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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

Influence of New Synthetic Xanthones on the Proliferation and Migration Potential of Cancer Cell Lines In Vitro

Author(s): Natalia Szkaradek*, Daniel Sypniewski, Dorota Żelaszczyk, Sabina Gałka, Paulina Borzdziłowska, Henryk Marona and Ilona Bednarek

Volume 19, Issue 16, 2019

Page: [1949 - 1965] Pages: 17

DOI: 10.2174/1871520619666190405113519

Price: $65

Abstract

Background: Natural plant metabolites and their semisynthetic derivatives have been used for years in cancer therapy. Xanthones are oxygenated heterocyclic compounds produced as secondary metabolites by higher plants, fungi or lichens. Xanthone core may serve as a template in the synthesis of many derivatives that have broad biological activities.

Objective: This study synthesized a series of 17 new xanthones, and their anticancer potential was also evaluated.

Methods: The anticancer potential was evaluated in vitro using a highly invasive T24 cancer cell line. Direct cytotoxic effects of the xanthones were established by IC50 estimation based on XTT assay.

Results: 5 compounds of the total 17 showed significant cytotoxicity toward the studied cancer cultures and were submitted to further detailed analysis, including studies examining their influence on gelatinase A and B expression, as well as on the cancer cells migration and adhesion to an extracellular matrix. These analyses were carried out on five human tumor cell lines: A2780 (ovarian cancer), A549 (lung cancer), HeLa (cervical cancer), Hep G2 (liver cancer), and T24 (urinary bladder cancer). All the compounds, especially 4, showed promising anticancer activity: they exhibited significant cytotoxicity towards all the evaluated cell lines, including MCF-7 breast cancer, and hindered migration-motility activity of cancer cells demonstrating more potent activity than α-mangostin which served as a reference xanthone.

Conclusion: These results suggest that our xanthone derivatives may be further analyzed in order to include them in cancer treatment protocols.

Keywords: Xanthones, cancer, cytotoxicity, apoptosis, proliferation, cell migration.

