Skip to main content

Advertisement

SpringerLink
Log in

4-Aryl-1,3,2-oxathiazolylium-5-olate: a novel GST inhibitor to release JNK and activate c-Jun for cancer therapy

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The over-expression of glutathion S-transferase Pi (GSTπ) in tumors and inhibitory effect of GSTπ to JNK are two possible causes of the development of drug-resistance in chemotherapy. This research is to develop a novel pH-controlled NO donor to inhibit GSTπ(and to activate the JNK/c-Jun pathway (omit “to induce apoptosis”).

Methods

Four 4-Aryl-1,3,2-oxathiazolylium-5-olate (OZO) derivatives with varying aryl para-substitutions (–H, –CF3, –Cl, and –OCH3) were synthesized. Anticancer activity was determined by MTS assay. GST activity was measured with spectrophotometry using 1-chlro-2,4-dinitrobenzene (CDNB) and GSH as substrates. (omit “Apoptosis was evaluated by annexin V staining and flow cytometry”). c-Jun N-terminal kinase 1 (JNK1) association with GSTπ and activation of c-Jun were evaluated with immunoprecipitation and western blot.

Results

OZO derivatives showed anticancer effect against leukemia and breast cancer cells by MTS assay. The relative potency of their anticancer effects is OZO-H > OZO-Cl, OZO-OMe > OZO-CF3. The anticancer activity of these compounds was correlated with their inhibition of GST activity in cancer cells. The immunoprecipitaion result showed that the treatment of OZO-H released JNK1 from GSTπ-JNK1 complex. Consequently, the treatment of OZO-H in cancer cells induced JNK1 phophorylation and activated c-Jun in cancer cells.

Conclusion

OZO-H is a novel GST inhibitor to release JNK1 for activation of JNK/c-Jun pathway (original is “c-Jun to trigger apoptosis in cancer cells”). It provides a new class of GST target compound for anticancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

OZO:

4-Aryl-1,3,2-oxathiazolylium-5-olate

GST:

Glutathion S-transferases

JNK:

c-Jun H2-terminal kinase

MAP kinase:

Mitogen-activated protein kinase

GSH:

Glutathione

SAR:

Structure activity relationship

References

  1. Alemagna A, Bacchetti T (1976) 4-Phenyl-1,3,2-oxathiazol-5-one. III: unusual sulfenamidic derivatives from the reaction with thiolates. Chimica e l’Industria (Milan, Italy) 58:616–617

    CAS  Google Scholar 

  2. Armstrong RN (1997) Structure, catalytic mechanism, and evolution of the glutathione transferases. Chem Res Toxicol 10:2–18

    Article  PubMed  CAS  Google Scholar 

  3. Adler V, Yin Z, Fuchs SY et al (1999) Regulation of JNK signaling by GSTpi. EMBO J 18:1321–1334

    Article  PubMed  CAS  Google Scholar 

  4. Boesgaard S, Aldershvile J, Poulsen HE et al (1994) Nitrate tolerance in vivo is not associated with depletion of arterial or venous thiol levels. Circ Res 74:115–120

    PubMed  CAS  Google Scholar 

  5. Burg D, Filippov Dmitri V, Hermanns R et al (2002) Peptidomimetic glutathione analogues as novel gammaGT stable GST inhibitors. Bioorg Med Chem 10:195–205

    Article  PubMed  CAS  Google Scholar 

  6. Burg D, Mulder GJ (2002) Glutathione conjugates and their synthetic derivatives as inhibitors of glutathione-dependent enzymes involved in cancer and drug resistance. Drug Metab Rev 34:821–863

    Article  PubMed  CAS  Google Scholar 

  7. Burg D, Riepsaame J, Pont C, Mulder G, van de Water B (2006) Peptide-bond modified glutathione conjugate analogs modulate GSTp function in GSH-conjugation, drug sensitivity and JNK signaling. Biochem Pharmacol 71:268–277

