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Chemical Compound Review

Prevatec     2-[(3E)-6-fluoro-2-methyl-3- [(4...

Synonyms: Aptosyn, Exisulind, FGN-1, Lopac-S-1438, FGN 1, ...
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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


Biological context of Exisulind


Anatomical context of Exisulind


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


  1. Phase I and II study of exisulind in combination with capecitabine in patients with metastatic breast cancer. Pusztai, L., Zhen, J.H., Arun, B., Rivera, E., Whitehead, C., Thompson, W.J., Nealy, K.M., Gibbs, A., Symmans, W.F., Esteva, F.J., Booser, D., Murray, J.L., Valero, V., Smith, T.L., Hortobagyi, G.N. J. Clin. Oncol. (2003) [Pubmed]
  2. Sporadic adenomatous polyp regression with exisulind is effective but toxic: a randomised, double blind, placebo controlled, dose-response study. Arber, N., Kuwada, S., Leshno, M., Sjodahl, R., Hultcrantz, R., Rex, D. Gut (2006) [Pubmed]
  3. Exisulind, a novel proapoptotic drug, inhibits rat urinary bladder tumorigenesis. Piazza, G.A., Thompson, W.J., Pamukcu, R., Alila, H.W., Whitehead, C.M., Liu, L., Fetter, J.R., Gresh, W.E., Klein-Szanto, A.J., Farnell, D.R., Eto, I., Grubbs, C.J. Cancer Res. (2001) [Pubmed]
  4. Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Thompson, W.J., Piazza, G.A., Li, H., Liu, L., Fetter, J., Zhu, B., Sperl, G., Ahnen, D., Pamukcu, R. Cancer Res. (2000) [Pubmed]
  5. Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis. van Stolk, R., Stoner, G., Hayton, W.L., Chan, K., DeYoung, B., Kresty, L., Kemmenoe, B.H., Elson, P., Rybicki, L., Church, J., Provencher, K., McLain, D., Hawk, E., Fryer, B., Kelloff, G., Ganapathi, R., Budd, G.T. Clin. Cancer Res. (2000) [Pubmed]
  6. Sulindac sulfide and exisulind inhibit expression of the estrogen and progesterone receptors in human breast cancer cells. Lim, J.T., Joe, A.K., Suzui, M., Shimizu, M., Masuda, M., Weinstein, I.B. Clin. Cancer Res. (2006) [Pubmed]
  7. p38MAPK inhibitor SB203580 sensitizes human SNU-C4 colon cancer cells to exisulind-induced apoptosis. Lim, S.J., Lee, Y.J., Lee, E. Oncol. Rep. (2006) [Pubmed]
  8. A phase I/II study of exisulind in combination with docetaxel/carboplatin in patients with metastatic non-small-cell lung cancer. Jones, S.F., Kuhn, J.G., Greco, F.A., Raefsky, E.L., Hainsworth, J.D., Dickson, N.R., Thompson, D.S., Willcutt, N.T., White, M.B., Burris, H.A. Clinical lung cancer. (2005) [Pubmed]
  9. Alpha-tocopheryl succinate sensitizes human colon cancer cells to exisulind-induced apoptosis. Lim, S.J., Lee, Y.J., Park, D.H., Lee, E., Choi, M.K., Park, W., Chun, K.H., Choi, H.G., Cho, J.S. Apoptosis (2007) [Pubmed]
  10. Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines. Soriano, A.F., Helfrich, B., Chan, D.C., Heasley, L.E., Bunn, P.A., Chou, T.C. Cancer Res. (1999) [Pubmed]
  11. Exisulind in combination with docetaxel inhibits growth and metastasis of human lung cancer and prolongs survival in athymic nude rats with orthotopic lung tumors. Chan, D.C., Earle, K.A., Zhao, T.L., Helfrich, B., Zeng, C., Baron, A., Whitehead, C.M., Piazza, G., Pamukcu, R., Thompson, W.J., Alila, H., Nelson, P., Bunn, P.A. Clin. Cancer Res. (2002) [Pubmed]