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[1]
Marona, H.; Szkaradek, N.; Rapacz, A.; Filipek, B.; Dybała, M.; Siwek, A.; Cegła, M.; Szneler, E. Preliminary evaluation of pharmacological properties of some xanthone derivatives. Bioorg. Med. Chem., 2009, 17(3), 1345-1352.
[http://dx.doi.org/10.1016/j.bmc.2008.12.031] [PMID: 19131251]
[2]
Pedraza-Chaverri, J.; Cárdenas-Rodríguez, N.; Orozco-Ibarra, M.; Pérez-Rojas, J.M. Medicinal properties of mangosteen (Garcinia mangostana). Food Chem. Toxicol., 2008, 46(10), 3227-3239.
[http://dx.doi.org/10.1016/j.fct.2008.07.024] [PMID: 18725264]
[3]
Jung, H-A.; Su, B-N.; Keller, W.J.; Mehta, R.G.; Kinghorn, A.D. Antioxidant xanthones from the pericarp of Garcinia mangostana (Mangosteen). J. Agric. Food Chem., 2006, 54(6), 2077-2082.
[http://dx.doi.org/10.1021/jf052649z] [PMID: 16536578]
[4]
Jantan, I.; Saputri, F.C. Benzophenones and xanthones from Garcinia cantleyana var. cantleyana and their inhibitory activities on human low-density lipoprotein oxidation and platelet aggregation. Phytochemistry, 2012, 80, 58-63.
[http://dx.doi.org/10.1016/j.phytochem.2012.05.003] [PMID: 22640928]
[5]
Hung, S-H.; Shen, K-H.; Wu, C-H.; Liu, C-L.; Shih, Y-W. α-mangostin suppresses PC-3 human prostate carcinoma cell metastasis by inhibiting matrix metalloproteinase-2/9 and urokinase-plasminogen expression through the JNK signaling pathway. J. Agric. Food Chem., 2009, 57(4), 1291-1298.
[http://dx.doi.org/10.1021/jf8032683] [PMID: 19178296]
[6]
Lee, Y-B.; Ko, K-C.; Shi, M-D.; Liao, Y-C.; Chiang, T-A.; Wu, P-F.; Shih, Y-X.; Shih, Y-W. alpha-Mangostin, a novel dietary xanthone, suppresses TPA-mediated MMP-2 and MMP-9 expressions through the ERK signaling pathway in MCF-7 human breast adenocarcinoma cells. J. Food Sci., 2010, 75(1), H13-H23.
[http://dx.doi.org/10.1111/j.1750-3841.2009.01407.x] [PMID: 20492173]
[7]
Shibata, M-A.; Iinuma, M.; Morimoto, J.; Kurose, H.; Akamatsu, K.; Okuno, Y.; Akao, Y.; Otsuki, Y. α-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn) reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation. BMC Med., 2011, 9(1), 69-86.
[http://dx.doi.org/10.1186/1741-7015-9-69] [PMID: 21639868]
[8]
Wang, L.; Kuang, L.; Pan, X.; Liu, J.; Wang, Q.; Du, B.; Li, D.; Luo, J.; Liu, M.; Hou, A.; Qian, M. Isoalvaxanthone inhibits colon cancer cell proliferation, migration and invasion through inactivating Rac1 and AP-1. Int. J. Cancer, 2010, 127(5), 1220-1229.
[http://dx.doi.org/10.1002/ijc.25119] [PMID: 20017136]
[9]
Na, Y. Recent cancer drug development with xanthone structures. J. Pharm. Pharmacol., 2009, 61(6), 707-712.
[http://dx.doi.org/10.1211/jpp.61.06.0002] [PMID: 19505360]
[10]
Su, Q-G.; Liu, Y.; Cai, Y-C.; Sun, Y-L.; Wang, B.; Xian, L-J. Anti-tumour effects of xanthone derivatives and the possible mechanisms of action. Invest. New Drugs, 2011, 29(6), 1230-1240.
[http://dx.doi.org/10.1007/s10637-010-9468-5] [PMID: 20577894]
[11]
Ullmann, F.; Kipper, H. Over methoxy chlorobenzoic acid. Ber. Dtsch. Chem. Ges., 1905, 38, 2120-2126.
[http://dx.doi.org/10.1002/cber.190503802155]
[12]
Ullmann, F.; Zlokasoff, M. Over aryl salicylic acids and their transfer into xanthones. Ber. Dtsch. Chem. Ges., 1905, 38, 2111-2119.
[http://dx.doi.org/10.1002/cber.190503802154]
[13]
Pickert, M.; Frahm, A.W. Substituted xanthones as antimycobacterial agents, part 1: Synthesis and assignment of 1 H/13 C NMR chemical shifts. Arch. Pharm. Pharm. Med. Chem., 1998, 331(5), 177-192.
[http://dx.doi.org/10.1002/(SICI)1521-4184(199805)331:5<177:AID-ARDP177>3.0.CO;2-K]
[14]
Eckstein, M.; Marona, H. Preparation and properties of some 2-mercaptomethylxanthones. Pol. J. Chem., 1980, 54, 1281-1285.