    Article  PubMed  CAS  Google Scholar 

  8. Ciaccio PJ, Shen H, Jaiswal AK et al (1995) Modulation of detoxification gene expression in Human colon HT29 cells by glutathione-S-transferase inhibitors. Mol Pharmacol 48:639–647

    PubMed  CAS  Google Scholar 

  9. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252

    Article  PubMed  CAS  Google Scholar 

  10. Fan M, Chambers TC (2001) Role of mitogen-activated protein kinases in the response of tumor cells to chemotherapy. Drug Resist Updat 4:253–267

    Article  PubMed  CAS  Google Scholar 

  11. Filomeni G, Aquilano K, Rotilio G et al (2003) Reactive oxygen species-dependent c-jun NH2-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide. Cancer Res 63:5940–5909

    PubMed  CAS  Google Scholar 

  12. Flatgaard JE, Bauer KE, Kauvar LM (1993) Isozyme specificity of novel glutathione-S-transferase inhibitors. Cancer Chemother Pharmacol 33:63–70

    Article  PubMed  CAS  Google Scholar 

  13. Govoni M, Casagrande S, Maucci R et al (2006) In vitro metabolism of (nitrooxy)butyl ester nitric oxide-releasing compounds: comparison with glyceryl trinitrate. J Pharmacol Exp Ther 317:752–761

    Article  PubMed  CAS  Google Scholar 

  14. Habig WH, Jakoby WB (1981) Assays for differentiation of glutathione S-transferases. Methods Enzymol 77:398–405

    PubMed  CAS  Google Scholar 

  15. Hamilton D, Batist G (2005) TLK-199 Telik. IDrugs 8:662–669

    PubMed  CAS  Google Scholar 

  16. Hansson J, Berhane K, Castro VM et al (1991) Sensitization of human melanoma cells to the cytotoxic effect of melphalan by the glutathione transferase inhibitor ethacrynic acid. Cancer Res 51:94–98

    PubMed  CAS  Google Scholar 

  17. Kauvar LM, Morgan AS, Sanderson PE et al (1998) Glutathione based approaches to improving cancer treatment. Chem Biol Interact 111:225–238

    Article  PubMed  Google Scholar 

  18. Lemercier J-N, Meier BW, Gomez JD et al (2004) Inhibition of glutathione S-transferase P1-1 in mouse lung epithelial cells by the tumor promoter 2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadienone (BHT-Quinone Methide): protein adducts investigated by electrospray mass spectrometry. Chem Res Toxicol 17:1675–1683

    Article  PubMed  CAS  Google Scholar 

  19. Lu DN, Nadas J, Zhang GS et al (2007) 4-Aryl-1,3,2-oxathiazolylium-5-olates as pH-controlled NO-donors: the next generation of S-nitrosothiols. J Am Chem Soc 129:5503–5514

    Article  PubMed  CAS  Google Scholar 

  20. Lyttle MH, Satyam A, Hocker MD et al (1994) Glutathione-S-transferase activates novel alkylating agents. J Med Chem 37:1501–1507

    Article  PubMed  CAS  Google Scholar 

  21. Mahajan S, Atkins WM (2005) The chemistry and biology of inhibitors and pro-drugs targeted to glutathione S-transferases. Cell Mol Life Sci 62:1221–1233

    Article  PubMed  CAS  Google Scholar 

  22. Mantle TJ, Parraga A, Vega MC et al (2000) Studies on the reaction mechanism of mouse liver glutathione S-transferase P1-1. Clin Chem Enzymol Commun 8:223–230

    CAS  Google Scholar 

  23. Morgan AS, Ciaccio PJ, Tew KD et al (1996) Isozymespecific glutathione S-transferase inhibitors potentiate drug sensitivity in cultured human tumor cell lines. Cancer Chemother Pharmacol 37:363–370

    Article  PubMed  CAS  Google Scholar 

  24. Morgan AS, Sanderson PE, Borch RF et al (1998) Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase. Cancer Res 58:2568–2575

