Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 4, pp 699–706 | Cite as

Molecular predictors of human nervous system cancer responsiveness to enediyne chemotherapy

  • Danny Rogers
  • Karen D. Nylander
  • Zhiping Mi
  • Tong Hu
  • Nina F. Schor
Original Article

Abstract

Purpose

To identify and mathematically model molecular predictors of response to the enediyne chemotherapeutic agent, neocarzinostatin, in nervous system cancer cell lines.

Methods

Human neuroblastoma, breast cancer, glioma, and medulloblastoma cell lines were maintained in culture. Content of caspase-3 and Bcl-2, respectively, was determined relative to actin content for each cell line by Western blotting and optical densitometry. For each cell line, sensitivity to neocarzinostatin was determined. Brain tumor cell lines were stably transfected with human Bcl-2 cDNA cloned into the pcDNA3 plasmid vector.

Results

In human tumor cell lines of different tissue origins, sensitivity to neocarzinostatin is proportional to the product of the relative contents of Bcl-2 and caspase-3 (r 2 = 0.9; P < 0.01). Neuroblastoma and brain tumor cell lines are particularly sensitive to neocarzinostatin; the sensitivity of brain tumor lines to neocarzinostatin is enhanced by transfection with an expression construct for Bcl-2 and is proportional in transfected cells to the product of the relative contents of Bcl-2 and caspase-3 (r 2 = 0.7).

Conclusion

These studies underscore the potential of molecular profiling in identifying effective chemotherapeutic paradigms for cancer in general and tumors of the nervous system in particular.

Notes

Acknowledgments

The studies described were funded by grants to NFS from the National Cancer Institute (R01-CA074289) and the National Institute of Neurological Diseases and Stroke (R01-NS038569).

