In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 214-214
Abstract:
Glucocorticoids (GCs) are widely used in chemotherapy of blood cancers, including childhood acute leukemia. The biological effects of GCs are mediated by the glucocorticoid receptor (GR), a well known transcription factor. Therapeutic effects of GCs are mainly mediated via GR transrepression that involves negative interaction between GR and other transcription factors. In contrast, many adverse metabolic effects of glucocorticoids are mediated by GR transactivation that requires GR binding to hormone-responsive elements in gene promoters. Thus, selective GR activators (SEGRA) that modify GR, shift GR functions towards transrepression resulting in improved therapeutic index, hold a great potential for the GR-targeted chemotherapies. Recently we and others characterized novel non-steroidal GR ligand, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride or Compound A (CpdA), and showed that CpdA prevents GR dimerization and transactivation, but strongly enhances GR transrepression. We also revealed that CpdA possesses anti-cancer properties: it inhibited growth and viability of prostate cancer cells in GR-dependent fashion. Here we report that CpdA at concentrations 10−6-10−5M exerted cytostatic (evaluated by MTT test) and cytotoxic (evaluated by FACS analysis of DNA fragmentation as sub-G1 peak in propidium iodide-labeled cells) effects in K564, NB-4 and CEM leukemia cell lines. We found that these cell lines express wild type nonmutated GR. Consequently, these cell lines present a good model system for the further comparative analysis of CpdA and GCs effects. Leukemia cell lines were sensitive to apoptotic effect of both GR ligands: Dexamethasone (Dex) and CpdA. Dex induced apoptosis at the concentrations 10−7 to 10−5M; and CpdA affected cell viability at concentrations 5×10−6−10−5M. As a first step towards the evaluation of toxicological profile of this promising anti-cancer compound, we assessed its mutagenicity using Ames test. CpdA was not mutagenic either in frameshift or in base-substitution indicator strains, TA98 and TA100, respectively, at the wide range of concentrations (10−9-10−4M). Overall, our data suggest that novel non-mutagenic GR modulator has a high chemotherapeutic potential. The detailed mechanisms of its anti-cancer effects in leukemia cell lines is under investigation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 214.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-214
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
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