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Efficacy of SSG and SSG/IFNα2 against human prostate cancer xenograft tumors in mice: a role for direct growth inhibition in SSG anti-tumor action

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Abstract

Background

Pre-clinical activity of SSG against melanoma and renal cancer has been identified recently although the drug’s mechanism of action and activity against tumors of additional histological-types remain undefined.

Methods

The effects of SSG and SSG combination with other agents on DU145 human prostate carcinoma xenograft tumors in mice and on DU145 cell subpopulations of differential SSG sensitivities were evaluated.

Results

DU145 tumor growth was inhibited by SSG (69%), IFNα2 (33%) or the combination (80%) that induced complete regression of WM9 human melanoma tumors. DU145 cells in culture were also partially growth inhibited by SSG at killing doses (200–800 μg/ml) for WM9 cells, indicating a correlation of SSG inhibition of cancer cell growth in vitro and in vivo. DU145 cells formed multiple micro tumors in mice treated with SSG or SSG/IFNα2 in contrast to the single large tumors in the control or IFNα2-treated mice, suggesting the existence of an SSG-resistant subpopulation in DU145 cells. Indeed, DU145 but not WM9 cells formed colonies (∼4% frequency) when cultured in the presence of SSG. Single cell clone (DU145–7) isolated from DU145 cells showed SSG-resistant growth in culture, unassociated with cross-resistance to IFNα2 and converted to SSG-responsive cells by BSO that inhibited intracellular glutathione levels.

Conclusions

These results implicate a role for direct growth inhibition in SSG anti-tumor action, provide novel insights into the mechanism of tumor resistance to the drug and suggest a therapeutic potential for SSG and its combinations with IFNα2 or BSO for prostate cancer that warrants further investigation.

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Abbreviations

SSG:

Sodium stibogluconate

IFNα2:

Interferon-α2b

BSO:

l Buthionine-sulfoximine

Mφ:

Macrophage

References

  1. Anderson ME (1998) Glutathione: an overview of biosynthesis and modulation. Chem Biol Interact 111–112:1–14

    Article  PubMed  Google Scholar 

  2. Bailey HH, Mulcahy RT, Tutsch KD, Arzoomanian RZ, Alberti D, Tombes MB, Wilding G, Pomplun M, Spriggs DR (1994) Phase I clinical trial of intravenous l-buthionine sulfoximine and melphalan: an attempt at modulation of glutathione. J Clin Oncol 12:194–205

    PubMed  CAS  Google Scholar 

  3. Bailey HH, Ripple G, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C, Mahvi D, Schink J, Pomplun M, Mulcahy RT, Wilding G (1997) Phase I study of continuous-infusion l-s, r-buthionine sulfoximine with intravenous melphalan. J Natl Cancer Inst 89:1789–1796

    Article  PubMed  CAS  Google Scholar 

  4. Budzynski W, Radzikowski C (1994) Cytotoxic cells in immunodeficient athymic mice. Immunopharmacol Immunotoxicol 16:319–346

    PubMed  CAS  Google Scholar 

  5. Burshtyn DN, Scharenberg AM, Wagtmann N, Rajagopalan S, Berrada K, Yi T, Kinet JP, Long EO (1996) Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor. Immunity 4:77–85

    Article  PubMed  CAS  Google Scholar 

  6. Burshtyn DN, Yang W, Yi T, Long EO (1997) A novel phosphotyrosine motif with a critical amino acid at position -2 for the SH2 domain-mediated activation of the tyrosine phosphatase SHP- 1 [in process citation]. J Biol Chem 272:13066–13072

    Article  PubMed  CAS  Google Scholar 

  7. Carter JD, Neel BG, Lorenz U (1999) The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds. Int Immunol 11:1999–2014

    Article  PubMed  CAS  Google Scholar 

  8. Chinnaiyan P, Vallabhaneni G, Armstrong E, Huang SM, Harari PM (2005) Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 62:223–229

    Article  PubMed  CAS  Google Scholar 

  9. Estrela JM, Ortega A, Obrador E (2006) Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci 43:143–181

    Article  PubMed  CAS  Google Scholar 

  10. Fan K, Zhou M, Pathak MK, Lindner DJ, Altuntas CZ, Tuohy VK, Borden EC, Yi T (2005) Sodium stibogluconate interacts with IL-2 in anti-Renca tumor action via a T cell-dependent mechanism in connection with induction of tumor-infiltrating macrophages. J Immunol 175:7003–7008

