[12]
Juranić, Z.; Žižak, Ž. Biological activities of berries: From antioxidant capacity to anti-cancer effects. Biofactors, 2005, 23(4), 207-211.
[http://dx.doi.org/10.1002/biof.5520230405]
[http://dx.doi.org/10.1002/biof.5520230405]
[13]
Ma, L.; Li, W.; Wang, R.; Nan, Y.; Wang, Q.; Liu, W.; Jin, F. Resveratrol enhanced anticancer effects of cisplatin on non-small cell lung cancer cell lines by inducing mitochondrial dysfunction and cell apoptosis. Int. J. Oncol., 2015, 47(4), 1460-1468.
[http://dx.doi.org/10.3892/ijo.2015.3124] [PMID: 26314326]
[http://dx.doi.org/10.3892/ijo.2015.3124] [PMID: 26314326]
[14]
Rauf, A.; Imran, M.; Butt, M.S.; Nadeem, M.; Peters, D.G.; Mubarak, M.S. Resveratrol as an anti-cancer agent: A review. Crit. Rev. Food Sci. Nutr., 2018, 58(9), 1428-1447.
[http://dx.doi.org/10.1080/10408398.2016.1263597] [PMID: 28001084]
[http://dx.doi.org/10.1080/10408398.2016.1263597] [PMID: 28001084]
[15]
Liu, Y.; Grimm, M.; Dai, W.; Hou, M.; Xiao, Z.X.; Cao, Y. CB-Dock: A web server for cavity detection-guided protein–ligand blind docking. Acta Pharmacol. Sin., 2020, 41(1), 138-144.
[http://dx.doi.org/10.1038/s41401-019-0228-6] [PMID: 31263275]
[http://dx.doi.org/10.1038/s41401-019-0228-6] [PMID: 31263275]
[16]
Danial, N.N.; Korsmeyer, S. J. Cell Death. Cell, 2004, 116(2), 205-219.
[http://dx.doi.org/10.1016/S0092-8674(04)00046-7] [PMID: 14744432]
[http://dx.doi.org/10.1016/S0092-8674(04)00046-7] [PMID: 14744432]
[17]
Strasser, A.; Harris, A.W.; Bath, M.L.; Cory, S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature, 1990, 348(6299), 331-333.
[http://dx.doi.org/10.1038/348331a0] [PMID: 2250704]
[http://dx.doi.org/10.1038/348331a0] [PMID: 2250704]
[19]
Adams, J.; Cory, S. Bcl-2-regulated apoptosis: Mechanism and therapeutic potential. Curr. Opin. Immunol., 2007, 19(5), 488-496.
[http://dx.doi.org/10.1016/j.coi.2007.05.004] [PMID: 17629468]
[http://dx.doi.org/10.1016/j.coi.2007.05.004] [PMID: 17629468]
[20]
Banjara, S.; Suraweera, C.D.; Hinds, M.G.; Kvansakul, M. The Bcl-2 family: Ancient origins, conserved structures, and divergent mechanisms. Biomolecules, 2020, 10(1), 128.
[http://dx.doi.org/10.3390/biom10010128] [PMID: 31940915]
[http://dx.doi.org/10.3390/biom10010128] [PMID: 31940915]
[21]
Kale, J.; Osterlund, E.J.; Andrews, D.W. BCL-2 family proteins: Changing partners in the dance towards death. Cell Death Differ., 2018, 25(1), 65-80.
[http://dx.doi.org/10.1038/cdd.2017.186] [PMID: 29149100]
[http://dx.doi.org/10.1038/cdd.2017.186] [PMID: 29149100]
[22]
Campbell, K.J.; Tait, S.W.G. Targeting BCL-2 regulated apoptosis in cancer. Open Biol., 2018, 8(5), 180002.
[http://dx.doi.org/10.1098/rsob.180002] [PMID: 29769323]
[http://dx.doi.org/10.1098/rsob.180002] [PMID: 29769323]
[23]
Frenzel, A.; Grespi, F.; Chmelewskij, W.; Villunger, A. Bcl2 family proteins in carcinogenesis and the treatment of cancer. Apoptosis, 2009, 14(4), 584-596.
[http://dx.doi.org/10.1007/s10495-008-0300-z] [PMID: 19156528]
[http://dx.doi.org/10.1007/s10495-008-0300-z] [PMID: 19156528]
[24]
Kaiser, U.; Schilli, M.; Haag, U.; Neumann, K.; Kreipe, H.; Kogan, E.; Havemann, K. Expression of bcl-2 - protein in small cell lung cancer. Lung Cancer, 1996, 15(1), 31-40.
[http://dx.doi.org/10.1016/0169-5002(96)00568-5] [PMID: 8865121]
[http://dx.doi.org/10.1016/0169-5002(96)00568-5] [PMID: 8865121]
[25]
Zhou, X.L.; Wang, M. Expression levels of survivin, Bcl-2, and KAI1 proteins in cervical cancer and their correlation with metastasis. Genet. Mol. Res., 2015, 14(4), 17059-17067.
