A Review on Shikonin and its Derivatives as Potent Anticancer
Agents Targeted against Topoisomerases

Olagoke   Zacchaeus   Olatunde; Jianping      Yong; Canzhong      Lu; Yanlin      Ming
doi:10.2174/0929867330666230208094828
Abstract

The topoisomerases (TOPO) play indispensable roles in DNA metabolism, by regulating the topological state of DNA. Topoisomerase I and II are the well-established drug-targets for the development of anticancer agents and antibiotics. These drugs-targeting enzymes have been used to establish the relationship between drug-stimulated DNA cleavable complex formation and cytotoxicity. Some anticancer drugs (such as camptothecin, anthracyclines, mitoxantrone) are also widely used as Topo I and Topo II inhibitors, but the poor water solubility, myeloma suppression, dose-dependent cardiotoxicity, and multidrug resistance (MDR) limited their prolong use as therapeutics. Also, most of these agents displayed selective inhibition only against Topo I or II. In recent years, researchers focus on the design and synthesis of the dual Topo I and II inhibitors, or the discovery of the dual Topo I and II inhibitors from natural products. Shikonin (a natural compound with anthraquinone skeleton, isolated from the roots of Lithospermum erythrorhizon) has drawn much attention due to its wide spectrum of anticancer activities, especially due to its dual Topo inhibitive performance, and without the adverse side effects, and different kinds of shikonin derivatives have been synthesized as TOPO inhibitors for the development of anticancer agents. In this review, the progress of the shikonin and its derivatives together with their anticancer activities, anticancer mechanism, and their structure-activity relationship (SAR) was comprehensively summarized by searching the CNKI, PubMed, Web of Science, Scopus, and Google Scholar databases.
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[1]
Li, T.K.; Liu, L.F. Tumor cell death induced by topoisomerase-targeting drugs. Annu. Rev. Pharmacol. Toxicol.,  2001, 41(1), 53-77.
 [http://dx.doi.org/10.1146/annurev.pharmtox.41.1.53] [PMID: 11264450]

[2]
Pommier, Y. Topoisomerase I inhibitors: Camptothecins and beyond. Nat. Rev. Cancer,  2006, 6(10), 789-802.
 [http://dx.doi.org/10.1038/nrc1977] [PMID: 16990856]

[3]
McClendon, A.K.; Osheroff, N. DNA topoisomerase II, genotoxicity, and cancer. Mutat. Res.,  2007, 623(1-2), 83-97.
 [http://dx.doi.org/10.1016/j.mrfmmm.2007.06.009] [PMID: 17681352]

[4]
Nitiss, J.L. Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer,  2009, 9(5), 338-350.
 [http://dx.doi.org/10.1038/nrc2607] [PMID: 19377506]

[5]
Nitiss, J.L. DNA topoisomerase II and its growing repertoire of biological functions. Nat. Rev. Cancer,  2009, 9(5), 327-337.
 [http://dx.doi.org/10.1038/nrc2608] [PMID: 19377505]

[6]
Schoeffler, A.J.; Berger, J.M. DNA topoisomerases: Harnessing and constraining energy to govern chromosome topology. Q. Rev. Biophys.,  2008, 41(1), 41-101.
 [http://dx.doi.org/10.1017/S003358350800468X] [PMID: 18755053]

[7]
Drake, F.H.; Zimmerman, J.P.; McCabe, F.L.; Bartus, H.F.; Per, S.R.; Sullivan, D.M.; Ross, W.E.; Mattern, M.R.; Johnson, R.K.; Crooke, S.T. Purification of topoisomerase II from amsacrine-resistant P388 leukemia cells. Evidence for two forms of the enzyme. J. Biol. Chem.,  1987, 262(34), 16739-16747.
 [http://dx.doi.org/10.1016/S0021-9258(18)49317-9] [PMID: 2824504]

[8]
Drake, F.H.; Hofmann, G.A.; Bartus, H.F.; Mattern, M.R.; Crooke, S.T.; Mirabelli, C.K. Biochemical and pharmacological properties of p170 and p180 forms of topoisomerase II. Biochemistry,  1989, 28(20), 8154-8160.
 [http://dx.doi.org/10.1021/bi00446a029] [PMID: 2557897]

[9]
Vicker, N.; Burgess, L.; Chuckowree, I.S.; Dodd, R.; Folkes, A.J.; Hardick, D.J.; Hancox, T.C.; Miller, W.; Milton, J.; Sohal, S.; Wang, S.; Wren, S.P.; Charlton, P.A.; Dangerfield, W.; Liddle, C.; Mistry, P.; Stewart, A.J.; Denny, W.A. Novel angular benzophenazines: Dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents. J. Med. Chem.,  2002, 45(3), 721-739.
 [http://dx.doi.org/10.1021/jm010329a] [PMID: 11806724]

[10]
Arepalli, S.K.; Lee, C.; Sim, S.; Lee, K.; Jo, H.; Jun, K.Y.; Kwon, Y.; Kang, J.S.; Jung, J.K.; Lee, H. Development of 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and their salts as potent cytotoxic agents and topoisomerase I/IIα inhibitors. Bioorg. Med. Chem.,  2018, 26(18), 5181-5193.
 [http://dx.doi.org/10.1016/j.bmc.2018.09.019] [PMID: 30253887]

[11]
Khadka, D.B.; Cho, W.J. Topoisomerase inhibitors as anticancer agents: A patent update. Expert Opin. Ther. Pat.,  2013, 23(8), 1033-1056.
 [http://dx.doi.org/10.1517/13543776.2013.790958] [PMID: 23611704]

[12]
Tan, K.B.; Dorman, T.E.; Falls, K.M.; Chung, T.D.; Mirabelli, C.K.; Crooke, S.T.; Mao, J. Topoisomerase II α and topoisomerase II β genes: Characterization and mapping to human chromosomes 17 and 3, respectively. Cancer Res.,  1992, 52(1), 231-234.
 [PMID: 1309226]