    PubMed  CAS  Google Scholar 

  25. Nagourney RA, Messenger JC, Kern DH et al (1990) Enhancement of anthracycline and alkylator cytotoxicity by ethacrynic acid in primary cultures of human tissues. Cancer Chemother Pharmacol 26:318–322

    Article  PubMed  CAS  Google Scholar 

  26. O’Brien ML, Tew KD (1996) Glutathione and related enzymes in multidrug resistance. Eur J Cancer 32:967–978

    Article  Google Scholar 

  27. Ono K, Han J (2000) The p38 signal transduction pathway: activation and function. Cell Signal 12:1–13

    Article  PubMed  CAS  Google Scholar 

  28. Ploemen JH, van Ommen B, van Bladeren PJ (1990) Inhibition of rat and human glutathione S-transferase isoenzymes by ethacrynic acid and its glutathione conjugate. Biochem Pharmacol 40:1631–1635

    Article  PubMed  CAS  Google Scholar 

  29. Potapova O, Haghighi A, Bost F et al (1997) The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin. J Biol Chem 272:14041–14044

    Article  PubMed  CAS  Google Scholar 

  30. Ralat LA, Colman RF (2003) Monobromobimane occupies a distinct xenobiotic substrate site in glutathione S-transferase p. Protein Sci 12:2575–2587

    Article  PubMed  CAS  Google Scholar 

  31. Ricci G, De Maria F, Antonini G et al (2005) 7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases: mechanism of action of potential anticancer drugs. J Biol Chem 280:26397–26405

    Article  PubMed  CAS  Google Scholar 

  32. Ricci G, Caccuri AM, Lo Bello M et al (1996) Structural flexibility modulates the activity of human glutathione transferase P1-1. Role of helix 2 flexibility in the catalytic mechanism. J Biol Chem 271:16187–16192

    Article  PubMed  CAS  Google Scholar 

  33. Schultz M, Dutta S, Tew KD (1997) Inhibitors of glutathione S-transferases as therapeutic agents. Adv Drug Deliv Rev 26:91–104

    Article  PubMed  CAS  Google Scholar 

  34. Tellez-Sanz R, Cesareo E, Nuccetelli M et al (2006) Calorimetric and structural studies of the nitric oxide carrier S-nitrosoglutathione bound to human glutathione transferase P1-1. Protein Sci 15:1093–1105

    Article  PubMed  CAS  Google Scholar 

  35. Tew KD (2005) TLK-286: a novel glutathione S-transferase-activated prodrug. Expert Opin Investig Drugs 14:1047–1054

    Article  PubMed  CAS  Google Scholar 

  36. Tew KD, Bomber AM, Hoffman SJ (1988) Ethacrynic acid and piriprost as enhancers of cytotoxicity in Drug resistant and sensitive cell lines. Cancer Res 48:3622–3625

    PubMed  CAS  Google Scholar 

  37. Tew KD (1994) Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 54:4313–4320

    PubMed  CAS  Google Scholar 

  38. Tew KD, Monks A, Barone L et al (1996) Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program. Mol Pharmacol 50:149–159

    PubMed  CAS  Google Scholar 

  39. Thatcher GRJ, Nicolescu AC, Bennett BM et al (2004) Nitrates and NO release: Contemporary aspects in biological and medicinal chemistry. Free Radic Biol Med 37:1122–1143

    Article  PubMed  CAS  Google Scholar 

  40. Townsend DM, Findlay VJ, Fazilev F et al (2006) A glutathione S-transferase p-activated prodrug causes kinase activation concurrent with S-glutathionylation of proteins. Mol Pharmacol 69:501–508

    Article  PubMed  CAS  Google Scholar 

  41. Townsend DM, Tew KD (2003) The role of glutathione-Stransferase in anti-cancer drug resistance. Oncogene 22:7369–75

    Article  PubMed  CAS  Google Scholar 

  42. Turella P, Cerella C, Filomeni G et al (2005) Proapoptotic activity of new glutathione S-transferase inhibitors. Cancer Res 65:3751–3761

