Discovery of a novel 2,5-dihydroxycinnamic acid-based 5-lipoxygenase inhibitor that induces apoptosis and may impair autophagic flux in RCC4 renal cancer cells

Abstract

The inhibition of 5-lipoxygenase (5-LO), the key enzyme for the biosynthesis of leukotrienes (LTs), has generated increasing enthusiasm as anti-inflammatory and antitumor strategies in recent years. Based on our previous studies, we synthesized a series of dihydroxycinnamic acid-based analogs that might be 5-LO inhibitors. LTs biosynthesis inhibition in HEK293 cells and polymorphonuclear leukocytes (PMNL) was measured and antitumor activities were investigated in Renal Cell Carcinoma (RCC). Results showed that the 2,5-dihydroxycinnamic acid phenethyl ester (10b) was the best 5-LO inhibitor and was 7-fold more potent than Zileuton (1), the only clinically approved 5-LO inhibitor. 2,5-Dihydroxy substitution was more favorable to 5-LO inhibition since compound 10b is twice as active as CAPE (2) which is a 3,4-dihydroxylcinnamic acid ester. Meanwhile, 10b reduced the cell viability of renal cancer cells and was more selective toward RCC4 and 786.0 cells which are deficient for the Von Hippel-Lindau (VHL) tumor suppressor gene. As to the underlying cell-death mechanisms, 10b induced apoptosis in VHL-deficient RCC4 cells. Also, increases in LC3B and p62 expression suggest a blockage of the autophagic flux in RCC in response to 10b.

Keywords: 5-LO inhibitors; Anti-leukotriene therapy; Caffeic acid; Renal cell carcinoma.