[13]
Vos, S.M.; Tretter, E.M.; Schmidt, B.H.; Berger, J.M. All tangled up: How cells direct, manage and exploit topoisomerase function. Nat. Rev. Mol. Cell Biol.,  2011, 12(12), 827-841.
 [http://dx.doi.org/10.1038/nrm3228] [PMID: 22108601]

[14]
Woessner, R.D.; Mattern, M.R.; Mirabelli, C.K.; Johnson, R.K.; Drake, F.H. Proliferation- and cell cycle-dependent differences in expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Differ.,  1991, 2(4), 209-214.
 [PMID: 1651102]

[15]
Velez-Cruz, R.; Osheroff, N. DNA topoisomerases: Type II. In: Encyclopedia of Biological Chemistry; Elsevier: San Diego, United States, 2004; pp. 806-811.
 [http://dx.doi.org/10.1016/B0-12-443710-9/00680-3]

[16]
Lisby, M.; Olesen, J.R.; Skouboe, C.; Krogh, B.O.; Straub, T.; Boege, F.; Velmurugan, S.; Martensen, P.M.; Andersen, A.H.; Jayaram, M.; Westergaard, O.; Knudsen, B.R. Residues within the N-terminal domain of human topoisomerase I play a direct role in relaxation. J. Biol. Chem.,  2001, 276(23), 20220-20227.
 [http://dx.doi.org/10.1074/jbc.M010991200] [PMID: 11283003]

[17]
Kim, K.H.; Kanbe, T.; Akashi, T.; Mizuguchi, I.; Kikuchi, A. Identification of a single nuclear localization signal in the C-terminal domain of an Aspergillus DNA topoisomerase II. Mol. Genet. Genomics,  2002, 268(3), 287-297.
 [http://dx.doi.org/10.1007/s00438-002-0758-2] [PMID: 12436251]

[18]
Berger, J.M.; Gamblin, S.J.; Harrison, S.C.; Wang, J.C. Structure and mechanism of DNA topoisomerase II. Nature,  1996, 379(6562), 225-232.
 [http://dx.doi.org/10.1038/379225a0] [PMID: 8538787]

[19]
Dutta, R.; Inouye, M. GHKL, an emergent ATPase/kinase superfamily. Trends Biochem. Sci.,  2000, 25(1), 24-28.
 [http://dx.doi.org/10.1016/S0968-0004(99)01503-0] [PMID: 10637609]

[20]
Lindsey, R.H., Jr; Pendleton, M.; Ashley, R.E.; Mercer, S.L.; Deweese, J.E.; Osheroff, N. Catalytic core of human topoisomerase IIα: Insights into enzyme-DNA interactions and drug mechanism. Biochemistry,  2014, 53(41), 6595-6602.
 [http://dx.doi.org/10.1021/bi5010816] [PMID: 25280269]

[21]
Lee, S.; Jung, S.R.; Heo, K.; Byl, J.A.W.; Deweese, J.E.; Osheroff, N.; Hohng, S. DNA cleavage and opening reactions of human topoisomerase IIα are regulated via Mg2+ -mediated dynamic bending of gate-DNA. Proc. Natl. Acad. Sci. USA,  2012, 109(8), 2925-2930.
 [http://dx.doi.org/10.1073/pnas.1115704109] [PMID: 22323612]

[22]
Chen, S.F.; Huang, N.L.; Lin, J.H.; Wu, C.C.; Wang, Y.R.; Yu, Y.J.; Gilson, M.K.; Chan, N.L. Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate. Nat. Commun.,  2018, 9(1), 3085.
 [http://dx.doi.org/10.1038/s41467-018-05406-y] [PMID: 30082834]

[23]
Dong, K.C.; Berger, J.M. Structural basis for gate-DNA recognition and bending by type IIA topoisomerases. Nature,  2007, 450(7173), 1201-1205.
 [http://dx.doi.org/10.1038/nature06396] [PMID: 18097402]

[24]
Leroy, D.; Alghist, G.C.; Roberts, E.; Filhol-Cochet, O.; Gasser, S.M. Mutations in the C-terminal domain of topoisomerase II affect meiotic function and interaction with the casein kinase 2 beta subunit. Mol. Cell. Biochem.,  1999, 191(1/2), 85-95.
 [http://dx.doi.org/10.1023/A:1006858210835] [PMID: 10094396]

[25]
Cowell, I.G.; Willmore, E.; Chalton, D.; Marsh, K.L.; Jazrawi, E.; Fisher, L.M.; Austin, C.A. Nuclear distribution of human DNA topoisomerase IIbeta: A nuclear targeting signal resides in the 116-residue C-terminal tail. Exp. Cell Res.,  1998, 243(2), 232-240.
 [http://dx.doi.org/10.1006/excr.1998.4150] [PMID: 9743583]

[26]
Champoux, J.J. DNA topoisomerases: Structure, function, and mechanism. Annu. Rev. Biochem.,  2001, 70(1), 369-413.
 [http://dx.doi.org/10.1146/annurev.biochem.70.1.369] [PMID: 11395412]

[27]
Wang, J.C. Cellular roles of DNA topoisomerases: A molecular perspective. Nat. Rev. Mol. Cell Biol.,  2002, 3(6), 430-440.
 [http://dx.doi.org/10.1038/nrm831] [PMID: 12042765]

[28]
Hsiang, Y.H.; Hertzberg, R.; Hecht, S.; Liu, L.F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem.,  1985, 260(27), 14873-14878.
 [http://dx.doi.org/10.1016/S0021-9258(17)38654-4] [PMID: 2997227]