[15]
Eckstein, M.; Marona, H.; Mazur, J. Synthesis and some biological properties of substituted xanthone-2-carboxylic acids. Pol. J. Pharmacol. Pharm., 1983, 35(2), 159-167.
[PMID: 6604908]
[16]
Rewcastle, G.W.; Atwell, G.J.; Baguley, B.C.; Calveley, S.B.; Denny, W.A. Potential antitumor agents. 58. Synthesis and structure-activity relationships of substituted xanthenone-4-acetic acids active against the colon 38 tumor in vivo. J. Med. Chem., 1989, 32(4), 793-799.
[http://dx.doi.org/10.1021/jm00124a012] [PMID: 2704025]
[17]
Marona, H.; Szkaradek, N.; Kubacka, M.; Bednarski, M.; Filipek, B.; Cegla, M.; Szneler, E. Synthesis and evaluation of some xanthone derivatives for anti-arrhythmic, hypotensive properties and their affinity for adrenergic receptors. Arch. Pharm. (Weinheim), 2008, 341(2), 90-98.
[http://dx.doi.org/10.1002/ardp.200700156] [PMID: 18240129]
[18]
Marona, H. Synthesis and anticonvulsant effects of some aminoalkanolic derivatives of xanthone. Pharmazie, 1998, 53(10), 672-676.
[PMID: 9812332]
[19]
Szkaradek, N.; Stachura, K.; Waszkielewicz, A.M.; Cegła, M.; Szneler, E.; Marona, H. Synthesis and antimycobacterial assay of some xanthone derivatives. Acta Pol. Pharm., 2008, 65(1), 21-28.
[PMID: 18536169]
[20]
Marona, H.; Szkaradek, N.; Karczewska, E.; Trojanowska, D.; Budak, A.; Bober, P.; Przepiórka, W.; Cegla, M.; Szneler, E. Antifungal and antibacterial activity of the newly synthesized 2-xanthone derivatives. Arch. Pharm. (Weinheim), 2009, 342(1), 9-18.
[http://dx.doi.org/10.1002/ardp.200800089] [PMID: 19051197]
[21]
Librowski, T.; Czarnecki, R.; Jastrzebska-Wiesek, M.; Opoka, W.; Marona, H. The influence of some aminoalkanolic xanthone derivatives on central nervous and cardiovascular systems in rodents. Boll. Chim. Farm., 2004, 143(7), 267-274.
[PMID: 15881806]
[22]
Waszkielewicz, A.M.; Słoczyńska, K.; Pękala, E.; Żmudzki, P.; Siwek, A.; Gryboś, A.; Marona, H. Design, synthesis, and anticonvulsant activity of some derivatives of xanthone with aminoalkanol moieties. Chem. Biol. Drug Des., 2017, 89(3), 339-352.
[http://dx.doi.org/10.1111/cbdd.12842] [PMID: 27543433]
[23]
Marona, H.; Librowski, T.; Cegła, M.; Erdoğan, C.; Şahin, N.Ö. Antiarrhythmic and antihypertensive activity of some xanthone derivatives. Acta Pol. Pharm., 2008, 65(3), 383-390.
[PMID: 18646559]
[24]
Szkaradek, N.; Sypniewski, D.; Waszkielewicz, A.M.; Gunia-Krzyżak, A.; Galilejczyk, A.; Gałka, S.; Marona, H.; Bednarek, I. Synthesis and in vitro evaluation of anticancer potential of new aminoalkanol derivatives of xanthone. Anticancer. Agents Med. Chem., 2016, 16(12), 1587-1604.
[http://dx.doi.org/10.2174/1871520616666160404110323] [PMID: 27039927]
[25]
Sypniewski, D.; Bednarek, I.; Gałka, S.; Loch, T.; Błaszczyk, D.; Sołtysik, D. Cytotoxicity of etoposide in cancer cell lines in vitro after BCL-2 and C-RAF gene silencing with antisense oligonucleotides. Acta Pol. Pharm., 2013, 70(1), 87-97.
[PMID: 23610963]
[26]
Orchel, J.; Slowinski, J.; Mazurek, U.; Wilczok, T. H3 mRNA level as a new proliferative marker in astrocytomas. Biochim. Biophys. Acta, 2004, 1689(1), 42-46.
[http://dx.doi.org/10.1016/j.bbadis.2004.01.006] [PMID: 15158912]
[27]
Yeh, M.W.; Rougier, J.P.; Park, J.W.; Duh, Q.Y.; Wong, M.; Werb, Z.; Clark, O.H. Differentiated thyroid cancer cell invasion is regulated through epidermal growth factor receptor-dependent activation of matrix metalloproteinase (MMP)-2/gelatinase A. Endocr. Relat. Cancer, 2006, 13(4), 1173-1183.
[http://dx.doi.org/10.1677/erc.1.01226] [PMID: 17158762]
[28]
