Document Detail


Aryl hydrocarbon receptor activation by aminoflavone: new molecular target for renal cancer treatment.
MedLine Citation:
PMID:  22485252     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aminoflavone (AF; NSC 686288, AFP464, NSC710464) is a new anticancer drug that has recently entered phase II clinical trials. It has demonstrated antiproliferative effects in MCF-7 human breast cancer cells mediated by the aryl hydrocarbon receptor (AhR). AF also exhibits noteworthy evidence of antitumor activity in vitro and in vivo against neoplastic cells of renal origin. AF treatment of sensitive renal cells, in contrast to resistant cells, promotes the induction of CYP1A1, the covalent binding of AF-reactive intermediates and apoptosis. Based on this evidence, the aim of this study was to evaluate the role of AhR, the main transcriptional regulator of CYP1A1, in the antiproliferative effects of AF in human renal cancer cells. AF-cytoxicity in human renal cell lines and a renal cancer cell strain was assessed by MTS assay in the presence or absence of an Ahr inhibitor. Drug-induced AhR nuclear translocation was evaluated by western blotting of AhR in cytosolic and nuclear fractions and by measuring xenobiotic response element-driven luciferase activity. Apoptosis induced by the drug was evaluated by 4,6-diamidino-2-phenylindole and acridine orange/ethidium bromide staining and by measuring phosphorylated P53 (p-P53) and P21 levels, caspase 3 activation and poly(ADP-ribose) polymerase cleavage. AF inhibited cell growth in a dose-dependent manner in TK-10, Caki-1, SN12-C and A498 human renal cells but not in ACHN cells. The antiproliferative effect of AF was abrogated by pre-incubation of TK-10, Caki-1 and SN12-C cells with the AhR antagonist, α-naphthoflavone. AF treatment also induced apoptosis in TK-10, Caki-1 and SN12-C cells, which was not observed in ACHN cells. AF induced time-dependent AhR nuclear translocation and AhR transcriptional activity in sensitive renal cancer cell lines. A renal cell strain derived from a human papillary tumor also showed sensitivity to AF, as well as AhR pathway activation and drug-induced apoptosis. AhR translocation could be included as a marker of sensitivity to AF in sensitive renal tumor cells of different histological origin, in ongoing phase II clinical trials.
Authors:
Mariana A Callero; Guadalupe V Suárez; Gabriela Luzzani; Boris Itkin; Binh Nguyen; Andrea I Loaiza-Perez
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-04-05
Journal Detail:
Title:  International journal of oncology     Volume:  41     ISSN:  1791-2423     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-05-09     Completed Date:  2012-08-31     Revised Date:  2014-01-08    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  125-34     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Active Transport, Cell Nucleus / drug effects
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Apoptosis Regulatory Proteins / metabolism
Aryl Hydrocarbon Hydroxylases / genetics
Carcinoma, Papillary / drug therapy*,  pathology
Carcinoma, Renal Cell / drug therapy*,  pathology
Cell Line, Tumor
Cell Nucleus / metabolism
Cell Proliferation / drug effects
Cytochrome P-450 CYP1A1 / genetics
Flavonoids / pharmacology*
Genes, Reporter
Humans
Kidney Neoplasms / drug therapy*,  pathology
Luciferases / biosynthesis,  genetics
Molecular Targeted Therapy
Promoter Regions, Genetic
Receptors, Aryl Hydrocarbon / metabolism*
Transcriptional Activation / drug effects
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Apoptosis Regulatory Proteins; 0/Flavonoids; 0/Receptors, Aryl Hydrocarbon; 0/aminoflavone; EC 1.13.12.-/Luciferases; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP1A1 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP1A1; EC 1.14.14.1/cytochrome P-450 CYP1B1

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