[29]
Nitiss, J.; Wang, J.C. DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc. Natl. Acad. Sci. USA,  1988, 85(20), 7501-7505.
 [http://dx.doi.org/10.1073/pnas.85.20.7501] [PMID: 2845409]

[30]
Lee, M.P.; Brown, S.D.; Chen, A.; Hsieh, T.S. DNA topoisomerase I is essential in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA,  1993, 90(14), 6656-6660.
 [http://dx.doi.org/10.1073/pnas.90.14.6656] [PMID: 8393572]

[31]
Kretzschmar, M.; Meisterernst, M.; Roeder, R.G. Identification of human DNA topoisomerase I as a cofactor for activator-dependent transcription by RNA polymerase II. Proc. Natl. Acad. Sci. USA,  1993, 90(24), 11508-11512.
 [http://dx.doi.org/10.1073/pnas.90.24.11508] [PMID: 8265582]

[32]
Mialon, A.; Sankinen, M.; Söderström, H.; Junttila, T.T.; Holmström, T.; Koivusalo, R.; Papageorgiou, A.C.; Johnson, R.S.; Hietanen, S.; Elenius, K.; Westermarck, J. DNA topoisomerase I is a cofactor for c-Jun in the regulation of epidermal growth factor receptor expression and cancer cell proliferation. Mol. Cell. Biol.,  2005, 25(12), 5040-5051.
 [http://dx.doi.org/10.1128/MCB.25.12.5040-5051.2005] [PMID: 15923621]

[33]
Soret, J.; Gabut, M.; Dupon, C.; Kohlhagen, G.; Stévenin, J.; Pommier, Y.; Tazi, J. Altered serine/arginine-rich protein phosphorylation and exonic enhancer-dependent splicing in Mammalian cells lacking topoisomerase I. Cancer Res.,  2003, 63(23), 8203-8211.
 [PMID: 14678976]

[34]
Fortune, J.M.; Osheroff, N. Topoisomerase II as a target for anticancer drugs: When enzymes stop being nice. Prog. Nucleic Acid Res. Mol. Biol.,  2000, 64, 221-253.
 [http://dx.doi.org/10.1016/S0079-6603(00)64006-0] [PMID: 10697411]

[35]
Radaeva, M.; Dong, X.; Cherkasov, A. The use of methods of computer-aided drug discovery in the development of topoisomerase II inhibitors: Applications and future directions. J. Chem. Inf. Model.,  2020, 60(8), 3703-3721.
 [http://dx.doi.org/10.1021/acs.jcim.0c00325] [PMID: 32687346]

[36]
Ketron, A.C.; Osheroff, N. Phytochemicals as anticancer and chemopreventive topoisomerase II poisons. Phytochem. Rev.,  2014, 13(1), 19-35.
 [http://dx.doi.org/10.1007/s11101-013-9291-7] [PMID: 24678287]

[37]
Deweese, J.E.; Osheroff, N. The DNA cleavage reaction of topoisomerase II: Wolf in sheep’s clothing. Nucleic Acids Res.,  2009, 37(3), 738-748.
 [http://dx.doi.org/10.1093/nar/gkn937] [PMID: 19042970]

[38]
Yang, X.; Li, W.; Prescott, E.D.; Burden, S.J.; Wang, J.C. DNA topoisomerase IIbeta and neural development. Science,  2000, 287(5450), 131-134.
 [http://dx.doi.org/10.1126/science.287.5450.131] [PMID: 10615047]

[39]
Linka, R.M.; Porter, A.C.G.; Volkov, A.; Mielke, C.; Boege, F.; Christensen, M.O. C-Terminal regions of topoisomerase II and II determine isoform-specific functioning of the enzymes in vivo. Nucleic Acids Res.,  2007, 35(11), 3810-3822.
 [http://dx.doi.org/10.1093/nar/gkm102] [PMID: 17526531]

[40]
Haince, J.F.; Rouleau, M.; Poirier, G.G. Transcription. Gene expression needs a break to unwind before carrying on. Science,  2006, 312(5781), 1752-1753.
 [http://dx.doi.org/10.1126/science.1129808] [PMID: 16794066]

[41]
Ju, B.G.; Lunyak, V.V.; Perissi, V.; Garcia-Bassets, I.; Rose, D.W.; Glass, C.K.; Rosenfeld, M.G. A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science,  2006, 312(5781), 1798-1802.
 [http://dx.doi.org/10.1126/science.1127196] [PMID: 16794079]

[42]
Bailly, C. Contemporary challenges in the design of topoisomerase II inhibitors for cancer chemotherapy. Chem. Rev.,  2012, 112(7), 3611-3640.
 [http://dx.doi.org/10.1021/cr200325f] [PMID: 22397403]

[43]
Pommier, Y. Drugging topoisomerases: Lessons and challenges. ACS Chem. Biol.,  2013, 8(1), 82-95.
 [http://dx.doi.org/10.1021/cb300648v] [PMID: 23259582]

[44]
Pommier, Y.; Leo, E.; Zhang, H.; Marchand, C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol.,  2010, 17(5), 421-433.
 [http://dx.doi.org/10.1016/j.chembiol.2010.04.012] [PMID: 20534341]

[45]
Chen, W.; Qiu, J.; Shen, Y.M. Topoisomerase IIα, rather than IIβ, is a promising target in development of anti- cancer drugs. Drug Discov. Ther.,  2012, 6(5), 230-237.
 [http://dx.doi.org/10.5582/ddt.2012.v6.5.230] [PMID: 23229142]

[46]
Fortune, J.M.; Osheroff, N. Merbarone inhibits the catalytic activity of human topoisomerase IIalpha by blocking DNA cleavage. J. Biol. Chem.,  1998, 273(28), 17643-17650.
 [http://dx.doi.org/10.1074/jbc.273.28.17643] [PMID: 9651360]