Quintero, M.; Brennan, P.A.; Thomas, G.J.; Moncada, S. Nitric oxide is a factor in the stabilization of hypoxia-inducible factor-1alpha in cancer: role of free radical formation. Cancer Res., 2006, 66(2), 770-774.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-0333] [PMID: 16424008]
[29]
Shen, R.; Wang, P.; Tang, N. Cytotoxic activity and DNA-binding properties of xanthone derivatives. J. Fluoresc., 2010, 20(6), 1287-1297.
[http://dx.doi.org/10.1007/s10895-010-0680-7] [PMID: 20532595]
[30]
Pedro, M.; Cerqueira, F.; Sousa, M.E.; Nascimento, M.S.J.; Pinto, M. Xanthones as inhibitors of growth of human cancer cell lines and their effects on the proliferation of human lymphocytes in vitro. Bioorg. Med. Chem., 2002, 10(12), 3725-3730.
[http://dx.doi.org/10.1016/S0968-0896(02)00379-6] [PMID: 12413829]
[31]
Castanheiro, R.A.P.; Silva, A.M.S.; Campos, N.A.N.; Nascimento, M.S.J.; Pinto, M.M.M. Antitumor activity of some prenylated xanthones. Pharmaceuticals (Basel), 2009, 2(2), 33-43.
[http://dx.doi.org/10.3390/ph2020033] [PMID: 27713221]
[32]
Batova, A.; Lam, T.; Wascholowski, V.; Yu, A.L.; Giannis, A.; Theodorakis, E.A. Synthesis and evaluation of caged Garcinia xanthones. Org. Biomol. Chem., 2007, 5(3), 494-500.
[http://dx.doi.org/10.1039/B612903J] [PMID: 17252132]
[33]
Hahnvajanawong, C.; Boonyanugomol, W.; Nasomyon, T.; Loilome, W.; Namwat, N.; Anantachoke, N.; Tassaneeyakul, W.; Sripa, B.; Namwat, W.; Reutrakul, V. Apoptotic activity of caged xanthones from Garcinia hanburyi in cholangiocarcinoma cell lines. World J. Gastroenterol., 2010, 16(18), 2235-2243.
[http://dx.doi.org/10.3748/wjg.v16.i18.2235] [PMID: 20458760]
[34]
Hashim, N.M.; Rahmani, M.; Ee, G.C.L.; Sukari, M.A.; Yahayu, M.; Oktima, W.; Ali, A.M.; Go, R. Antiproliferative activity of xanthones isolated from Artocarpus obtusus. J. Biomed. Biotechnol., 2012, 2012130627
[http://dx.doi.org/10.1155/2012/130627] [PMID: 21960741]
[35]
Sato, A.; Fujiwara, H.; Oku, H.; Ishiguro, K.; Ohizumi, Y. Alpha-mangostin induces Ca2+-ATPase-dependent apoptosis via mitochondrial pathway in PC12 cells. J. Pharmacol. Sci., 2004, 95(1), 33-40.
[http://dx.doi.org/10.1254/jphs.95.33] [PMID: 15153648]
[36]
Nakagawa, Y.; Iinuma, M.; Naoe, T.; Nozawa, Y.; Akao, Y. Characterized mechanism of alpha-mangostin-induced cell death: caspase-independent apoptosis with release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal cancer DLD-1 cells. Bioorg. Med. Chem., 2007, 15(16), 5620-5628.
[http://dx.doi.org/10.1016/j.bmc.2007.04.071] [PMID: 17553685]
[37]
Matsumoto, K.; Akao, Y.; Ohguchi, K.; Ito, T.; Tanaka, T.; Iinuma, M.; Nozawa, Y. Xanthones induce cell-cycle arrest and apoptosis in human colon cancer DLD-1 cells. Bioorg. Med. Chem., 2005, 13(21), 6064-6069.
[http://dx.doi.org/10.1016/j.bmc.2005.06.065] [PMID: 16112579]
[38]
Akao, Y.; Nakagawa, Y.; Iinuma, M.; Nozawa, Y. Anti-cancer effects of xanthones from pericarps of mangosteen. Int. J. Mol. Sci., 2008, 9(3), 355-370.
[http://dx.doi.org/10.3390/ijms9030355] [PMID: 19325754]
[39]
Watanapokasin, R.; Jarinthanan, F.; Jerusalmi, A.; Suksamrarn, S.; Nakamura, Y.; Sukseree, S.; Uthaisang-Tanethpongtamb, W.; Ratananukul, P.; Sano, T. Potential of xanthones from tropical fruit mangosteen as anti-cancer agents: caspase-dependent apoptosis induction in vitro and in mice. Appl. Biochem. Biotechnol., 2010, 162(4), 1080-1094.
[http://dx.doi.org/10.1007/s12010-009-8903-6] [PMID: 20101528]
[40]
Watanapokasin, R.; Jarinthanan, F.; Nakamura, Y.; Sawasjirakij, N.; Jaratrungtawee, A.; Suksamrarn, S. Effects of α-mangostin on apoptosis induction of human colon cancer. World J. Gastroenterol., 2011, 17(16), 2086-2095.