References

  1. 1.
    Bartholomeusz C, Itamochi H, Yuan LX et al (2005) Bcl-2 antisense oligonucleotide overcomes resistance to E1A gene therapy in a low HER2-expressing ovarian cancer xenograft model. Cancer Res 65:8406–8413PubMedCrossRefGoogle Scholar
  2. 2.
    Bush JA, Li G (2003) The role of Bcl-2 family members in the progression of cutaneous melanoma. Clin Exp Metastasis 20:531–539PubMedCrossRefGoogle Scholar
  3. 3.
    Del Principe MI, Del Poeta G, Maurillo L et al (2003) P-glycoprotein and BCL-2 levels predict outcome in adult acute lymphoblastic leukaemia. Br J Haematol 121:730–738PubMedCrossRefGoogle Scholar
  4. 4.
    Fennell DA (2003) Bcl-2 as a target for overcoming chemoresistance in small-cell lung cancer. Clin Lung Cancer 4:307–313PubMedCrossRefGoogle Scholar
  5. 5.
    Hopkins-Donaldson S, Cathomas R, Simoes-Wust AP et al (2003) Induction of apoptosis and chemosensitization of mesothelioma cells by Bcl-2 and Bcl-xL antisense treatment. Int J Cancer 106:160–166PubMedCrossRefGoogle Scholar
  6. 6.
    Real PJ, Sierra A, De Juan A et al (2002) Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene 21:7611–7618PubMedCrossRefGoogle Scholar
  7. 7.
    Zhu CJ, Li YB, Wong MC (2003) Expression of antisense bcl-2 cDNA abolishes tumorigenicity and enhances chemosensitivity of human malignant glioma cells. J Neurosci Res 74:60–66PubMedCrossRefGoogle Scholar
  8. 8.
    Cortazzo M, Schor NF (1996) Potentiation of enediyne-induced apoptosis and differentiation by Bcl-2. Cancer Res 56:1199–1203PubMedGoogle Scholar
  9. 9.
    Mi Z, Hong B, Mirnics ZK et al (2006) Bcl-2-mediated potentiation of neocarzinostatin-induced apoptosis: requirement for caspase-3, sulfhydryl groups, and cleavable Bcl-2. Cancer Chemother Pharmacol 57:357–367PubMedCrossRefGoogle Scholar
  10. 10.
    Schor NF, Tyurina YY, Fabisiak JP et al (1999) Selective oxidation and externalization of membrane phosphatidylserine: Bcl-2-induced potentiation of the final common pathway for apoptosis. Brain Res 831:125–130PubMedCrossRefGoogle Scholar
  11. 11.
    Schor NF, Rudin CM, Hartman AR et al (2000) Cell line dependence of Bcl-2-induced alteration of glutathione handling. Oncogene 19:472–476PubMedCrossRefGoogle Scholar
  12. 12.
    Kane DJ, Sarafian TA, Anton R et al (1993) Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science 262:1274–1277PubMedCrossRefGoogle Scholar
  13. 13.
    Liang Y, Nylander KD, Yan C et al (2002) Role of caspase 3-dependent Bcl-2 cleavage in potentiation of apoptosis by Bcl-2. Mol Pharmacol 61:142–149PubMedCrossRefGoogle Scholar
  14. 14.
    Hartsell TL, Yalowich JC, Ritke MK et al (1995) Induction of apoptosis in murine and human neuroblastoma cell lines by the enediyne natural product neocarzinostatin. J Pharmacol Exp Ther 275:479–485PubMedGoogle Scholar
  15. 15.
    Schor NF, Tyurina YY, Tyurin VA et al (1999) Differential membrane antioxidant effects of immediate and long-term estradiol treatment of MCF-7 breast cancer cells. Biochem Biophys Res Commun 260:410–415PubMedCrossRefGoogle Scholar
  16. 16.
    Tweddle DA, Malcolm AJ, Cole M, Pearson ADJ, Lunec J (2001) p53 cellular localization and function in neuroblastoma. Am J Pathol 158:2087–2077Google Scholar
  17. 17.
    Cerrato JA, Yung WK, Liu TJ (2001) Introduction of mutant p53 into a wild-type p53-expressing glioma cell line confers sensitivity to Ad-p53-induced apoptosis. Neuro Oncol 3:113–122PubMedGoogle Scholar
  18. 18.
    Castellino RC, De Bortoli M, Lu X et al (2007) Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D. J Neuro-oncol 86:245–256CrossRefGoogle Scholar
  19. 19.
    Ramnath V, Rekha PS, Kuttan G, Kuttan R (2007) Regulation of caspase-3 and Bcl-2 expression in Dalton’s lymphoma ascites cells by abrin. Evid-based Complement Alter Med (e-pub).  doi:10.1093/ecam/nem099
  20. 20.
    American Cancer Society (2007) What are the key statistics for brain and spinal cord tumors? http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_brain_and_spinal_cord_tumors_3.asp?sitearea=
  21. 21.
    Jenkin D, Greenberg M, Hoffman H et al (1995) Brain tumors in children: long-term survival after radiation treatment. Int J Radiat Oncol Biol Phys 31:445–451PubMedGoogle Scholar
  22. 22.
    Haase GM, Perez C, Atkinson JB (1999) Current aspects of biology, risk assessment, and treatment of neuroblastoma. Semin Surg Oncol 16:91–104PubMedCrossRefGoogle Scholar
  23. 23.
    Cotterill SJ, Pearson AD, Pritchard J et al (2000) Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group ‘Survey’ 1982–1992. Eur J Cancer 36:901–908PubMedCrossRefGoogle Scholar
