Inhibition of Testosterone Aromatization by the Indole-3-carbinol Derivative CTet in CYP19A1-overexpressing MCF-7 Breast Cancer Cells

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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Inhibition of Testosterone Aromatization by the Indole-3-carbinol Derivative CTet in CYP19A1-overexpressing MCF-7 Breast Cancer Cells



Anti-Cancer Agents in Medicinal Chemistry, 15(7): 896-904.

Author(s): Mauro De Santi, Elisa Carloni, Luca Galluzzi, Aurora Diotallevi, Simone Lucarini, Mauro Magnani and Giorgio Brandi.

Affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via Saffi, 2, 61029 Urbino, Italy.

Abstract

Natural products such as aromatase inhibitors have been the object of growing attention in recent years because of their potential to inhibit aromatase with fewer side effects and the possible translation of their current use as chemotherapeutic agents to future clinical applications in breast cancer chemoprevention. We have previously investigated CTet, a novel anticancer agent obtained from the broccoli-derived compound indole-3- carbinol (I3C), that shows great anticancer potential in both in vitro and in vivo studies. Here we evaluated the potential of CTet as a chemopreventive agent in aromatase expressing MCF-7/AROM-1 breast cancer cells. The testosterone (TE) aromatization in estradiol (E2) was indirectly evaluated in terms of inhibition of TE-induced cell proliferation, ERα phosphorylation/activation and Bcl-2 and IGF-1R ERE-regulated protein accumulation. Our results showed that CTet inhibited TE-driven ERα phosphorylation of both cytosolic and nuclear ERα pools, suggesting an inhibitory effect of TE aromatization in E2. CTet did not inhibit E2-driven nuclear ERα phosphorylation, but partially inhibited E2-driven cytosolic ERα phosphorylation. Moreover, CTet inhibited Bcl-2 and IGF-1R accumulation induced by TE but not that which was induced by E2. A cell-free enzymatic assay showed that CTet did not inhibit aromatase activity directly; however, since CTet treatment induced endoplasmic reticulum stress, the TE aromatization could be affected because the aromatase enzyme is located within the endoplasmic reticulum. Finally, CTet and letrozole synergistically inhibited TE-induced cell proliferation. These results showed the potential of the I3C derivative CTet as a chemopreventive agent that interferes with aromatase activity.




Keywords:

Aromatase inhibition, chemoprevention, endoplasmic reticulum stress, I3C derivative CTet, MCF-7/AROM-1 cells.



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Article Details

Volume: 15
Issue Number: 7
First Page: 896
Last Page: 904
Page Count: 9
DOI: 10.2174/1871520615666150121123053
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