[47]
Ohno, R.; Okada, K.; Masaoka, T.; Kuramoto, A.; Arima, T.; Yoshida, Y.; Ariyoshi, H.; Ichimaru, M.; Sakai, Y.; Oguro, M. An early phase II study of CPT-11: A new derivative of camptothecin, for the treatment of leukemia and lymphoma. J. Clin. Oncol.,  1990, 8(11), 1907-1912.
 [http://dx.doi.org/10.1200/JCO.1990.8.11.1907] [PMID: 2230878]

[48]
Houghton, P.J.; Cheshire, P.J.; Myers, L.; Stewart, C.F.; Synold, T.W.; Houghton, J.A. Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother. Pharmacol.,  1992, 31(3), 229-239.
 [http://dx.doi.org/10.1007/BF00685553] [PMID: 1464161]

[49]
Johnson, R.K. SK&F 10864, Water soluble analogs of camptothecin with broad-spectrum activity in preclinical tumor models. Proc. Am. Assoc. Cancer Res.,  1989, 30, 623.

[50]
O’Connor, P.M.; Kerrigan, D.; Bertrand, R.; Kohn, K.W.; Pommier, Y. 10,11-Methylenedioxycamptothecin, a topoisomerase I inhibitor of increased potency: DNA damage and correlation to cytotoxicity in human colon carcinoma (HT-29) cells. Cancer Commun.,  1990, 2(12), 395-400.
 [http://dx.doi.org/10.3727/095535490820873912] [PMID: 2176090]

[51]
Young, R.C.; Ozols, R.F.; Myers, C.E. The anthracycline antineoplastic drugs. N. Engl. J. Med.,  1981, 305(3), 139-153.
 [http://dx.doi.org/10.1056/NEJM198107163050305] [PMID: 7017406]

[52]
D’Arpa, P.; Liu, L.F. Topoisomerase-targeting antitumor drugs. Biochim. Biophys. Acta,  1989, 989(2), 163-177.
 [PMID: 2557085]

[53]
David Foglesong, P.; Reckord, C.; Swink, S. Doxorubicin inhibits human DNA topoisomerase I. Cancer Chemother. Pharmacol.,  1992, 30(2), 123-125.
 [http://dx.doi.org/10.1007/BF00686403] [PMID: 1318169]

[54]
Buzdar, A.U.; Marcus, C.; Blumenschein, G.R.; Smith, T.L. Early and delayed clinical cardiotoxicity of doxorubicin. Cancer,  1985, 55(12), 2761-2765.
 [http://dx.doi.org/10.1002/1097-0142(19850615)55:12<2761::AID-CNCR2820551206>3.0.CO;2-P] [PMID: 3922612]

[55]
Lee, J. H.; Ahn, B. Z. cytotoxic activity against L1210 cells of some raw drugs from the oriental medicine and folklore. Korean J. Pharmacogn.,  1986, 17(4), 286-291.

[56]
Kim, H.; Ahn, B.Z. Antitumor effects of acetylshikonin and some synthesized naphtharazin on L1210 and S-180 systems. Yakhak Hoeji,  1990, 34(4), 262-266.

[57]
Murdock, K.C.; Child, R.G.; Fabio, P.F.; Angier, R.D.; Wallace, R.E.; Durr, F.E.; Citarella, R.V. Antitumor agents. 1. 1,4-Bis[(aminoalkyl)amino]-9,10-anthracenediones. J. Med. Chem.,  1979, 22(9), 1024-1030.
 [http://dx.doi.org/10.1021/jm00195a002] [PMID: 490545]

[58]
Bodley, A.; Liu, L.F.; Israel, M.; Seshadri, R.; Koseki, Y.; Giuliani, F.C.; Kirschenbaum, S.; Silber, R.; Potmesil, M. DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA. Cancer Res.,  1989, 49(21), 5969-5978.
 [PMID: 2551497]

[59]
Ahn, B.Z.; Baik, K.U.; Kweon, G.R.; Lim, K.; Hwang, B.D. Acylshikonin analogues: Synthesis and inhibition of DNA topoisomerase-I. J. Med. Chem.,  1995, 38(6), 1044-1047.
 [http://dx.doi.org/10.1021/jm00006a025] [PMID: 7699697]

[60]
Evison, B.J.; Sleebs, B.E.; Watson, K.G.; Phillips, D.R.; Cutts, S.M. Mitoxantrone, more than just another topoisomerase II poison. Med. Res. Rev.,  2016, 36(2), 248-299.
 [http://dx.doi.org/10.1002/med.21364] [PMID: 26286294]

[61]
De Isabella, P.; Capranico, G.; Palumbo, M.; Sissi, C.; Krapcho, A.P.; Zunino, F. Sequence selectivity of topoisomerase II DNA cleavage stimulated by mitoxantrone derivatives: Relationships to drug DNA binding and cellular effects. Mol. Pharmacol.,  1993, 43(5), 715-721.
 [PMID: 8388987]

[62]
Capranico, G.; Binaschi, M.; Borgnetto, M.E.; Zunino, F.; Palumbo, M. A protein-mediated mechanism for the DNA sequence-specific action of topoisomerase II poisons. Trends Pharmacol. Sci.,  1997, 18(9), 323-329.
 [http://dx.doi.org/10.1016/S0165-6147(97)01095-X] [PMID: 9345851]

[63]
Capranico, G.; De Isabella, P.; Tinelli, S.; Bigioni, M.; Zunino, F. Similar sequence specificity of mitoxantrone and VM-26 stimulation of in vitro DNA cleavage by mammalian DNA topoisomerase II. Biochemistry,  1993, 32(12), 3038-3046.
 [http://dx.doi.org/10.1021/bi00063a015] [PMID: 8384486]

