title: Potent Apoptotic Response Induced by Chloroacetamidine Anthrathiophenediones in Bladder Cancer Cells.
abstract: We previously found that two neighboring G-quadruplexes behave as a molecular switch controlling the expression of HRAS (Cogoi, S.; Schekotikhin, A. E.; Xodo, L. E. Nucl. Acids Res. 2014, DOI: 10.1093/nar/gku574). In this study we have designed anthrathiophenediones with two chloroacetamidine-containing side chains (CATDs) as G-quadruplex binders and have examined their anticancer activity in T24 bladder cancer cells bearing mutant HRAS and in T24 xenografts. The designed CATDs (3a-e), bearing alkyl side chains of different length, penetrate T24 cancer cells more than their analogues with guanidine-containing side chains. The lead compounds 3a and 3c inhibit HRAS expression, metabolic activity, and colony formation in T24 cancer cells. They also activate a strong apoptotic response, as indicated by PARP-1, caspases 3/7, and annexin V/propidium iodide assays. Apoptosis occurs under conditions where cyclin D1 is down-regulated and the cell cycle arrested in G2 phase. Finally, compound 3a inhibits the growth of T24 xenografts and increases the median survival time of nude mice.
authors.affiliation: †Department of Medical and Biological Sciences, University of Udine, P.le Kolbe 4, 33100 Udine, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Cogoi
authors.affiliation: ‡Department of Life Science, University of Trieste, Via Giorgieri 7-9, 34100 Trieste, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Zorzet
authors.affiliation: §Gause Institute of New Antibiotics, B. Pirogovskaya, 11, Moscow 119021, Russia.
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Shchekotikhin
authors.affiliation: †Department of Medical and Biological Sciences, University of Udine, P.le Kolbe 4, 33100 Udine, Italy.
authors.forename: Luigi E
authors.initials: LE
authors.lastname: Xodo
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D015195:Drug Design; D054856:G-Quadruplexes / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D051379:Mice; D013379:Substrate Specificity; D016019:Survival Analysis; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D013876:Thiophenes; D019938:Cyclin D1; C013874:chloroacetamide