    Article  PubMed  CAS  Google Scholar 

  43. Turella P, Filomeni G, Dupuis ML et al (2006) A strong glutathione S-transferase inhibitor overcomes the P-glycoprotein-mediated resistance in tumor cells: 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) triggers a caspase-dependent apoptosis in MDR1-expressing leukemia cells. J Biol Chem 281:23725–23732

    Article  PubMed  CAS  Google Scholar 

  44. van Iersel MLPS, Ploemen J-PHTM, Lo Bello M et al (1997) Interactions of a,b-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1. Chem Biol Interact 108:67–78

    Article  PubMed  Google Scholar 

  45. van Zanden JJ, Ben Hamman O, van Iersel MLPS et al (2003) Inhibition of human glutathione S-transferase P1-1 by the flavonoid quercetin. Chem Biol Interact 145:139–148

    Article  PubMed  CAS  Google Scholar 

  46. Vega MC, Walsh SB, Mantle TJ et al (1998) The three-dimensional structure of Cys-47-modified mouse liver glutathione S-transferase P1-1. Carboxymethylation dramatically decreases the affinity for glutathione and is associated with a loss of electron density in the aB-310B region. J Biol Chem 273:2844–2850

    Article  PubMed  CAS  Google Scholar 

  47. Wu Z, Minhas GS, Wen D et al (2004) Design, synthesis, and structure-activity relationships of haloenol lactones: site-directed and isozyme-selective glutathione S-transferase inhibitors. J Med Chem 47:3282–3294

    Article  PubMed  CAS  Google Scholar 

  48. Xu BH, Singh SV (1992) Effect of buthionine sulfoximine and ethacrynic acid on cytotoxic activity of Mitomycin C analogues BMY 25282 and BMY 25067. Cancer Res 52:6666–6670

    PubMed  CAS  Google Scholar 

  49. Yeates RA, Laufen H, Leitold M (1985) The reaction between organic nitrates and sulfhydryl compounds. A possible model system for the activation of organic nitrates. Mol Pharmacol 28:555–559

    PubMed  CAS  Google Scholar 

  50. Yin Z, Ivanov V, Habelhah H, et al (2000). Glutathione S-transferase pi elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res (Adv Brief) 60:4053–4057

    CAS  Google Scholar 

  51. Zhao G, Wang X (2006) Advance in antitumor agents targeting glutathione-S-transferase. Curr Med Chem 13:1461–1471

    Article  PubMed  CAS  Google Scholar 

  52. Zheng J, Liu G, Tozkoparan B et al (2005) Mechanistic studies of inactivation of glutathione S-transferase Pi isozyme by a haloenol lactone derivative. Med Chem 1:191–198

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by NIH (GM54074) to P. G. Wang, and the grant from the Ohio Cancer Research Associates to D.S.

Author information

Authors and Affiliations

  1. School of Pharmaceutical Science, Shandong University, Jinan, China

    Huifei Cui

  2. Departments of Biochemistry and Chemistry, Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA

    Jie Shen, Dongning Lu, Wenpeng Zhang & Peng George Wang

  3. Department of Pharmaceutics, College of Pharmacy, Ohio State University, 500 West 12th Avenue, Columbus, OH, 43210, USA

    Tao Zhang & Duxin Sun

Authors
  1. Huifei Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dongning Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenpeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Duxin Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peng George Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Duxin Sun or Peng George Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cui, H., Shen, J., Lu, D. et al. 4-Aryl-1,3,2-oxathiazolylium-5-olate: a novel GST inhibitor to release JNK and activate c-Jun for cancer therapy. Cancer Chemother Pharmacol 62, 509–515 (2008). https://doi.org/10.1007/s00280-007-0632-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0632-3

Keywords

Search

Navigation