[64]
Wu, C.C.; Li, Y.C.; Wang, Y.R.; Li, T.K.; Chan, N.L. On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs. Nucleic Acids Res.,  2013, 41(22), 10630-10640.
 [http://dx.doi.org/10.1093/nar/gkt828] [PMID: 24038465]

[65]
Crespi, M.D.; Ivanier, S.E.; Genovese, J.; Baldi, A. Mitoxantrone affects topoisomerase activities in human breast cancer cells. Biochem. Biophys. Res. Commun.,  1986, 136(2), 521-528.
 [http://dx.doi.org/10.1016/0006-291X(86)90471-7] [PMID: 3010982]

[66]
Bhalla, K.; Ibrado, A.M.; Tourkina, E.; Tang, C.; Grant, S.; Bullock, G.; Huang, Y.; Ponnathpur, V.; Mahoney, M.E. High-dose mitoxantrone induces programmed cell death or apoptosis in human myeloid leukemia cells. Blood,  1993, 82(10), 3133-3140.
 [http://dx.doi.org/10.1182/blood.V82.10.3133.3133] [PMID: 8219202]

[67]
Bellosillo, B.; Colomer, D.; Pons, G.; Gil, J. Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells. Br. J. Haematol.,  1998, 100(1), 142-146.
 [http://dx.doi.org/10.1046/j.1365-2141.1998.00520.x] [PMID: 9450803]

[68]
Zhang, S.; Liu, X.; Bawa-Khalfe, T.; Lu, L.S.; Lyu, Y.L.; Liu, L.F.; Yeh, E.T.H. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med.,  2012, 18(11), 1639-1642.
 [http://dx.doi.org/10.1038/nm.2919] [PMID: 23104132]

[69]
Achmatowicz, O.; Szechner, B. Synthesis of enantiomerically pure anthracyclinones. Top. Curr. Chem.,  2007, 282, 143-186.
 [http://dx.doi.org/10.1007/128_2007_146]

[70]
Gottesman, M.M. How cancer cells evade chemotherapy: Sixteenth Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res.,  1993, 53(4), 747-754.
 [PMID: 8094031]

[71]
Kaye, S.B. The multidrug resistance phenotype. Br. J. Cancer,  1988, 58(6), 691-694.
 [http://dx.doi.org/10.1038/bjc.1988.291] [PMID: 3066393]

[72]
Aligiannis, N.; Pouli, N.; Marakos, P.; Skaltsounis, A.L.; Florent, J.C.; Perchellet, E.M.; Sperfslage, B.J.; McILVAIN, C.J.; Perchellet, J.P. Preparation and cytotoxic activity of some new rhodomycin derivatives bearing modifications in the sugar moiety. J. Antibiot. (Tokyo),  2002, 55(2), 181-190.
 [http://dx.doi.org/10.7164/antibiotics.55.181] [PMID: 12003000]

[73]
Sut, S.; Pavela, R.; Kolarčik, V.; Cappellacci, L.; Petrelli, R.; Maggi, F.; Dall’Acqua, S.; Benelli, G. Identification of onosma visianii roots extract and purified shikonin derivatives as potential acaricidal agents against tetranychus urticae. Molecules,  2017, 22(6), 1002.
 [http://dx.doi.org/10.3390/molecules22061002] [PMID: 28621748]

[74]
Majima, R.; Kuroda, C. On the colouring matter of lithospermum erythrorhizon. Acta Phytochim. (Tokyo),  1922, 1, 43-65.

[75]
Brockmann, H. Die Konstitution des alkannins, shikonins and alkannans. Justus Liebigs Ann. Chem.,  1936, 521(1), 1-47.
 [http://dx.doi.org/10.1002/jlac.19365210102]

[76]
Papageorgiou, V.P.; Assimopoulou, A.N.; Couladouros, E.A.; Hepworth, D.; Nicolaou, K.C. The chemistry and biology of alkannin, shikonin, and related naphthazarin natural products. Angew. Chem. Int. Ed.,  1999, 38(3), 270-301.
 [http://dx.doi.org/10.1002/(SICI)1521-3773(19990201)38:3<270::AID-ANIE270>3.0.CO;2-0] [PMID: 29711637]

[77]
Yang, F.; Chen, Y.; Duan, W.; Zhang, C.; Zhu, H.; Ding, J. SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor. Int. J. Cancer,  2006, 119(5), 1184-1193.
 [http://dx.doi.org/10.1002/ijc.21943] [PMID: 16570288]

[78]
Yoshida, L.S.; Kawada, T.; Irie, K.; Yuda, Y.; Himi, T.; Ikemoto, F.; Takano-Ohmuro, H. Shikonin directly inhibits nitric oxide synthases: Possible targets that affect thoracic aorta relaxation response and nitric oxide release from RAW 264.7 macrophages. J. Pharmacol. Sci.,  2010, 112(3), 343-351.
 [http://dx.doi.org/10.1254/jphs.09340FP] [PMID: 20197636]

[79]
Liang, W.; Cai, A.; Chen, G.; Xi, H.; Wu, X.; Cui, J.; Zhang, K.; Zhao, X.; Yu, J.; Wei, B.; Chen, L. Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species. Sci. Rep.,  2016, 6(1), 38267-38278.
 [http://dx.doi.org/10.1038/srep38267] [PMID: 27905569]

[80]
Mao, X.; Rong Yu, C.; Hua Li, W.; Xin Li, W. Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells. Cell Res.,  2008, 18(8), 879-888.
 [http://dx.doi.org/10.1038/cr.2008.86] [PMID: 18663379]

[81]
Baloch, S.K.; Ling, L.J.; Qiu, H.Y.; Ma, L.; Lin, H.Y.; Huang, S.C.; Qi, J.L.; Wang, X.M.; Lu, G.H.; Yang, Y.H. Synthesis and biological evaluation of novel shikonin ester derivatives as potential anti-cancer agents. RSC Adv.,  2014, 4(67), 35588-35596.
 [http://dx.doi.org/10.1039/C4RA05610H]