[http://dx.doi.org/10.4238/2015.December.16.6] [PMID: 26681053]
[http://dx.doi.org/10.4238/2015.December.16.6] [PMID: 26681053]
[26]
Chauhan, D.; Velankar, M.; Brahmandam, M.; Hideshima, T.; Podar, K.; Richardson, P.; Schlossman, R.; Ghobrial, I.; Raje, N.; Munshi, N.; Anderson, K.C. A novel Bcl-2/Bcl-XL/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene, 2007, 26(16), 2374-2380.
[http://dx.doi.org/10.1038/sj.onc.1210028] [PMID: 17016430]
[http://dx.doi.org/10.1038/sj.onc.1210028] [PMID: 17016430]
[27]
Trudel, S.; Stewart, A. K.; Li, Z.; Shu, Y.; Liang, S. Ben, ; Trieu, Y.; Reece, D.; Paterson, J.; Wang, D.; Wen, X. Y. The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin. Cancer Res., 2007, 13(2 I)
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1526]
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1526]
[28]
Kline, M.P.; Rajkumar, S.V.; Timm, M.M.; Kimlinger, T.K.; Haug, J.L.; Lust, J.A.; Greipp, P.R.; Kumar, S. ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells. Leukemia, 2007, 21(7), 1549-1560.
[http://dx.doi.org/10.1038/sj.leu.2404719] [PMID: 17460700]
[http://dx.doi.org/10.1038/sj.leu.2404719] [PMID: 17460700]
[29]
Punnoose, E.A.; Leverson, J.D.; Peale, F.; Boghaert, E.R.; Belmont, L.D.; Tan, N.; Young, A.; Mitten, M.; Ingalla, E.; Darbonne, W.C.; Oleksijew, A.; Tapang, P.; Yue, P.; Oeh, J.; Lee, L.; Maiga, S.; Fairbrother, W.J.; Amiot, M.; Souers, A.J.; Sampath, D. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Mol. Cancer Ther., 2016, 15(5), 1132-1144.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0730] [PMID: 26939706]
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0730] [PMID: 26939706]
[30]
Yecies, D.; Carlson, N.E.; Deng, J.; Letai, A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood, 2010, 115(16), 3304-3313.
[http://dx.doi.org/10.1182/blood-2009-07-233304] [PMID: 20197552]
[http://dx.doi.org/10.1182/blood-2009-07-233304] [PMID: 20197552]
[31]
Mazumder, S.; Choudhary, G.S.; Al-harbi, S.; Almasan, A. Mcl-1 Phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B cells. Cancer Res., 2012, 72(12), 3069-3079.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-4106] [PMID: 22525702]
[http://dx.doi.org/10.1158/0008-5472.CAN-11-4106] [PMID: 22525702]
[32]
Morales, A.A.; Kurtoglu, M.; Matulis, S.M.; Liu, J.; Siefker, D.; Gutman, D.M.; Kaufman, J.L.; Lee, K.P.; Lonial, S.; Boise, L.H. Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1–expressing myeloma cells. Blood, 2011, 118(5), 1329-1339.
[http://dx.doi.org/10.1182/blood-2011-01-327197] [PMID: 21659544]
[http://dx.doi.org/10.1182/blood-2011-01-327197] [PMID: 21659544]
[33]
Konopleva, M.; Contractor, R.; Tsao, T.; Samudio, I.; Ruvolo, P.P.; Kitada, S.; Deng, X.; Zhai, D.; Shi, Y.X.; Sneed, T.; Verhaegen, M.; Soengas, M.; Ruvolo, V.R.; McQueen, T.; Schober, W.D.; Watt, J.C.; Jiffar, T.; Ling, X.; Marini, F.C.; Harris, D.; Dietrich, M.; Estrov, Z.; McCubrey, J.; May, W.S.; Reed, J.C.; Andreeff, M. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell, 2006, 10(5), 375-388.
[http://dx.doi.org/10.1016/j.ccr.2006.10.006] [PMID: 17097560]
[http://dx.doi.org/10.1016/j.ccr.2006.10.006] [PMID: 17097560]
[34]
Tromp, J.M.; Geest, C.R.; Breij, E.C.W.; Elias, J.A.; van Laar, J.; Luijks, D.M.; Kater, A.P.; Beaumont, T.; van Oers, M.H.J.; Eldering, E. Tipping the Noxa/Mcl-1 balance overcomes ABT-737 resistance in chronic lymphocytic leukemia. Clin. Cancer Res., 2012, 18(2), 487-498.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1440] [PMID: 22128299]
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1440] [PMID: 22128299]
[35]
Tahir, S.K.; Wass, J.; Joseph, M.K.; Devanarayan, V.; Hessler, P.; Zhang, H.; Elmore, S.W.; Kroeger, P.E.; Tse, C.; Rosenberg, S.H.; Anderson, M.G. Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines. Mol. Cancer Ther., 2010, 9(3), 545-557.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0651] [PMID: 20179162]
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0651] [PMID: 20179162]
[36]
Zhao, F.; Qin, J.; Liang, Y.; Zhou, R. Exploring anti-liver cancer targets and mechanisms of oxyresveratrol: In silico and verified findings. Bioengineered, 2021, 12(2), 9939-9948.
