Inhibition of aromatase activity and expression in MCF-7 cells by the chemopreventive retinoid N -(4-hydroxy-phenyl)-retinamide

Ciolino, Henry P.; Wang, T T Y; Sathyamoorthy, Neeraja

doi:10.1054/bjoc.2000.1269

Cited by 17 publications

(17 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The effect of the chemopreventive synthetic retinoid 4-HPR on aromatase activity inhibition in microsomes of JEG3 cells and in MCF-7 cells has been shown previously (41). Because VN/14-1 also possesses retinoidal properties and, in addition, also inhibits retinoic acid metabolism by blocking CYP-mediated catabolism of ATRA, we investigated its effect on CYP-19 (aromatase) activity.…”

Section: Resultsmentioning

confidence: 90%

Effects of Novel Retinoic Acid Metabolism Blocking Agent (VN/14-1) on Letrozole-Insensitive Breast Cancer Cells

2006

View full text Add to dashboard Cite

Aromatase inhibitors are proving to be more effective than tamoxifen for postmenopausal estrogen receptor (ER)-positive breast cancer. However, the inevitable development of resistance to treatment is a concern. We investigated the effects of novel retinoic acid metabolism blocking agent, VN/14-1, in overcoming letrozole resistance in long-term letrozole cultured (LTLC) cells. Compared with MCF-7 cells stably transfected with aromatase (MCF-7Ca), LTLC cells were no longer sensitive to growth inhibition by aromatase inhibitors. The HER-2/phosphorylated mitogen-activated protein kinase (pMAPK) growth factor signaling pathways were activated, and ERA and coactivator amplified in breast cancer 1 (AIB1) were up-regulated f3-fold in LTLC cells. VN/14-1 inhibited aromatase activity and growth values of in MCF-7Ca cells with IC 50 of 8.5 and 10.5 nmol/L, respectively. In human placental microsomes, aromatase activity was inhibited with IC 50 of 8.0 pmol/L. The IC 50 in LTLC cells was 0.83 nmol/L, similar to letrozole (IC 50 , 0.3 nmol/L) in MCF-7Ca cells. LTLC cells were 10-fold more sensitive to growth inhibition by VN/14-1 than MCF-7Ca cells. VN/14-1 treatment effectively down-regulated ERA, AIB1, pMAPK, HER-2, cyclin D1, cyclin-dependent kinase 4 (CDK4), and Bcl2 and up-regulated cytokeratins 8/18, Bad, and Bax. Tumor growth of LTLC cells in ovariectomized nude mice was independent of estrogens but was inhibited by VN/ 14-1 (20 mg/kg/d; P < 0.002). Decreases in ERA, cyclin D1, CDK4, and pMAPK and up-regulation of cytokeratins, Bad, and Bax with VN/14-1 in tumor samples may be responsible for the efficacy of this compound in inhibiting LTLC cell growth in vitro and in vivo. (Cancer Res 2006; 66(23): 11485-93)

show abstract

Section: Resultsmentioning

confidence: 90%

Effects of Novel Retinoic Acid Metabolism Blocking Agent (VN/14-1) on Letrozole-Insensitive Breast Cancer Cells

2006

View full text Add to dashboard Cite

show abstract

“…As a result, there is a recognized need for next generation inhibitors [23]. A large number of investigators have invested significant effort in the search for novel structures [24][25][26][27] and mechanisms [28][29][30] that bring about adequate aromatase inhibition, while limiting side effects. This search remains active.…”

Section: Introductionmentioning

confidence: 99%

The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents

Pei

et al. 2011

Breast Cancer Res Treat

View full text Add to dashboard Cite

To improve the treatment of breast cancer, there has been a need for alternative aromatase inhibitors (AIs) that bring about adequate aromatase inhibition, while limiting side effects. Since two tamoxifen metabolites have been documented as AIs, we tested a wide range of tamoxifen metabolites on aromatase in order to better understand structural interactions with aromatase and constructed structure-function relationships as a first step toward the development of novel inhibitors. The ability of ten tamoxifen metabolites to inhibit recombinant aromatase (CYP19) was tested using microsomal incubations. The selectivity of the most potent aromatase inhibitor identified, norendoxifen, was characterized by studying its ability to inhibit CYP450 enzymes important in clinical drug-drug interactions, including CYP2B6, 2C9, 2C19, 2D6, and 3A. Computerized molecular docking with the X-ray crystallographic structure of aromatase was used to describe the detailed biochemical interactions involved. The inhibitory potency order of the tested compounds was as follows: norendoxifen ≫ 4,4'-dihydroxy-tamoxifen > endoxifen > N-desmethyl-tamoxifen, N-desmethyl-4'-hydroxy-tamoxifen, tamoxifen-N-oxide, 4'-hydroxy-tamoxifen, N-desmethyl-droloxifene > 4-hydroxy-tamoxifen, tamoxifen. Norendoxifen inhibited recombinant aromatase via a competitive mechanism with a K ( i ) of 35 nM. Norendoxifen inhibited placental aromatase with an IC(50) of 90 nM, while it inhibited human liver CYP2C9 and CYP3A with IC(50) values of 990 and 908 nM, respectively. Inhibition of human liver CYP2C19 by norendoxifen appeared even weaker. No substantial inhibition of CYP2B6 and CYP2D6 by norendoxifen was observed. These data suggest that multiple metabolites of tamoxifen may contribute to its action in the treatment of breast cancer via aromatase inhibition. Most of all, norendoxifen may be able to serve as a potent and selective lead compound in the development of improved therapeutic agents. The range of structures tested in this study and their pharmacologic potencies provide a reasonable pharmacophore upon which to build novel AIs.

show abstract

“…We [31] and others [32,33] previously demonstrated that the synthetic retinoid 4-hydroxyphenylretinamide (4-HPR) inhibits the activity of aromatase in vitro. However, despite the established chemopreventive effect of retinoids towards breast cancer, and the crucial role of aromatase in the growth of estrogen-dependent tumors, the effects of ROH and other naturally occurring retinoids on aromatase activity have not, to the best of our knowledge, been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…1A). Therefore we examined the kinetics of enzyme inhibition using a double-reciprocal plot and found that ROH, like 4-HPR [31], involved both competition for the substrate binding site and noncompetitive components (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

Retinol inhibits aromatase activity and expression in vitro

Ciolino¹,

Nair²

2011

The Journal of Nutritional Biochemistry

View full text Add to dashboard Cite

Inhibition of aromatase activity and expression in MCF-7 cells by the chemopreventive retinoid N -(4-hydroxy-phenyl)-retinamide

Cited by 17 publications

References 29 publications

Effects of Novel Retinoic Acid Metabolism Blocking Agent (VN/14-1) on Letrozole-Insensitive Breast Cancer Cells

Effects of Novel Retinoic Acid Metabolism Blocking Agent (VN/14-1) on Letrozole-Insensitive Breast Cancer Cells

The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents

Retinol inhibits aromatase activity and expression in vitro

Contact Info

Product

Resources

About