[82]
Kim, S.H.; Kang, I.C.; Yoon, T.J.; Park, Y.M.; Kang, K.S.; Song, G.Y.; Ahn, B.Z. Antitumor activities of a newly synthesized shikonin derivative, 2-hyim-DMNQ-S-33. Cancer Lett.,  2001, 172(2), 171-175.
 [http://dx.doi.org/10.1016/S0304-3835(01)00665-6] [PMID: 11566493]

[83]
Lu, Q.; Liu, W.; Ding, J.; Cai, J.; Duan, W. Shikonin derivatives: Synthesis and inhibition of human telomerase. Bioorg. Med. Chem. Lett.,  2002, 12(10), 1375-1378.
 [http://dx.doi.org/10.1016/S0960-894X(02)00158-0] [PMID: 11992780]

[84]
Hashimoto, S.; Xu, Y.; Masuda, Y.; Aiuchi, T.; Nakajo, S.; Uehara, Y.; Shibuya, M.; Yamori, T.; Nakaya, K. β-hydroxyisovalerylshikonin is a novel and potent inhibitor of protein tyrosine kinases. Jpn. J. Cancer Res.,  2002, 93(8), 944-951.
 [http://dx.doi.org/10.1111/j.1349-7006.2002.tb01341.x] [PMID: 12716473]

[85]
Wang, W.; Dai, M.; Zhu, C.; Zhang, J.; Lin, L.; Ding, J.; Duan, W. Synthesis and biological activity of novel shikonin analogues. Bioorg. Med. Chem. Lett.,  2009, 19(3), 735-737.
 [http://dx.doi.org/10.1016/j.bmcl.2008.12.032] [PMID: 19111464]

[86]
Su, Y.; Xie, J.; Wang, Y.; Hu, X.; Lin, X. Synthesis and antitumor activity of new shikonin glycosides. Eur. J. Med. Chem.,  2010, 45(7), 2713-2718.
 [http://dx.doi.org/10.1016/j.ejmech.2010.02.002] [PMID: 20403646]

[87]
Zhou, W.; Peng, Y.; Li, S.S. Semi-synthesis and anti-tumor activity of 5,8-O-dimethyl acylshikonin derivatives. Eur. J. Med. Chem.,  2010, 45(12), 6005-6011.
 [http://dx.doi.org/10.1016/j.ejmech.2010.09.068] [PMID: 20970893]

[88]
Zhou, W.; Zhang, X.; Xiao, L.; Ding, J.; Liu, Q.H.; Li, S.S. Semi-synthesis and antitumor activity of 6-isomers of 5, 8-O-dimethyl acylshikonin derivatives. Eur. J. Med. Chem.,  2011, 46(8), 3420-3427.
 [http://dx.doi.org/10.1016/j.ejmech.2011.05.006] [PMID: 21620530]

[89]
Wu, Y.; Wan, L.; Zheng, X.; Shao, Z.; Chen, J.; Chen, X.; Liu, L.; Kuang, W.; Tan, X.; Zhou, L. Inhibitory effects of β,β-dimethylacrylshikonin on hepatocellular carcinoma in vitro and in vivo. Phytother. Res.,  2012, 26(5), 764-771.
 [http://dx.doi.org/10.1002/ptr.3623] [PMID: 22109831]

[90]
Shen, X.J.; Wang, H.B.; Ma, X.Q.; Chen, J.H. β,β-Dimethylacrylshikonin induces mitochondria dependent apoptosis through ERK pathway in human gastric cancer SGC-7901 cells. PLoS One,  2012, 7(7), e41773.
 [http://dx.doi.org/10.1371/journal.pone.0041773] [PMID: 22848597]

[91]
Rao, Z.; Liu, X.; Zhou, W.; Yi, J.; Li, S.S. Synthesis and antitumour activity of β-hydroxyisovalerylshikonin analogues. Eur. J. Med. Chem.,  2011, 46(9), 3934-3941.
 [http://dx.doi.org/10.1016/j.ejmech.2011.05.065] [PMID: 21689869]

[92]
He, H.; Bai, L.P.; Jiang, Z.H. Synthesis and human telomeric G-quadruplex DNA-binding activity of glucosaminosides of shikonin/alkannin. Bioorg. Med. Chem. Lett.,  2012, 22(4), 1582-1586.
 [http://dx.doi.org/10.1016/j.bmcl.2011.12.143] [PMID: 22281188]

[93]
Kretschmer, N.; Rinner, B.; Deutsch, A.J.A.; Lohberger, B.; Knausz, H.; Kunert, O.; Blunder, M.; Boechzelt, H.; Schaider, H.; Bauer, R. Naphthoquinones from Onosma paniculata induce cell-cycle arrest and apoptosis in melanoma Cells. J. Nat. Prod.,  2012, 75(5), 865-869.
 [http://dx.doi.org/10.1021/np2006499] [PMID: 22530779]

[94]
Lin, H.Y.; Chen, W.; Shi, J.; Kong, W.Y.; Qi, J.L.; Wang, X.M.; Yang, Y.H. Design, synthesis and biological evaluation of cinnamic acyl shikonin derivatives. Chem. Biol. Drug Des.,  2013, 81(2), 275-283.
 [http://dx.doi.org/10.1111/cbdd.12077] [PMID: 23066914]

[95]
Wang, X.M.; Lin, H.Y.; Kong, W.Y.; Guo, J.; Shi, J.; Huang, S.C.; Qi, J.L.; Yang, R.W.; Gu, H.W.; Yang, Y.H. Synthesis and biological evaluation of heterocyclic carboxylic acyl shikonin derivatives. Chem. Biol. Drug Des.,  2014, 83(3), 334-343.
 [http://dx.doi.org/10.1111/cbdd.12247] [PMID: 24118825]

