Desmethyl Derivatives of Indomethacin and Sulindac as Probes for Cyclooxygenase-Dependent Biology

Felts, Andrew S.; Ji, Chuan; Stafford, Jennifer B.; Crews, Brenda C.; Kingsley, Philip J.; Rouzer, Carol A.; Washington, Mary Kay; Subbaramaiah, Kotha; Siegel, Brianna S.; Young, Shiu M.; Dannenberg, Andrew J.; Marnett, Lawrence J.

doi:10.1021/cb700077z

Cited by 22 publications

(34 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…24,25,56 Thus, the E -DMSS analogues described in the present report may be useful leads for novel COX-1 inhibitors or useful probes for the involvement of COX-1 in physiological or pathophysiological processes. However, some of the inhibitors may have off-target effects that would limit their utility in vivo.…”

Section: Discussionmentioning

confidence: 77%

Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

et al. 2012

Self Cite

View full text Add to dashboard Cite

Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2′-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

show abstract

Section: Discussionmentioning

confidence: 77%

Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…These findings suggest that NAG-1 is linked to apoptosis and that reduced expression of NAG-1 may enhance tumorigenesis. It is known that the PPARg-dependent activation of NAG-1 by troglitazone is due to induction of EGR-1, which in turn activates NAG-1 (Rokos and Ledwith, 1997;Chintharlapalli et al, 2006;Yamaguchi et al, 2006;Felts et al, 2007). Like troglitazone, the PPAR-g active 1,1-bis (3'-indolyl)-1-( p-substituted phenyl) methanes also induce EGR-1, which in turn interacts with the proximal GC-rich EGR-1 motifs in the NAG-1 promoter (Chintharlapalli et al, 2006).…”

mentioning

confidence: 99%

Synergistic anti‐tumor activity of isochaihulactone and paclitaxel on human lung cancer cells

Chen

et al. 2011

Journal Cellular Physiology

View full text Add to dashboard Cite

Drug resistance frequently develops in tumors during chemotherapy. Therefore, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Here, we show that isochaihulactone (K8) enhanced paclitaxel-induced apoptotic death in human lung cancer cells, and the enhancing effect was related to increased NSAID-activated gene-1 (NAG-1) expression. CalcuSyn software was used to evaluate the synergistic interaction of K8 and paclitaxel on human lung cancer cells; the synergistic effect of K8 in combination with paclitaxel was increased more than either of these drugs alone. Furthermore, the activity of ERK1/2 was enhanced by the combination of K8 and paclitaxel, and an ERK1/2 inhibitor dramatically inhibited NAG-1 expression in human lung cancer cells. Therefore, this synergistic apoptotic effect in human lung cancer cells may be directly associated with K8-induced NAG-1 expression through ERK1/2 activation. Moreover, over-expression of NAG-1 enhanced K8/paclitaxel-induced apoptosis in human lung cancer cells. In addition, treatment of nude mice with K8 combined with paclitaxel induced phospho-ERK1/2 and NAG-1 expression in vivo. Targeting of NAG-1 signaling could enhance therapeutic efficacy in lung cancer. Our results reveal that activation of NAG-1 by K8 enhanced the therapeutic efficacy of paclitaxel in human lung cancer cells via the ERK1/2 signaling pathway.

show abstract

“…DM-sulindac and DM-sulindac sulfide were synthesized as described in the Chemical Synthesis Core Facility of the Vanderbilt Institute of Chemical Biology (25). Polyclonal β-actin antibody was obtained from Abcam.…”

Section: Methodsmentioning

confidence: 99%

The Role of NAG-1/GDF15 in the Inhibition of Intestinal Polyps in APC/Min Mice by Sulindac

Wang

Kingsley²,

Marnett³

et al. 2011

Cancer Prevention Research

Self Cite

View full text Add to dashboard Cite

The antitumor effects of nonsteroidal anti-inflammatory drugs (NSAID) are assumed to be due to the inhibition of COX activity, but COX-independent mechanisms may also play an important role. NSAID-activated gene (NAG-1/GDF15) is induced by NSAIDs and has antitumorigenic activities. To determine the contribution of COX-2 inhibition and NAG-1/GDF15 expression to the prevention of colon carcinogenesis by NSAIDs, we evaluated several sulindac derivatives [des-methyl (DM)-sulindac sulfide and its prodrug DM-sulindac] that do not inhibit COX-2 activity. Sulindac sulfide and DM-sulindac induced the expression of NAG-1/GDF15 in HCT116 cells as determined by quantitative real-time PCR and Western blot. We fed APC/Min mice with 320 ppm of sulindac and doses of DM-sulindac. Only sulindac significantly inhibited tumor formation in APC/Min mice. To determine the pharmacokinetic properties of sulindac and DM-sulindac in vivo, wild-type C57/B6 mice were fed with sulindac and DM-sulindac at 80, 160, and 320 ppm. High-performance liquid chromatography analysis revealed that the conversion of DM-sulindac to DM-sulindac sulfide (active form) was less efficient than the conversion of sulindac to sulindac sulfide (active form) in the mice. Lower levels of DM-sulindac sulfide accumulated in intestinal and colon tissues in comparison with sulindac sulfide. In addition, NAG-1/GDF15 was induced in the liver of sulindac-fed mice but not in the DM-sulindac–fed mice. Collectively, our results suggest that the tumor-inhibitory effects of sulindac in APC/Min mice may be due to, in part, NAG-1/GDF15 induction in the liver. Our study also suggests that pharmacologic properties should be carefully evaluated when developing drug candidates.

show abstract

Desmethyl Derivatives of Indomethacin and Sulindac as Probes for Cyclooxygenase-Dependent Biology

Cited by 22 publications

References 25 publications

Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

Synergistic anti‐tumor activity of isochaihulactone and paclitaxel on human lung cancer cells

The Role of NAG-1/GDF15 in the Inhibition of Intestinal Polyps in APC/Min Mice by Sulindac

Contact Info

Product

Resources

About