Novel Sulfonanilide Analogues Suppress Aromatase Expression and Activity in Breast Cancer Cells Independent of COX-2 Inhibition

Abstract

Aromatase is a particularly attractive target in the treatment of estrogen receptor positive breast cancer. Aromatase levels in breast cancer cells are enhanced by prostaglandins and reduced by COX inhibitors. The synthesis and biological evaluation of a novel series of sulfonanilide analogues derived from the COX-2 selective inhibitor NS-398 are described. The compounds suppress aromatase enzyme activity in SK-BR-3 breast cancer cells in a dose- and time-dependent manner. The effect of these compounds on COX-2 inhibition is investigated in breast cancer cells as well. Structure-activity analysis does not find a correlation between aromatase suppression and COX-2 inhibition. Microsomal aromatase inhibition studies rule out the possibility of direct enzyme inhibition. Real-time PCR analysis demonstrates that the sulfonanilide analogues decrease aromatase gene transcription in SK-BR-3 cells. These studies suggest that the novel sulfonanilide compounds suppress aromatase activity and transcription in SK-BR-3 breast cancer cells independent of COX-2 inhibition.

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

“…Safi et al, [68] reports that orphan nuclear receptor liver receptor homolog-1 (LRH-1) is a specific transcriptional activator of aromatase in human breast preadipocytes and proposes LRH-1 as a target for selective inhibition of aromatase in the breast. Recently, Bruggemeier and colleagues found that a novel series of sulfonilide analogs could suppress aromatase activity and transcription independent of Cox-2 [69]. This separation of activities may provide a basis for developing tissue specific aromatase inhibitors.…”

Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

“…1) Zhong et al, 2011;Su et al, 2008) and SKBR-3 breast cancer cell growth is inhibited by it with an IC 50 which is more active than nimesulide about 100 folds. The potential COX-2 activity is abolished by the N-methylation of JCC76 which blocks the ionization of its sulfonamide group (Su et al, 2006;Renard et al, 2006;Julemont et al, 2002). Due to the multistep nitroreductive bioactivation, nimesulide shows hepatotoxicity that produces the hazardous nitroanion radical and nitroso intermediate.…”

CoMFA, LeapFrog and blind docking studies on sulfonanilide derivatives acting as selective aromatase expression regulators

“…Besides, it has been shown that COX-1 and COX-2 inhibitors (Nonsteroidal anti-inflammatory drugs) can suppress the aromatase activity in SK-BR-3 breast cancer cells at transcriptional level [12], and consequently, the COX selective inhibitors could serve as the first generation of selective aromatase expression regulators (SAERs). Recently, the derivative analogue series of COX-2 inhibitors Nimesulide [13] and NS-398 [14] has been synthesized and tested in SK-BR-3 breast cancer cells [15][16][17], which suppress aromatase activity in breast cancer cells by suppressing its transcription [12]. Derivatives of NS-398 suppress aromatase activity at similar levels with the compound itself, whereas the N-methyl derivatives of NS-398 exhibit no COX-2 inhibition [15][16][17].…”

“…Recently, the derivative analogue series of COX-2 inhibitors Nimesulide [13] and NS-398 [14] has been synthesized and tested in SK-BR-3 breast cancer cells [15][16][17], which suppress aromatase activity in breast cancer cells by suppressing its transcription [12]. Derivatives of NS-398 suppress aromatase activity at similar levels with the compound itself, whereas the N-methyl derivatives of NS-398 exhibit no COX-2 inhibition [15][16][17].…”