[96]
Guo, J.; Chen, X.F.; Liu, J.; Lin, H.Y.; Han, H.W.; Liu, H.C.; Huang, S.C.; Shahla, B.K.; Kulek, A.; Qi, J.L.; Wang, X.M.; Ling, L.J.; Yang, Y.H. Novel shikonin derivatives targeting tubulin as anticancer agents. Chem. Biol. Drug Des.,  2014, 84(5), 603-615.
 [http://dx.doi.org/10.1111/cbdd.12353] [PMID: 24797889]

[97]
Lin, H.Y.; Han, H.W.; Bai, L.F.; Qiu, H.Y.; Yin, D.Z.; Qi, J.L.; Wang, X.M.; Gu, H.W.; Yang, Y.H. Design, synthesis and biological evaluation of shikonin thio-glycoside derivatives: New anti-tubulin agents. RSC Adv.,  2014, 4(91), 49796-49805.
 [http://dx.doi.org/10.1039/C4RA08810G]

[98]
Baloch, S.K.; Ma, L.; Xu, G.H.; Bai, L.F.; Zhao, H.; Tang, C.Y.; Pang, Y.J.; Yang, R.W.; Wang, X.M.; Lu, G.H.; Yang, Y.H. A potent anticancer agent of shikonin derivative targeting tubulin. Chirality,  2015, 27(3), 274-280.
 [http://dx.doi.org/10.1002/chir.22425] [PMID: 25663187]

[99]
Lin, H.Y.; Li, Z.K.; Bai, L.F.; Baloch, S.K.; Wang, F.; Qiu, H.Y.; Wang, X.; Qi, J.L.; Yang, R.W.; Wang, X.M.; Yang, Y.H. Synthesis of aryl dihydrothiazol acyl shikonin ester derivatives as anticancer agents through microtubule stabilization. Biochem. Pharmacol.,  2015, 96(2), 93-106.
 [http://dx.doi.org/10.1016/j.bcp.2015.04.021] [PMID: 25957661]

[100]
Durchschein, C.; Hufner, A.; Rinner, B.; Stallinger, A.; Deutsch, A.; Lohberger, B.; Bauer, R.; Kretschmer, N. Synthesis of novel shikonin derivatives and pharmacological effects of cyclopropylacetylshikonin on melanoma cells. Molecules,  2018, 23(11), 2820.
 [http://dx.doi.org/10.3390/molecules23112820] [PMID: 30380765]

[101]
Park, D.G.; Kim, D.J.; Woo, B.H.; Kim, H.J.; Choi, Y.W.; Park, H.R. Isobutyrylshikonin has a potentially stronger cytotoxic effect in oral cancer cells than its analogue shikonin in vitro. Arch. Oral Biol.,  2020, 116, 104774.
 [http://dx.doi.org/10.1016/j.archoralbio.2020.104774] [PMID: 32470830]

[102]
Shao, Y.Y.; Yin, Y.; Lian, B.P.; Leng, J.F.; Xia, Y.Z.; Kong, L.Y. Synthesis and biological evaluation of novel shikonin-benzo[b]furan derivatives as tubulin polymerization inhibitors targeting the colchicine binding site. Eur. J. Med. Chem.,  2020, 190, 112105.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112105] [PMID: 32035399]

[103]
Ross, W.; Rowe, T.; Glisson, B.; Yalowich, J.; Liu, L. Role of topoisomerase II in mediating epipodophyllotoxin-induced DNA cleavage. Cancer Res.,  1984, 44(12 Pt 1), 5857-5860.
 [PMID: 6094001]

[104]
Atwell, G.J.; Rewcastle, G.W.; Baguley, B.C.; Denny, W.A. Potential antitumor agents. 50. In vivo solid-tumor activity of derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide. J. Med. Chem.,  1987, 30(4), 664-669.
 [http://dx.doi.org/10.1021/jm00387a014] [PMID: 3560161]

[105]
Fortune, J.M.; Velea, L.; Graves, D.E.; Utsugi, T.; Yamada, Y.; Osheroff, N. DNA topoisomerases as targets for the anticancer drug TAS-103: DNA interactions and topoisomerase catalytic inhibition. Biochemistry,  1999, 38(47), 15580-15586.
 [http://dx.doi.org/10.1021/bi991792g] [PMID: 10569942]

[106]
Lhoste, J.M.; Lavelle, F.; Bissery, M.C.; Bisagni, E.; Bisagni, E. Synthesis and antitumor activity of 1-[[(dialkylamino)alkyl]amino]-4-methyl-5H-pyrido[4,3-b]benzo[e]- and -benzo[g])indoles. A new class of antineoplastic agents. J. Med. Chem.,  1990, 33(5), 1519-1528.
 [http://dx.doi.org/10.1021/jm00167a037] [PMID: 2329575]

[107]
Perrin, D.; van Hille, B.; Barret, J.M.; Kruczynski, A.; Etiévant, C.; Imbert, T.; Hill, B.T. F 11782, a novel epipodophylloid non-intercalating dual catalytic inhibitor of topoisomerases I and II with an original mechanism of action. Biochem. Pharmacol.,  2000, 59(7), 807-819.
 [http://dx.doi.org/10.1016/S0006-2952(99)00382-2] [PMID: 10718339]

[108]
Adjei, A.A.; Charron, M.; Rowinsky, E.K.; Svingen, P.A.; Miller, J.; Reid, J.M.; Sebolt-Leopold, J.; Ames, M.M.; Kaufmann, S.H. Effect of pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II. Clin. Cancer Res.,  1998, 4(3), 683-691.
 [PMID: 9533538]