    PubMed  CAS  Google Scholar 

  11. Feng GS (1999) Shp-2 tyrosine phosphatase: signaling one cell or many. Exp Cell Res 253:47–54

    Article  PubMed  CAS  Google Scholar 

  12. Forsberg K, Valyi-Nagy I, Heldin CH, Herlyn M, Westermark B (1993) Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. Proc Natl Acad Sci USA 90:393–397

    Article  PubMed  CAS  Google Scholar 

  13. Fragale A, Tartaglia M, Wu J, Gelb BD (2004) Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat 23:267–277

    Article  PubMed  CAS  Google Scholar 

  14. Griffith OW, Meister A (1979) Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-N-butyl homocysteine sulfoximine). J Biol Chem 254:7558–7560

    PubMed  CAS  Google Scholar 

  15. Hellerstedt BA, Pienta KJ (2002) The current state of hormonal therapy for prostate cancer. CA Cancer J Clin 52:154–179

    Article  PubMed  Google Scholar 

  16. Herwaldt BL, Berman JD (1992) Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 46:296–306

    PubMed  CAS  Google Scholar 

  17. Jiao H, Yang W, Berrada K, Tibrizi M, Shultz L, Yi T (1997) Macrophages from motheaten and viable motheaten mutant mice show increased proliferative response to GM-CSF: detection of potential HCP substrates in GM-CSF signal transduction. Exp Hematol 25:592–600

    PubMed  CAS  Google Scholar 

  18. Johnson KG, LeRoy FG, Borysiewicz LK, Matthews RJ (1999) TCR signaling thresholds regulating T cell development and activation are dependent upon SHP-1. J Immunol 162:3802–3813

    PubMed  CAS  Google Scholar 

  19. Kramer G, Steiner GE, Sokol P, Handisurya A, Klingler HC, Maier U, Foldy M, Marberger M (2001) Local intratumoral tumor necrosis factor-alpha and systemic IFN-alpha 2b in patients with locally advanced prostate cancer. J Interferon Cytokine Res 21:475–484

    Article  PubMed  CAS  Google Scholar 

  20. Lindner DJ, Borden EC, Kalvakolanu DV (1997) Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. Clin Cancer Res 3:931–937

    PubMed  CAS  Google Scholar 

  21. Meredith RF, Khazaeli MB, Macey DJ, Grizzle WE, Mayo M, Schlom J, Russell CD, LoBuglio AF (1999) Phase II study of interferon-enhanced 131I-labeled high affinity CC49 monoclonal antibody therapy in patients with metastatic prostate cancer. Clin Cancer Res 5:3254s–3258s

    PubMed  CAS  Google Scholar 

  22. Mickey DD, Stone KR, Wunderli H, Mickey GH, Vollmer RT, Paulson DF (1977) Heterotransplantation of a human prostatic adenocarcinoma cell line in nude mice. Cancer Res 37:4049–4058

    PubMed  CAS  Google Scholar 

  23. Migone TS, Cacalano NA, Taylor N, Yi T, Waldmann TA, Johnston JA (1998) Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells. Proc Natl Acad Sci USA 95:3845–3850

    Article  PubMed  CAS  Google Scholar 

  24. Neel BG, Gu H, Pao L (2003) The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 28:284–293

    Article  PubMed  CAS  Google Scholar 

  25. O’Dwyer PJ, Hamilton TC, LaCreta FP, Gallo JM, Kilpatrick D, Halbherr T, Brennan J, Bookman MA, Hoffman J, Young RC, Comis RL, Ozols RF (1996) Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer. J Clin Oncol 14:249–256

    PubMed  CAS  Google Scholar 

  26. Pathak MK, Hu X, Yi T (2002) Effects of sodium stibogluconate on differentiation and proliferation of human myeloid leukemia cell lines in vitro. Leukemia 16:2285–2291

    Article  PubMed  CAS  Google Scholar 

  27. Pathak MK, Yi T (2001) Sodium stibogluconate is a potent inhibitor of protein tyrosine phosphatases and augments cytokine responses in hemopoietic cell lines. J Immunol 167:3391–3397

    PubMed  CAS  Google Scholar 

  28. Richman PG, Meister A (1975) Regulation of gamma-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione. J Biol Chem 250:1422–1426

    PubMed  CAS  Google Scholar 

  29. Sathish JG, Johnson KG, LeRoy FG, Fuller KJ, Hallett MB, Brennan P, Borysiewicz LK, Sims MJ, Matthews RJ (2001) Requirement for CD28 co-stimulation is lower in SHP-1-deficient T cells. Eur J Immunol 31:3649–3658