[http://dx.doi.org/10.1080/21655979.2021.1985328] [PMID: 34592904]
[http://dx.doi.org/10.1080/21655979.2021.1985328] [PMID: 34592904]
[37]
Pezzuto, J.M. Resveratrol as an inhibitor of carcinogenesis. Pharm. Biol., 2008, 46(7-8), 443-573.
[http://dx.doi.org/10.1080/13880200802116610]
[http://dx.doi.org/10.1080/13880200802116610]
[38]
Varoni, E.M.; Lo Faro, A.F.; Sharifi-Rad, J.; Iriti, M. Anticancer molecular mechanisms of resveratrol. Front. Nutr., 2016, 3, 8.
[http://dx.doi.org/10.3389/fnut.2016.00008] [PMID: 27148534]
[http://dx.doi.org/10.3389/fnut.2016.00008] [PMID: 27148534]
[39]
Li, L.; Qiu, R.L.; Lin, Y.; Cai, Y.; Bian, Y.; Fan, Y.; Gao, X.J. Resveratrol suppresses human cervical carcinoma cell proliferation and elevates apoptosis via the mitochondrial and p53 signaling pathways. Oncol. Lett., 2018, 15(6), 9845-9851.
[http://dx.doi.org/10.3892/ol.2018.8571] [PMID: 29928358]
[http://dx.doi.org/10.3892/ol.2018.8571] [PMID: 29928358]
[40]
Xu, B.; Tao, Z.Z. Piceatannol enhances the antitumor efficacy of gemcitabine in human A549 non-small cell lung cancer cells. Oncol. Res., 2015, 22(4), 213-217.
[http://dx.doi.org/10.3727/096504015X14386062091398] [PMID: 26351210]
[http://dx.doi.org/10.3727/096504015X14386062091398] [PMID: 26351210]
[41]
Wang, D.; Zhang, Y.; Zhang, C.; Gao, L.; Li, J. Piceatannol pretreatment alleviates acute cardiac injury via regulating PI3K-Akt-eNOS signaling in H9c2 cells. Biomed. Pharmacother., 2019, 109, 886-891.
[http://dx.doi.org/10.1016/j.biopha.2018.10.120] [PMID: 30551542]
[http://dx.doi.org/10.1016/j.biopha.2018.10.120] [PMID: 30551542]
[42]
Kim, Y.; Park, C.; Lee, J.; Kim, G.; Lee, W.; Choi, Y.; Ryu, C. Induction of apoptosis by piceatannol in human leukemic U937 cells through down-regulation of Bcl-2 and activation of caspases. Oncol. Rep., 2008, 19(4), 961-967.
[http://dx.doi.org/10.3892/or.19.4.961] [PMID: 18357382]
[http://dx.doi.org/10.3892/or.19.4.961] [PMID: 18357382]
[43]
Kim, J.S.; Kang, C.G.; Kim, S.H.; Lee, E.O. Rhapontigenin suppresses cell migration and invasion by inhibiting the PI3K-dependent Rac1 signaling pathway in MDA-MB-231 human breast cancer cells. J. Nat. Prod., 2014, 77(5), 1135-1139.
[http://dx.doi.org/10.1021/np401078g] [PMID: 24828286]
[http://dx.doi.org/10.1021/np401078g] [PMID: 24828286]
[44]
Riche, D.M.; McEwen, C.L.; Riche, K.D.; Sherman, J.J.; Wofford, M.R.; Deschamp, D.; Griswold, M. Analysis of safety from a human clinical trial with pterostilbene. J. Toxicol., 2013, 2013, 1-5.
[http://dx.doi.org/10.1155/2013/463595] [PMID: 23431291]
[http://dx.doi.org/10.1155/2013/463595] [PMID: 23431291]
[45]
Chatterjee, K.; AlSharif, D.; Mazza, C.; Syar, P.; Al Sharif, M.; Fata, J. Resveratrol and pterostilbene exhibit anticancer properties involving the downregulation of HPV oncoprotein E6 in cervical cancer cells. Nutrients, 2018, 10(2), 243.
[http://dx.doi.org/10.3390/nu10020243] [PMID: 29485619]
[http://dx.doi.org/10.3390/nu10020243] [PMID: 29485619]
[46]
Kong, Y.; Chen, G.; Xu, Z.; Yang, G.; Li, B.; Wu, X.; Xiao, W.; Xie, B.; Hu, L.; Sun, X.; Chang, G.; Gao, M.; Gao, L.; Dai, B.; Tao, Y.; Zhu, W.; Shi, J. Pterostilbene induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma cells. Sci. Rep., 2016, 6(1), 37417.
[http://dx.doi.org/10.1038/srep37417] [PMID: 27869173]
[http://dx.doi.org/10.1038/srep37417] [PMID: 27869173]
Article Metrics
21
2