[109]
Salerno, S.; Da Settimo, F.; Taliani, S.; Simorini, F.; La Motta, C.; Fornaciari, G.; Marini, A.M. Recent advances in the development of dual topoisomerase I and II inhibitors as anticancer drugs. Curr. Med. Chem.,  2010, 17(35), 4270-4290.
 [http://dx.doi.org/10.2174/092986710793361252] [PMID: 20939813]

[110]
Denny, W.; Baguley, B. Dual topoisomerase I/II inhibitors in cancer therapy. Curr. Top. Med. Chem.,  2003, 3(3), 339-353.
 [http://dx.doi.org/10.2174/1568026033452555] [PMID: 12570767]

[111]
Tseng, C.H.; Tzeng, C.C.; Yang, C.L.; Lu, P.J.; Chen, H.L.; Li, H.Y.; Chuang, Y.C.; Yang, C.N.; Chen, Y.L. Synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives. Part 2. J. Med. Chem.,  2010, 53(16), 6164-6179.
 [http://dx.doi.org/10.1021/jm1005447] [PMID: 20662543]

[112]
Karki, R.; Thapa, P.; Yoo, H.Y.; Kadayat, T.M.; Park, P.H.; Na, Y.; Lee, E.; Jeon, K.H.; Cho, W.J.; Choi, H.; Kwon, Y.; Lee, E.S. Dihydroxylated 2,4,6-triphenyl pyridines: Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship study. Eur. J. Med. Chem.,  2012, 49, 219-228.
 [http://dx.doi.org/10.1016/j.ejmech.2012.01.015] [PMID: 22318164]

[113]
Abdel-Aziz, M.; Park, S.E.; Abuo-Rahma, G.E.D.A.A.; Sayed, M.A.; Kwon, Y. Novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids: Synthesis, physicochemical properties, anticancer and topoisomerase I and II inhibitory activity. Eur. J. Med. Chem.,  2013, 69, 427-438.
 [http://dx.doi.org/10.1016/j.ejmech.2013.08.040] [PMID: 24090914]

[114]
Dalla Via, L.; Marzaro, G.; Ferrarese, A.; Gia, O.; Chilin, A. Pyrroloquinolinone-based dual topoisomerase I/II inhibitor. Eur. J. Med. Chem.,  2014, 77, 103-109.
 [http://dx.doi.org/10.1016/j.ejmech.2014.02.064] [PMID: 24631729]

[115]
Yao, B.L.; Mai, Y.W.; Chen, S.B.; Xie, H.T.; Yao, P.F.; Ou, T.M.; Tan, J.H.; Wang, H.G.; Li, D.; Huang, S.L.; Gu, L.Q.; Huang, Z.S. Design, synthesis and biological evaluation of novel 7-alkylamino substituted benzo[a]phenazin derivatives as dual topoisomerase I/II inhibitors. Eur. J. Med. Chem.,  2015, 92, 540-553.
 [http://dx.doi.org/10.1016/j.ejmech.2015.01.024] [PMID: 25599951]

[116]
Karki, R.; Jun, K.Y.; Kadayat, T.M.; Shin, S.; Thapa Magar, T.B.; Bist, G.; Shrestha, A.; Na, Y.; Kwon, Y.; Lee, E.S. A new series of 2-phenol-4-aryl-6-chlorophenyl pyridine derivatives as dual topoisomerase I/II inhibitors: Synthesis, biological evaluation and 3D-QSAR study. Eur. J. Med. Chem.,  2016, 113, 228-245.
 [http://dx.doi.org/10.1016/j.ejmech.2016.02.050] [PMID: 26945111]

[117]
Fujii, N.; Yamashita, Y.; Arima, Y.; Nagashima, M.; Nakano, H. Induction of topoisomerase II-mediated DNA cleavage by the plant naphthoquinones plumbagin and shikonin. Antimicrob. Agents Chemother.,  1992, 36(12), 2589-2594.
 [http://dx.doi.org/10.1128/AAC.36.12.2589] [PMID: 1336338]

[118]
Plyta, Z.F.; Li, T.; Papageorgiou, V.P.; Mellidis, A.S.; Assimopoulou, A.N.; Pitsinos, E.N.; Couladouros, E.A. Inhibition of topoisomerase I by naphthoquinone derivatives. Bioorg. Med. Chem. Lett.,  1998, 8(23), 3385-3390.
 [http://dx.doi.org/10.1016/S0960-894X(98)00600-3] [PMID: 9873739]

[119]
Zhang, F.L.; Wang, P.; Liu, Y.H.; Liu, L.; Liu, X.B.; Li, Z.; Xue, Y.X. Topoisomerase I inhibitors, shikonin and topotecan, inhibit growth and induce apoptosis of glioma cells and glioma stem cells. PLoS One,  2013, 8(11), e81815.
 [http://dx.doi.org/10.1371/journal.pone.0081815] [PMID: 24303074]

[120]
Ogawa, Y.; Kawano, Y.; Yamazaki, Y.; Onishi, Y. Shikonin shortens the circadian period: Possible involvement of Top2 inhibition. Biochem. Biophys. Res. Commun.,  2014, 443(1), 339-343.
 [http://dx.doi.org/10.1016/j.bbrc.2013.11.116] [PMID: 24321095]

[121]
Su, L.; Liu, L.; Wang, Y.; Yan, G.; Zhang, Y. Long-term systemic toxicity of shikonin derivatives in Wistar rats. Pharm. Biol.,  2014, 52(4), 486-490.
 [http://dx.doi.org/10.3109/13880209.2013.846913] [PMID: 24192282]
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DOI https://dx.doi.org/10.2174/0929867330666230208094828	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

A Review on Shikonin and its Derivatives as Potent Anticancer Agents Targeted against Topoisomerases

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