    Article  PubMed  CAS  Google Scholar 

  30. Shen H, Kauvar L, Tew KD (1997) Importance of glutathione and associated enzymes in drug response. Oncol Res 9:295–302

    PubMed  CAS  Google Scholar 

  31. Shinohara N, Demura T, Matsumura K, Toyoda K, Kashiwagi A, Nagamori S, Ohmuro H, Ohzono S, Koyanagi T (1998) 5-fluorouracil and low-dose recombinant interferon-alpha-2a in patients with hormone-refractory adenocarcinoma of the prostate. Prostate 35:56–62

    Article  PubMed  CAS  Google Scholar 

  32. Shultz LD, Coman DR, Bailey CL, Beamer WG, Sidman CL (1984) “Viable motheaten,” a new allele at the motheaten locus. I. Pathology. Am J Pathol 116:179–192

    PubMed  CAS  Google Scholar 

  33. Shultz LD, Schweitzer PA, Rajan TV, Yi T, Ihle JN, Matthews RJ, Thomas ML, Beier DR (1993) Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73:1445–1454

    Article  PubMed  CAS  Google Scholar 

  34. Stewart AB, Lwaleed BA, Douglas DA, Birch BR (2005) Current drug therapy for prostate cancer: an overview. Curr Med Chem Anticancer Agents 5:603–612

    Article  PubMed  CAS  Google Scholar 

  35. Tartaglia M, Gelb BD (2005) Germ-line and somatic PTPN11 mutations in human disease. Eur J Med Genet 48:81–96

    Article  PubMed  Google Scholar 

  36. Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD (2002) PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 70:1555–1563

    Article  PubMed  CAS  Google Scholar 

  37. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465–468

    Article  PubMed  CAS  Google Scholar 

  38. Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD (2003) Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34:148–150

    Article  PubMed  CAS  Google Scholar 

  39. Tartaglia M, Niemeyer CM, Shannon KM, Loh ML (2004) SHP-2 and myeloid malignancies. Curr Opin Hematol 11:44–50

    Article  PubMed  CAS  Google Scholar 

  40. Thalasila A, Poplin E, Shih J, Dvorzhinski D, Capanna T, Doyle-Lindrud S, Beers S, Goodin S, Rubin E, DiPaola RS (2003) A phase I trial of weekly paclitaxel, 13- cisretinoic acid, and interferon alpha in patients with prostate cancer and other advanced malignancies. Cancer Chemother Pharmacol 52:119–124

    Article  PubMed  CAS  Google Scholar 

  41. Vestal DJ, Yi T, Borden EC (2001) Pharmacology of interferons: inducedb proteins cell activation and antitumor activity. Cancer Chemother biother. Third Edn, pp 752–778

  42. Yi T, Pathak MK, Lindner DJ, Ketterer ME, Farver C, Borden EC (2002) Anticancer activity of sodium stibogluconate in synergy with IFNs. J Immunol 169:5978–5985

    PubMed  CAS  Google Scholar 

  43. Zhang J, Somani AK, Watt S, Mills GB, Siminovitch KA (1999) The Srchomology domain 2-bearing protein tyrosine phosphatase-1 inhibits antigen receptor-induced apoptosis of activated peripheral T cells. J Immunol 162:6359–6367

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work is supported in part by grants CA0890344, CA 090914, M01 RR-018390 and CA 096636.

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Authors and Affiliations

  1. Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, NB4-67, Cleveland, OH, 44195, USA

    Jing Li, Daniel J. Lindner, Ernest C. Borden & Taolin Yi

  2. Taussig Cancer Center, The Cleveland Clinic, Cleveland, OH, 44195, USA

    Daniel J. Lindner, Ernest C. Borden & Taolin Yi

  3. Department of Pathology, The Cleveland Clinic, Cleveland, OH, 44195, USA

    Carol Farver

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  1. Jing Li
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  2. Daniel J. Lindner
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  3. Carol Farver
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  5. Taolin Yi
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Correspondence to Taolin Yi.

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Li, J., Lindner, D.J., Farver, C. et al. Efficacy of SSG and SSG/IFNα2 against human prostate cancer xenograft tumors in mice: a role for direct growth inhibition in SSG anti-tumor action. Cancer Chemother Pharmacol 60, 341–349 (2007). https://doi.org/10.1007/s00280-006-0378-3

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  • DOI: https://doi.org/10.1007/s00280-006-0378-3

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