[http://dx.doi.org/10.3748/wjg.v17.i16.2086] [PMID: 21547127]
[41]
Matsumoto, K.; Akao, Y.; Yi, H.; Ohguchi, K.; Ito, T.; Tanaka, T.; Kobayashi, E.; Iinuma, M.; Nozawa, Y. Preferential target is mitochondria in alpha-mangostin-induced apoptosis in human leukemia HL60 cells. Bioorg. Med. Chem., 2004, 12(22), 5799-5806.
[http://dx.doi.org/10.1016/j.bmc.2004.08.034] [PMID: 15498656]
[42]
Chantarasriwong, O.; Batova, A.; Chavasiri, W.; Theodorakis, E.A. Chemistry and biology of the caged Garcinia xanthones. Chemistry, 2010, 16(33), 9944-9962.
[http://dx.doi.org/10.1002/chem.201000741] [PMID: 20648491]
[43]
Zhang, Y.; Song, Z.; Hao, J.; Qiu, S.; Xu, Z. Two new prenylated xanthones and a new prenylated tetrahydroxanthone from the pericarp of Garcinia mangostana. Fitoterapia, 2010, 81(6), 595-599.
[http://dx.doi.org/10.1016/j.fitote.2010.02.002] [PMID: 20176087]
[44]
Ding, L.; Liu, B.; Qi, L-L.; Zhou, Q-Y.; Hou, Q.; Li, J.; Zhang, Q. Anti-proliferation, cell cycle arrest and apoptosis induced by a natural xanthone from Gentianopsis paludosa Ma, in human promyelocytic leukemia cell line HL-60 cells. Toxicol. In Vitro, 2009, 23(3), 408-417.
[http://dx.doi.org/10.1016/j.tiv.2009.01.010] [PMID: 19344684]
[45]
Xiao, Q.; Zeng, Y-B.; Mei, W-L.; Zhao, Y-X.; Deng, Y-Y.; Dai, H-F. Cytotoxic prenylated xanthones from Calophyllum inophyllum. J. Asian Nat. Prod. Res., 2008, 10(9-10), 993-997.
[http://dx.doi.org/10.1080/10519990802240387] [PMID: 19003621]
[46]
Lin, C-N.; Liou, S-J.; Lee, T-H.; Chuang, Y-C.; Won, S-J. Xanthone derivatives as potential anti-cancer drugs. J. Pharm. Pharmacol., 1996, 48(5), 539-544.
[http://dx.doi.org/10.1111/j.2042-7158.1996.tb05970.x] [PMID: 8799883]
[47]
Shadid, K.A.; Shaari, K.; Abas, F.; Israf, D.A.; Hamzah, A.S.; Syakroni, N.; Saha, K.; Lajis, N.H. Cytotoxic caged-polyprenylated xanthonoids and a xanthone from Garcinia cantleyana. Phytochemistry, 2007, 68(20), 2537-2544.
[http://dx.doi.org/10.1016/j.phytochem.2007.05.024] [PMID: 17602714]
[48]
Cheng, J-H.; Huang, A-M.; Hour, T-C.; Yang, S-C.; Pu, Y-S.; Lin, C-N. Antioxidant xanthone derivatives induce cell cycle arrest and apoptosis and enhance cell death induced by cisplatin in NTUB1 cells associated with ROS. Eur. J. Med. Chem., 2011, 46(4), 1222-1231.
[http://dx.doi.org/10.1016/j.ejmech.2011.01.043] [PMID: 21345544]
[49]
Bozzuto, G.; Ruggieri, P.; Molinari, A. Molecular aspects of tumor cell migration and invasion. Ann. Ist. Super. Sanita, 2010, 46(1), 66-80.
[http://dx.doi.org/10.1590/S0021-25712010000100009] [PMID: 20348621]
[50]
Shih, Y.W.; Chien, S.T.; Chen, P.S.; Lee, J.H.; Wu, S.H.; Yin, L.T. Alpha-mangostin suppresses phorbol 12-myristate 13-acetate-induced MMP-2/MMP-9 expressions via alphavbeta3 integrin/FAK/ERK and NF-kappaB signaling pathway in human lung adenocarcinoma A549 cells. Cell Biochem. Biophys., 2010, 58(1), 31-44.
[http://dx.doi.org/10.1007/s12013-010-9091-2] [PMID: 20652762]
[51]
Yoo, J.H.; Kang, K.; Jho, E.H.; Chin, Y.W.; Kim, J.; Nho, C.W. Alpha- and Gamma-Mangostin inhibit the proliferation of colon cancer cells via beta-catenin gene regulation in Wnt/CGMP signalling. Food Chem., 2011, 129(4), 1559-1566.
[http://dx.doi.org/10.1016/j.foodchem.2011.06.007] [PMID: 25213927]
[52]
Batova, A.; Altomare, D.; Chantarasriwong, O.; Ohlsen, K.L.; Creek, K.E.; Lin, Y-C.; Messersmith, A.; Yu, A.L.; Yu, J.; Theodorakis, E.A. The synthetic caged garcinia xanthone cluvenone induces cell stress and apoptosis and has immune modulatory activity. Mol. Cancer Ther., 2010, 9(11), 2869-2878.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0517] [PMID: 20881270]

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