Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations

Abstract

Sulindac is a non-selective inhibitor of cyclooxygenases (COX) used to treat inflammation and pain. Additionally, non-COX targets may account for the drug's chemo-preventive efficacy against colorectal cancer and reduced gastrointestinal toxicity. Here, we demonstrate that the pharmacologically active metabolite of sulindac, sulindac sulfide (SSi), targets 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of proinflammatory leukotrienes (LTs). SSi inhibited 5-LO in ionophore A23187- and LPS/fMLP-stimulated human polymorphonuclear leukocytes (IC(50) approximately 8-10 microM). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC(50) = 18.7 microM). SSi was 5-LO-selective as no inhibition of related lipoxygenases (12-LO, 15-LO) was observed. The sulindac prodrug and the other metabolite, sulindac sulfone (SSo), failed to inhibit 5-LO. Mechanistic analysis demonstrated that SSi directly suppresses 5-LO with an IC(50) of 20 muM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy.

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

“…The amount of LTB 4 and Ssi also exhibited different potencies in male and female blood. In contrast to other typical direct 5-LO inhibitors, licofelone and Ssi blocked 5-LO nuclear translocation, were more potent in intact cells than for isolated 5-LO, and, at least for licofelone, FLAP has been identified as a pharmacologically relevant target (32,33). Together, the agonist-induced assembly of the tight LTbiosynthetic 5-LO/FLAP complex occurs primarily in female cells, but hardly in male cells (impeded by androgens), which explains why LT synthesis inhibitors that act by preventing the 5-LO/FLAP interaction are more effective in females.…”

“…Similarly, the FLAP inhibitor from the quinoline series BAY-X 1005 (31), also known as DG-031 or veliflapon, was significantly more potent in female than in male blood ( Figure 3B), and a similar tendency was observed for the FLAP inhibitor MK591, an indole-quinoline hybrid (Supplemental Table 2). Finally, licofelone (a biphenyl pyrrolizine) and sulindac sulfide (Ssi, an indene derivative), which are classified as novel-type 5-LO inhibitors that preferentially interfere with cellular activation of 5-LO by blocking 5-LO translocation to the nuclear membrane where FLAP resides (32,33), were effective only in female blood ( Figure 3B and Supplemental Table 1). Together, FLAP inhibitors and distinct novel-type 5-LO inhibitors that block 5-LO nuclear translocation are more efficient in female blood, whereas no sex differences were observed for a cPLA 2 inhibitor and various types of direct 5-LO inhibitors.…”

“…A common feature of those LT synthesis inhibitors that were affected by the sex or 5α-DHT is their ability to prevent 5-LO/ FLAP interaction, either by blocking 5-LO nuclear translocation (i.e., licofelone and Ssi) (32,33) or by direct binding to FLAP (i.e., MK886 and BAY-X 1005) (7). We thus hypothesized that a sex bias in 5-LO/ FLAP interaction, due to androgens, might underlie the different efficiencies of FLAP inhibitors and licofelone/Ssi.…”

5-Lipoxygenase Is a Candidate Target for Therapeutic Management of Stem Cell–like Cells in Acute Myeloid Leukemia

“…Interestingly, 5-LO-inhibitory concentrations were similar to those for suppression of Wnt signaling and the aberrant self-renewal of LSCs (16,17).…”

“…6,7,[13][14][15][16][26][27][28][29]. It has recently been shown that sulindac sulfide (active metabolite of sulindac) is able to inhibit 5-LO at clinically relevant concentrations (17). Therefore, we investigated whether other NSAIDs such as indomethacin are able to inhibit 5-LO.…”