Phospho-sulindac inhibits pancreatic cancer growth: NFATc1 as a drug resistance candidate

  • Authors:
    • Onika T. Murray
    • Chi C. Wong
    • Kvetoslava Vrankova
    • Basil Rigas
  • View Affiliations

  • Published online on: November 27, 2013     https://doi.org/10.3892/ijo.2013.2190
  • Pages: 521-529
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Phospho-sulindac (P-S), a promising anticancer agent, is efficacious in pre-clinical models of human cancer and is apparently safe. Here, we studied the effect of P-S on pancreatic cancer growth. We found that P-S strongly inhibits the growth of human pancreatic cancer cells in vitro, is efficacious in inhibiting the growth of pancreatic xenografts in nude mice, and has an excellent safety profile. Microarray analysis revealed that P-S induced the expression of nuclear factor of activated T-cells, isoform c1 (NFATc1) gene. NFATc1, a calcineurin-responsive transcription factor associated with aggressive pancreatic cancer. The role of increased NFATc1 expression on the growth inhibitory effect of P-S on cancer growth was evaluated by silencing or by overexpressing it both in vitro and in vivo. We found that when the expression of NFATc1 was abrogated by RNAi, pancreatic cancer cells were more responsive to treatment with P-S. Conversely, overexpressing the NFATc1 gene made the pancreatic cancer cells less responsive to treatment with P-S. NFATc1 likely mediates drug resistance to P-S and is an unfavorable prognostic factor that predicts poor tumor response. We also demonstrated that NFATc1-mediated resistance can be overcome by cyclosporin A (CsA), an NFAT inhibitor, and that the combination of P-S and CsA synergistically inhibited pancreatic cancer cell growth. In conclusion, our preclinical data establish P-S as an efficacious drug for pancreatic cancer in preclinical models, which merits further evaluation.

References

1. 

Li D, Xie K, Wolff R and Abbruzzese JL: Pancreatic cancer. Lancet. 363:1049–1057. 2004. View Article : Google Scholar

2. 

Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N and Depinho RA: Genetics and biology of pancreatic ductal adeno-carcinoma. Genes Dev. 20:1218–1249. 2006. View Article : Google Scholar

3. 

Bardeesy N and DePinho RA: Pancreatic cancer biology and genetics. Nat Rev Cancer. 2:897–909. 2002. View Article : Google Scholar

4. 

Wolfe MM, Lichtenstein DR and Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 340:1888–1899. 1999. View Article : Google Scholar : PubMed/NCBI

5. 

Molina MA, Sitja-Arnau M, Lemoine MG, Frazier ML and Sinicrope FA: Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res. 59:4356–4362. 1999.PubMed/NCBI

6. 

Yip-Schneider MT, Wu H, Ralstin M, Yiannoutsos C, Crooks PA, Neelakantan S, Noble S, Nakshatri H, Sweeney CJ and Schmidt CM: Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo. Mol Cancer Ther. 6:1736–1744. 2007. View Article : Google Scholar : PubMed/NCBI

7. 

Yip-Schneider MT, Nakshatri H, Sweeney CJ, Marshall MS, Wiebke EA and Schmidt CM: Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-kappa B pathway in pancreatic carcinoma cells. Mol Cancer Ther. 4:587–594. 2005. View Article : Google Scholar : PubMed/NCBI

8. 

Yip-Schneider MT and Schmidt CM: MEK inhibition of pancreatic carcinoma cells by U0126 and its effect in combination with sulindac. Pancreas. 7:337–344. 2003. View Article : Google Scholar : PubMed/NCBI

9. 

Huang L, Zhu C, Sun Y, Xie G, Mackenzie GG, Qiao G, Komninou D and Rigas B: Phospho-sulindac (OXT-922) inhibits the growth of human colon cancer cell lines: a redox/polyamine-dependent effect. Carcinogenesis. 31:1982–1990. 2010. View Article : Google Scholar : PubMed/NCBI

10. 

Mackenzie GG, Sun Y, Huang L, Xie G, Ouyang N, Gupta RC, Johnson F, Komninou D, Kopelovich L and Rigas B: Phosphosulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice. Gastroenterology. 139:1320–1332. 2010. View Article : Google Scholar : PubMed/NCBI

11. 

