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Cisplatin Resistant Glioblastoma Cells may have Increased Concentration of Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor Type 1

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Abstract

Gliomas are the most common form of intrinsic primary brain tumors, that extensively invade the surrounding normal brain tissue. The failure of chemotherapy treatment of these tumors is chiefly attributed to drug-resistance. From human glioblastoma we developed two cell sublines resistant to cisplatin due to acute (AT cells) or continuos (CT cells) treatment with clinically relevant doses of cisplatin. We examined their sensitivity to different cytostatics by colorimetric MTT assay. The concentrations of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) were determined by the ELISA assay. The results reveal that both AT and CT cells became resistant to cisplatin and vincristine; AT cells became resistant also to etoposide. Both AT and CT cells did not significantly change their sensitivity to doxorubicin, 5-fluorouracil and chlorambucil. Concentrations of uPA and PAI-1 were increased in CT cells, with no change in AT cells. In the conditioned medium of both, AT and CT cells, the level of uPA were increased. No differences in concentrations of PAI-1 in the conditioned medium of these cells were found. Thus, our results show that drug-resistance of glioblastoma cells may be accompanied with the increased levels of markers for tumor invasion.

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References

  1. Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991

    Google Scholar 

  2. Laiho M, Keski-Oja J: Growth factors in the regulation of pericellular proteolysis: a review. Cancer Res 49: 2533–2553, 1989

    Google Scholar 

  3. Boyd D: Invasion and metastasis. Cancer Metast Rev 15: 77–89, 1996

    Google Scholar 

  4. Schmitt M, Janicke F, Graeff H: Tumor-associated proteases. Fibrinolysis 6: 3–26, 1992

    Google Scholar 

  5. Rijken DC: Plasminogen activators and plasminogen activator inhibitors: biochemical aspects. Bailliere's Clinical Haematology 8: 291–312, 1995

    Google Scholar 

  6. Yu H, Schultz R: Relationship between secreted urokinase plasminogen activator actitvity and metastatic potential in murine B16 cells transfected with human urokinase sense and antisense genes. Cancer Res 50: 7623–7633, 1991

    Google Scholar 

  7. Achbarou A, Kaiser S, Tremblay G, Ste-Marie L, Brodt P, Glotzman D, Rabbani SA: Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo Cancer Res 54: 2372–2377, 1994

    Google Scholar 

  8. Hsu DW, Efird JT, Hedleywbyte ET: Prognostic role of urokinase-type plasminogen activator in human gliomas. Am J Pathol 147: 114–123, 1995

    Google Scholar 

  9. Duffy MJ: Proteases as prognostic markers in cancer. Clinic Cancer Res 2: 613–618, 1996

    Google Scholar 

  10. Kruithof EK: Plasminogen activator inhibitors – a review. Enzyme 40: 113–121, 1988

    Google Scholar 

  11. Pappot H, Gardsvoll H, Romer J, Navrsted Pedersen A, Grondahl-Hansen J, Pyke C, Bruenner N: Plasminogen activator inhibitor type 1 in cancer: therapeutic and prognostic implications. Biol. Chem. Hoppe-Seyler, 376: 259–267, 1995

    Google Scholar 

  12. Ossowski L, Reich B: Antibodies to plasminogen activator inhibit human tumor metastasis. Cell 35: 611–619, 1983

    Google Scholar 

  13. Cajot JF, Bamat J, Bergonzelli GE: Plasminogen-activator inhibitor type 1 is potent natural inhibitor of extracellular matrix degradation by fibrosarcoma and colon carcinoma cells. Proc Natl Acad Sci USA 87: 6939–6943, 1990

    Google Scholar 

  14. Montgomery AMP, De Clerck YA, Langley KE, Reisfeld RA, Mueller BM: Melanoma-mediated dissolution of extracellular matrix: contribution of urokinase-dependent and metalloproteinase-dependent proteolytic pathways. Cancer Res 53: 693–700, 1993

    Google Scholar 

  15. Scanlon KJ, Kashani-Sabet M, Tone T, Funato T: Cisplatin resistance in human cancers. Pharm Ther 52: 385–406, 1991

    Google Scholar 

  16. Calsou P, Salles B: Role of DNA repair in the mechanisms of cell resistance to alkylating agents and cisplatin. Cancer Chemother Pharmacol 32: 85–89, 1993

    Google Scholar 

  17. Gately DP, Howell SB: Cellular accumulation of the anticancer agent cisplatin: a review. Br J Cancer 67: 1171–1179, 1993

