Summary
To explore the potential anti-tumour activities of xanthone derivatives, 26 hydroxylxanthones and benzoxanthones and their structurally modified analogues were examined for potential cytotoxic activities against eight human cancer cell lines. Most of the xanthone derivatives exhibited a higher degree of cytotoxicity on HepG2 cells than on the other seven cancer cell lines. Compound 24 (1,3,7-Trihydroxy-12H-benzo[b] xanthen-12-one) showed the highest degree of cytotoxicity of the tested compounds against HepG2 cells and demonstrated good tumour specificity by exhibiting a much higher degree of cytotoxicity against HepG2 cells than against normal liver cells (L02). Several valuable structure-activity relationships were derived from the cytotoxicity data. In addition, we found that compound 24 could downregulate the expression of the Mcl-1 protein, induce changes in the mitochondrial membrane potential and induce apoptosis in HepG2 cells via the mitochondrial pathway. Compound 24 was also shown to inhibit topoisomerase (topo) II activity and downregulate the levels of both topo II mRNA and protein in HepG2 cells. The present results suggest that due to its potent cytotoxicity and good tumour selectivity, compound 24 may be exploited as a potential lead compound in the development of a new anti-tumour agent with specific activity against liver cancer.
Similar content being viewed by others
References
Novotny L, Szekeres T (2003) Cancer therapy: new targets for chemotherapy. Hematology 8:129–137
Honea N, Brant J, Beck SL (2007) Treatment-related symptom clusters. Semin Oncol Nurs 23:142–151
Mahabusarakam W, Proudfoot J, Taylor W, Croft K (2000) Inhibition of lipoprotein oxidation by prenylated xanthones derived from mangostin. Free Radic Res 33:643–659
Palempalli UD, Gandhi U, Kalantari P, Vunta H, Arner RJ, Narayan V, Ravindran A, Prabhu KS (2009) Gambogic acid covalently modifies IkappaB kinase-beta subunit to mediate suppression of lipopolysaccharide-induced activation of NF-kappaB in macrophages. Biochem J 419:401–409
Sánchez GM, MA RH, Giuliani A, Núñez Sellés AJ, Rodríguez NP, León Fernández OS, Re L (2003) Protective effect of Mangifera indica L. extract (Vimang) on the injury associated with hepatic ischaemia reperfusion. Phytother Res 17:197–201
Liu Y, Zou L, Ma L, Chen WH, Wang B, Xu ZL (2006) Synthesis and pharmacological activities of xanthone derivatives as alpha-glucosidase inhibitors. Bioorg Med Chem 14:5683–5690
Liu Y, Ma L, Chen WH, Wang B, Xu ZL (2007) Synthesis of xanthone derivatives with extended pi-systems as alpha-glucosidase inhibitors: insight into the probable binding mode. Bioorg Med Chem 15:2810–2814
Liu Y, Ke Z, Cui J, Chen WH, Ma L, Wang B (2008) Synthesis, inhibitory activities, and QSAR study of xanthone derivatives as alpha-glucosidase inhibitors. Bioorg Med Chem 16:7185–7193
Krick A, Kehraus S, Gerhäuser C, Klimo K, Nieger M, Maier A, Fiebig HH, Atodiresei I, Raabe G, Fleischhauer J, König GM (2007) Potential cancer chemopreventive in vitro activities of monomeric xanthone derivatives from the marine algicolous fungus Monodictys putredinis. J Nat Prod 70:353–360
Sun HL, Tsai AC, Pan SL, Ding Q, Yamaguchi H, Lin CN, Hung MC, Teng CM (2009) EPOX inhibits angiogenesis by degradation of Mcl-1 through ERK inactivation. Clin Cancer Res 15:4904–4914
Na Y (2009) Recent cancer drug development with xanthone structures. J Pharm Pharmacol 61:707–712
Hou A, Fukai T, Shimazaki M, Sakagami H, Sun H, Nomura T (2001) Benzophenones and xanthones with isoprenoid groups from Cudrania cochinchinensis. J Nat Prod 64:65–70
Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257
Bae S, Ha TS, Yoon Y, Lee J, Cha HJ, Yoo H, Choe TB, Li S, Sohn I, Kim JY, Kim CS, Jin HO, Lee HC, Park IC, Kim CS, Jin YW, Ahn SK (2008) Genome-wide screening and identification of novel proteolytic cleavage targets of caspase-8 and -10 in vitro. Int J Mol Med 21:381–386
Adrain C, Martin SJ (2001) The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem Sci 26:390–397
Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629
Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssière JL, Petit PX, Kroemer G (1995) Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med 181:1661–1672
Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487
Sugiyama T, Shimizu S, Matsuoka Y, Yoneda Y, Tsujimoto Y (2002) Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic BH3-only protein. Bim Oncogene 21:4944–4956
Adams JM, Cory S (2001) Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci 26:61–66
Leu JI, Dumont P, Hafey M, Murphy ME, George DL (2004) Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6:443–450
Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F, Wang X (2003) Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev 17:1475–1486
Ferri KF, Kroemer G (2001) Organelle-specific initiation of cell death pathways. Nat Cell Biol 3:E255–E263
Wilstermann AM, Osheroff N (2003) Stabilization of eukaryotic topoisomerase II-DNA cleavage complexes. Curr Top Med Chem 3:321–338
Fortune JM, Prog ON (2000) Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice. Prog Nucleic Acid Res Mol Biol 64:221–253
Heck MM, Earnshaw WC (1986) Topoisomerase II: a specific marker for cell proliferation. J Cell Biol 103:2569–2581
Woessner RD, Mattern MR, Mirabelli CK, Johnson RK, Drake FH (1991) 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 2:209–214
Acknowledgements
This study was partially supported by a grant from the National Natural Science Foundation (No. 30371658).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Su, QG., Liu, Y., Cai, YC. et al. Anti-tumour effects of xanthone derivatives and the possible mechanisms of action. Invest New Drugs 29, 1230–1240 (2011). https://doi.org/10.1007/s10637-010-9468-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-010-9468-5