Xie G, Nie T, Mackenzie GG, Sun Y, Huang L, Ouyang N, Alston N, Zhu C, Murray OT, Constantinides PP, Kopelovich L and Rigas B: The metabolism and pharmacokinetics of phosphosulindac (OXT-328) and the effect of difluoromethylornithine. Br J Pharmacol. 165:2152–2166. 2012. View Article : Google Scholar : PubMed/NCBI

12. 

Muller MR and Rao A: NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol. 10:645–656. 2010. View Article : Google Scholar : PubMed/NCBI

13. 

Mancini M and Toker A: NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer. 9:810–820. 2009. View Article : Google Scholar : PubMed/NCBI

14. 

Cippa PE, Kraus AK, Lindenmeyer MT, Chen J, Guimezanes A, Bardwell PD, Wekerle T, Wuthrich RP and Fehr T: Resistance to ABT-737 in activated T lymphocytes: molecular mechanisms and reversibility by inhibition of the calcineurin-NFAT pathway. Cell Death Dis. 3:e2992012. View Article : Google Scholar : PubMed/NCBI

15. 

Gregory MA, Phang TL, Neviani P, Alvarez-Calderon F, Eide CA, O’Hare T, Zaberezhnyy V, Williams RT, Druker BJ, Perrotti D and Degregori J: Wnt/Ca2+/NFAT signaling maintains survival of Ph+leukemia cells upon inhibition of Bcr-Abl. Cancer Cell. 18:74–87. 2010.

16. 

Sun Y and Rigas B: The thioredoxin system mediates redox-induced cell death in human colon cancer cells: implications for the mechanism of action of anticancer agents. Cancer Res. 68:8269–8277. 2008. View Article : Google Scholar : PubMed/NCBI

17. 

Ouyang N, Williams JL, Tsioulias GJ, Gao J, Iatropoulos MJ, Kopelovich L, Kashfi K and Rigas B: Nitric oxide-donating aspirin prevents pancreatic cancer in a hamster tumor model. Cancer Res. 66:4503–4511. 2006. View Article : Google Scholar : PubMed/NCBI

18. 

Sun Y, Huang L, Mackenzie GG and Rigas B: Oxidative stress mediates through apoptosis the anticancer effect of phosphononsteroidal anti-inflammatory drugs: implications for the role of oxidative stress in the action of anticancer agents. J Pharmacol Exp Ther. 338:775–783. 2011. View Article : Google Scholar : PubMed/NCBI

19. 

Nie T, Wong CC, Alston N, Aro P, Constantinides PP and Rigas B: Phospho-ibuprofen (MDC-917) incorporated in nano-carriers: Anti-cancer activity in vitro and in vivo. Br J Pharmacol. 166:991–1001. 2011. View Article : Google Scholar : PubMed/NCBI

20. 

Buchholz M, Schatz A, Wagner M, Michl P, Linhart T, Adler G, Gress TM and Ellenrieder V: Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J. 25:3714–3724. 2006. View Article : Google Scholar : PubMed/NCBI

21. 

Duque J, Fresno M and Iniguez MA: Expression and function of the nuclear factor of activated T cells in colon carcinoma cells: involvement in the regulation of cyclooxygenase-2. J Biol Chem. 280:8686–8693. 2005. View Article : Google Scholar : PubMed/NCBI

22. 

Cao Z and Li Y: Chemical induction of cellular antioxidants affords marked protection against oxidative injury in vascular smooth muscle cells. Biochem Biophys Res Commun. 292:50–57. 2002. View Article : Google Scholar : PubMed/NCBI

23. 

Hogan PG, Chen L, Nardone J and Rao A: Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17:2205–2232. 2003. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

February 2014
Volume 44 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Murray, O.T., Wong, C.C., Vrankova, K., & Rigas, B. (2014). Phospho-sulindac inhibits pancreatic cancer growth: NFATc1 as a drug resistance candidate. International Journal of Oncology, 44, 521-529. https://doi.org/10.3892/ijo.2013.2190
MLA
Murray, O. T., Wong, C. C., Vrankova, K., Rigas, B."Phospho-sulindac inhibits pancreatic cancer growth: NFATc1 as a drug resistance candidate". International Journal of Oncology 44.2 (2014): 521-529.
Chicago
Murray, O. T., Wong, C. C., Vrankova, K., Rigas, B."Phospho-sulindac inhibits pancreatic cancer growth: NFATc1 as a drug resistance candidate". International Journal of Oncology 44, no. 2 (2014): 521-529. https://doi.org/10.3892/ijo.2013.2190