    Google Scholar 

  18. Andrews PA: Mechanisms of aquired resistance to cisplatin. In: Goldstien LJ, Ozols RF (eds) Anticancer Drug Resistance: Advances in Molecular and Clinical Research. KIuwer Academic Publishers, Norwell, 1994, pp 217–247

    Google Scholar 

  19. Fink D, Zheng H, Nebel S, Norris PS, Aebi S, Lin TP, Nehme A, Chirsten RD, Haas M, MacLeod CL, Howell SB: In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer Res 57: 1841–1845, 1997

    Google Scholar 

  20. Weller M, Malipiero U, Aguzzi A, Reed JC, Fontana A: Protooncogene bcl-2 gene transfer aborgates FAS/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic radiation. J Clin Invest 6: 2633–2643, 1995

    Google Scholar 

  21. Nagane M, Levitzki A, Gazit, A, Cavenee WK, Huang HJS: Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of bcl-x-1-and caspase-3-like proteases. Proc Natl Acad Sci USA 95: 5724–5729, 1998

    Google Scholar 

  22. Dorige O, Turla ST, Lebedeva S, Gjerset RA: Sensitisation of rat glioblastoma multiforme to cisplatin in vivo following restoration of wild-type p53 function. J Neurosurg 88: 535–540, 1998

    Google Scholar 

  23. Osmak M: Molecular alterations induced in drug-resistant cells. Radiol Oncol 32: 19–33, 1998

    Google Scholar 

  24. Osmak M, Nikšić, Brozović A, Vrhovec I, Škrk J: Molecular alterations induced in drug resistant cells. Period Biol 100(Supp 1): 48–49, 1998

    Google Scholar 

  25. Osmak M, Miljanić S, Kapitanović S: Low doses of γ-rays can induce the expression of mdr gene. Mutat Res 324: 35–41, 1994

    Google Scholar 

  26. Bradford MM: A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254, 1976

    Google Scholar 

  27. Osmak M, Eljuga D: The characterization of two human cervical carcinoma HeLa sublines resistant to cisplatin. Res Exptl Med 193: 389–396

  28. Beketić-Orešković L, Osmak M: Human larynx carcinoma cells resistant to cis-diamminedichloroplatinum(II): Crossresistance patterns. Neoplasma 41: 171–76, 1994

    Google Scholar 

  29. Dano K, Dabelsteen E, Nielsen LS, Kaltoft K, Wilson EL, Zeuthen J: Plasminogen activating enzyme in cultured glioblastoma cells. J Histochem Cytochem 30: 1165–1170, 1982

    Google Scholar 

  30. Gross JL Behrens DL, Mullins DE, Kornblith PL, Dexter DL: Plasminogen activator and inhibitor activity in human glioma cells and modulation by sodium butyrate. Cancer Res 48: 291–296, 1988

    Google Scholar 

  31. Rao JS, Steck PA, Mohanam S, Stetler-Stevenson WG, Liotta LA, Sawaya R: Elevated levels of Mr 92000 type IV collagenase in human brain tumors. Cancer Res 53: 2208–2211, 1993

    Google Scholar 

  32. Sivaparvathi M, Sawaya R, Wang SW, Rayford A, Yamamoto M, Liotta LA, Nicolson GL, Rao JS: Overexpression and localisation of cathepsin B during the progression of human glioblastomas. Clin Exp Metastasis 13: 49–56, 1995

    Google Scholar 

  33. Sivaparvathi M, Sawaya R, Chintala SK, Go Y, Gokaslan ZL, Rao JS: Expression of cathepsin D during the progression of human gliomas. Neurosci Letters 208: 171–174, 1996

    Google Scholar 

  34. Quax PHA, Van Leeuwen RTJ, Verspaget HW, Verheijen JH: Protein and messenger RNA levels of plasminogen activators and inhbitors analysed in 22 human tumor cell lines. Cancer Res 50: 1488–1494, 1990

    Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Genetics, Ruđer Bošković Institute, Zagreb, Croatia

    Maja Osmak

  2. Department of Radiobiology, Institute of Oncology, Ljubljana, Slovenia

    Ivan Vrhovec & Janez Škrk

Authors
  1. Maja Osmak
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  2. Ivan Vrhovec
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  3. Janez Škrk
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Osmak, M., Vrhovec, I. & Škrk, J. Cisplatin Resistant Glioblastoma Cells may have Increased Concentration of Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor Type 1. J Neurooncol 42, 95–102 (1999). https://doi.org/10.1023/A:1006125629887

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