Aryl Hydrocarbon Receptor Activation by Aminoflavone: New molecular target for renal cancer treatment

CALLERO, MARIANA A; SUAREZ, GUADALUPE V; LUZZANI, GABRIELA; ITKIN, BORIS; BINH,NGUYEN; LOAIZA PEREZ, ANDREA I.

INTERNATIONAL JOURNAL OF ONCOLOGY

SPANDIDOS PUBL LTD

Año: 2012 vol. 41 p. 125 - 134

1019-6439

Background: Aminoflavone (AF; NSC 686288, AFP464, NSC710464) is a new anticancer drug that recently entered Phase II clinical trials. It has demonstrated antiproliferative effect 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 CYP1A1 induction, covalent binding of AF-reactive intermediates and apoptosis. Based on this evidence, the aim of this study was to evaluate the role of AhR, main transcriptional regulator of CYP1A1, in the antiproliferative effect of AF in human renal cancer cells. Methods: AF-citoxicity in human renal cell lines and a renal cancer cell strain was assessed by MTS assays in the presence or absence of an Ahr inhibitor. Drug-induced AhR nuclear translocation was evaluated by western blot of AhR in cytosolic and nuclear fractions and by measuring XRE-driven luciferase activity. Apoptosis induced by the drug was evaluated by DAPI and Acridine orange/Ethidium bromide staining and by measuring p-P53 and P21 levels, Caspase 3 activation and PARP cleavage. Results: 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 preincubation of TK-10, Caki-1 and SN12-C cells with the AhR antagonist, á-naphtoflavone. AF treatment also induced apoptosis in TK-10, Caki-1 and SN12-C, which was not observed in ACHN cells. AF induced time dependent AhR nuclear translocation and AhR transcriptional activity in sensitive renal cancer cell lines. Also, a renal cell strain derived from a human papillary tumor was sensitive to AF and showed AhR pathway activation and drug induced apoptosis. Conclusions: AhR translocation could be included as a marker of sensitivity to AF in sensitive renal tumor cells of different histological origin, in the ongoing phase II clinical trials