  12. A phase I and pharmacokinetic study of exisulind and docetaxel in patients with advanced solid tumors. Witta, S.E., Gustafson, D.L., Pierson, A.S., Menter, A., Holden, S.N., Basche, M., Persky, M., O'Bryant, C.L., Zeng, C., Baron, A., Long, M.E., Gibbs, A., Kelly, K., Bunn, P.A., Chan, D.C., Pallansch, P., Eckhardt, S.G. Clin. Cancer Res. (2004) [Pubmed]
  13. Sulindac and exisulind exhibit a significant antiproliferative effect and induce apoptosis in human hepatocellular carcinoma cell lines. Rahman, M.A., Dhar, D.K., Masunaga, R., Yamanoi, A., Kohno, H., Nagasue, N. Cancer Res. (2000) [Pubmed]
  14. Cancer stem cells and therapeutic perspectives. Galmozzi, E., Facchetti, F., La Porta, C.A. Current medicinal chemistry. (2006) [Pubmed]
  15. Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells. Liu, L., Li, H., Underwood, T., Lloyd, M., David, M., Sperl, G., Pamukcu, R., Thompson, W.J. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  16. Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines. Lim, J.T., Piazza, G.A., Han, E.K., Delohery, T.M., Li, H., Finn, T.S., Buttyan, R., Yamamoto, H., Sperl, G.J., Brendel, K., Gross, P.H., Pamukcu, R., Weinstein, I.B. Biochem. Pharmacol. (1999) [Pubmed]
  17. Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells. Shimizu, M., Suzui, M., Deguchi, A., Lim, J.T., Xiao, D., Hayes, J.H., Papadopoulos, K.P., Weinstein, I.B. Clin. Cancer Res. (2004) [Pubmed]
  18. Regression of mouse prostatic intraepithelial neoplasia by nonsteroidal anti-inflammatory drugs in the transgenic adenocarcinoma mouse prostate model. Narayanan, B.A., Narayanan, N.K., Pittman, B., Reddy, B.S. Clin. Cancer Res. (2004) [Pubmed]
  19. Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival. Whitehead, C.M., Earle, K.A., Fetter, J., Xu, S., Hartman, T., Chan, D.C., Zhao, T.L., Piazza, G., Klein-Szanto, A.J., Pamukcu, R., Alila, H., Bunn, P.A., Thompson, W.J. Mol. Cancer Ther. (2003) [Pubmed]
  20. Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence. Narayanan, B.A., Reddy, B.S., Bosland, M.C., Nargi, D., Horton, L., Randolph, C., Narayanan, N.K. Clin. Cancer Res. (2007) [Pubmed]
  21. beta-Catenin signaling: therapeutic strategies in oncology. Li, H., Pamukcu, R., Thompson, W.J. Cancer Biol. Ther. (2002) [Pubmed]
  22. Vasodilator-stimulated phosphoprotein (VASP) phosphorylation provides a biomarker for the action of exisulind and related agents that activate protein kinase G. Deguchi, A., Soh, J.W., Li, H., Pamukcu, R., Thompson, W.J., Weinstein, I.B. Mol. Cancer Ther. (2002) [Pubmed]
  23. Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy. Goluboff, E.T., Prager, D., Rukstalis, D., Giantonio, B., Madorsky, M., Barken, I., Weinstein, I.B., Partin, A.W., Olsson, C.A. J. Urol. (2001) [Pubmed]
  24. Preclinical and clinical studies of docetaxel and exisulind in the treatment of human lung cancer. Bunn, P.A., Chan, D.C., Earle, K., Zhao, T.L., Helfrich, B., Kelly, K., Piazza, G., Whitehead, C.M., Pamukcu, R., Thompson, W., Alila, H. Semin. Oncol. (2002) [Pubmed]
  25. Docetaxel and exisulind in hormone-refractory prostate cancer. Ryan, C.W., Stadler, W.M., Vogelzang, N.J. Semin. Oncol. (2001) [Pubmed]
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