Disease relevance of Exisulind

• Phase I and II study of exisulind in combination with capecitabine in patients with metastatic breast cancer [1].
• The decrease in median polyp size was significantly greater (p=0.03) in patients who received exisulind 400 mg (-10 mm2) compared with those who received placebo (-4 mm2) [2].
• Sporadic adenomatous polyp regression with exisulind is effective but toxic: a randomised, double blind, placebo controlled, dose-response study [2].
• Complete or partial response was significantly higher in the exisulind 400 mg group (54.6%) compared with the placebo group (30.2%), and disease progression was significantly lower (6.1% v 27.9%) (p=0.04 and 0.02, respectively) [2].
• The aim of our study was to investigate if exisulind induces regression of sporadic colonic adenomas [2].

High impact information on Exisulind

• Fourteen specimens were available for immunohistochemical assessment of phosphodiesterase-5 isoenzyme (PDE-5) and PDE-2 expression, which are the targets of exisulind [1].
• Exisulind also induced apoptosis as determined by DNA fragmentation, caspase activation, and morphology [3].
• Experiments on the human bladder tumor cell line, HT1376, showed that exisulind inhibited growth with a GI(50) of 118 microM, suggesting that the antineoplastic activity of the drug in vivo involved a direct effect on neoplastic urothelium [3].
• Accumulated beta-catenin, shown to be a substrate for PKG, is decreased by exisulind, suggesting a mechanism to explain apoptosis induction in neoplastic cells harboring adenomatous polyposis coli gene mutations [4].
• A novel mechanism for exisulind to induce apoptosis is studied involving sustained increases in cGMP levels and cGMP-dependent protein kinase (PKG) induction not found with selective PDE5 or most other PDE inhibitors [4].

Chemical compound and disease context of Exisulind

• Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis [5].
• The present study focuses on the effects of sulindac sulfide and exisulind on hormone signaling components in breast cancer cells [6].
• p38MAPK inhibitor SB203580 sensitizes human SNU-C4 colon cancer cells to exisulind-induced apoptosis [7].
• This study evaluated the safety, efficacy, and pharmacokinetic interactions of exisulind and docetaxel/carboplatin in patients with metastatic non-small-cell lung cancer (NSCLC) [8].
• Alpha-tocopheryl succinate sensitizes human colon cancer cells to exisulind-induced apoptosis [9].

Biological context of Exisulind

• Paclitaxel was the most potent agent (IC50 = 0.003-0.150 microM); sulindac sulfide, NDGA, and 13-cis-retinoic acid had intermediate potency (IC50 = 4-80 microM), and cisplatin and exisulind were the least potent (IC50 = 150-500 microM) [10].
• The combination of exisulind with concentrations of docetaxel (in concentrations that alone did not alter cell cycle distribution) reduced the G(1) accumulation induced by exisulind, increased the fraction of cells in G(2)-M (9-17%), and increased apoptosis (5-62%) [11].
• Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa [12].
• Further studies indicated that sulindac sulfide and exisulind caused marked down-regulation of expression of the ER and PR-A and PR-B in T47D cells [6].
• In previous studies, we found that sulindac sulfide and exisulind (sulindac sulfone, Aptosyn) cause growth inhibition, arrest cells in the G1 phase of the cell cycle, and induce apoptosis in human breast cancer cell lines [6].

Anatomical context of Exisulind

• Also, exisulind exhibited a similar growth-inhibitory effect on the KYN-2 cell line [13].
• Finally, potential therapies using inhibitors acting on cancer stem cell population such as cyclopamine, an inhibitor of hedgehog signalling, 6-bromoindirubin-3'-oxime (BIO) which acts on GSK3 and inhibitors of beta-catenin signaling such as exisulind and the tyrosine-kinase inhibitor STI571/Gleevac/imatinib will also discuss [14].
• Activation of PKG by exisulind and analogs was also seen in the colon tumor cell lines HT29, T84, and HCT116 [15].
• Exisulind and analogs are proapoptotic drugs developed as inhibitors of cGMP phosphodiesterase gene families 5 and 2 that have been shown to sustain increased cGMP in SW480 and HT29 cells [15].
• Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively [16].

Associations of Exisulind with other chemical compounds

• Sulindac sulfone (exisulind), although a nonsteroidal anti-inflammatory drug derivative, induces apoptosis in tumor cells by a mechanism that does not involve cyclooxygenase inhibition [4].
• OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells [17].
• CONCLUSIONS: Overall, the findings from this study clearly show the effectiveness of celecoxib and exisulind in reducing the PIN lesions by modulating a cascade of molecular targets involved in COX-2-dependent and -independent mechanisms [18].
• We further found that apoptosis induced by a combination of exisulind and SB203580 was mediated through caspase activation [7].
• The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway [19].
• We show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key molecular events [20].

Gene context of Exisulind

• In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM [16].
• Exisulind and analogs reduce beta-catenin via a novel, GSK3beta independent processing mechanism [21].
• Since this pathway is independent of APC and GSK3beta, exisulind and analogs provide a superior approach to circumvent the molecular defects of wnt signaling pathway and to treat cancers with such defects [21].
• Vasodilator-stimulated phosphoprotein (VASP) phosphorylation provides a biomarker for the action of exisulind and related agents that activate protein kinase G [22].
• Analysis of phosphodiesterase (PDE) isozymes in HT1376 cells showed PDE5 and PDE4 isozymes that were inhibited by exisulind with IC(50)s of 112 and 116 microM, respectively [3].

Analytical, diagnostic and therapeutic context of Exisulind

• These results provide rationale for conducting clinical trials using the combination of exisulind and docetaxel in patients with advanced lung cancer [11].
• The maximum safe dose of exisulind is 300 mg p.o. twice a day in patients with subtotal colectomies [5].
• Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy [23].
• Exisulind was originally developed as a chemoprevention agent for colorectal cancer [24].
• Furthermore, exisulind has shown significant antineoplastic activity in prostate cancer cell lines in vitro and in nude mouse xenograft models [25].

References