  24. 24.
    Dole M, Nunez G, Merchant AK et al (1994) Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Cancer Res 54:3253–3259PubMedGoogle Scholar
  25. 25.
    Dole MG, Jasty R, Cooper MJ et al (1995) Bcl-xL is expressed in neuroblastoma cells and modulates chemotherapy-induced apoptosis. Cancer Res 55:2576–2582PubMedGoogle Scholar
  26. 26.
    Campos L, Rouault JP, Sabido O et al (1993) High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81:3091–3096PubMedGoogle Scholar
  27. 27.
    Nakasu S, Nakasu Y, Nioka H et al (1994) Bcl-2 protein expression in tumors of the central nervous system. Acta Neuropathol 88:520–526PubMedCrossRefGoogle Scholar
  28. 28.
    Teixeira C, Reed JC, Pratt MA (1995) Estrogen promotes chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human breast cancer cells. Cancer Res 55:3902–3907PubMedGoogle Scholar
  29. 29.
    Bonetti A, Zaninelli M, Pavanel F et al (1996) Bcl-2 expression is associated with resistance to chemotherapy in advanced breast cancer. Proc Am Assoc Cancer Res 37:192Google Scholar
  30. 30.
    Beham AW McDonnell TJ (1996) Bcl-2 confers resistance to androgen deprivation in prostate carcinoma cells. Proc Am Assoc Cancer Res 37:224Google Scholar
  31. 31.
    Tu Y, Renner S, Xu F et al (1998) BCL-X expression in multiple myeloma: possible indicator of chemoresistance. Cancer Res 58:256–262PubMedGoogle Scholar
  32. 32.
    van de Donk NW, de Weerdt O, Veth G et al (2004) G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma. Leukemia 18:1078–1084PubMedCrossRefGoogle Scholar
  33. 33.
    Williams J, Lucas PC, Griffith KA et al (2005) Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease. Gynec Oncol 96:287–295CrossRefGoogle Scholar
  34. 34.
    Ganigi PM, Santosh V, Anandh B et al (2005) Expression of p53, EGFR, pRb and bcl-2 proteins in pediatric glioblastoma multiforme: a study of 54 patients. Pediatr Neurosurg 41:292–299PubMedCrossRefGoogle Scholar
  35. 35.
    Albrecht H, Tschopp J, Jongeneel CV (1994) Bcl-2 protects from oxidative damage and apoptotic cell death without interfering with activation of NF-kappa B by TNF. FEBS Lett 351:45–48PubMedCrossRefGoogle Scholar
  36. 36.
    Tyurina YY, Tyurin VA, Carta G et al (1997) Direct evidence for antioxidant effect of Bcl-2 in PC12 rat pheochromocytoma cells. Arch Biochem Biophys 344:413–423PubMedCrossRefGoogle Scholar
  37. 37.
    Liang Y, Mirnics ZK, Yan C et al (2003) Bcl-2 mediates induction of neural differentiation. Oncogene 22:5515–5518PubMedCrossRefGoogle Scholar
  38. 38.
    Friesen C, Kiess Y, Debatin KM (2004) A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells. Cell Death Differ 11(Suppl 1):S73–85PubMedCrossRefGoogle Scholar
  39. 39.
    Chen Q, Chai YC, Mazumder S et al (2003) The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. Cell Death Differ 10:323–334PubMedCrossRefGoogle Scholar
  40. 40.
    Tyurina YY, Nylander KD, Mirnics ZK et al (2005) The intracellular domain of p75NTR as a determinant of cellular reducing potential and response to oxidant stress. Aging Cell 4:187–196PubMedCrossRefGoogle Scholar
  41. 41.
    Yang J, Liu X, Bhalla K et al (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275:1129–1132PubMedCrossRefGoogle Scholar
  42. 42.
    Kluck RM, Bossy-Wetzel E, Green DR et al (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136PubMedCrossRefGoogle Scholar
  43. 43.
    Baker A, Santos BD, Powis G (2000) Redox control of caspase-3 activity by thioredoxin and other reduced proteins. Biochem Biophys Res Commun 268:78–81PubMedCrossRefGoogle Scholar
  44. 44.
    Hartsell TL, Hinman LM, Hamann PR et al (1996) Determinants of the response of neuroblastoma cells to DNA damage: the roles of pre-treatment cell morphology and chemical nature of the damage. J Pharmacol Exp Ther 277:1158–1166PubMedGoogle Scholar
  45. 45.
    Beerman TA, Poon R, Goldberg IH (1977) Single-strand nicking of DNA in vitro by neocarzinostatin and its possible relationship to the mechanism of drug action. Biochim Biophys Acta 475:294–306PubMedGoogle Scholar
  46. 46.
    DeGraff WG, Mitchell JB (1985) Glutathione dependence of neocarzinostatin cytotoxicity and mutagenicity in Chinese hamster V-79 cells. Cancer Res 45:4760–4762PubMedGoogle Scholar
  47. 47.
    Schor NF (1992) Targeted enhancement of the biological activity of the antineoplastic agent, neocarzinostatin. Studies in murine neuroblastoma cells. J Clin Invest 89:774–781PubMedCrossRefGoogle Scholar
  48. 48.
    Samali A, Zhivotovsky B, Jones DP et al (1998) Detection of pro-caspase-3 in cytosol and mitochondria of various tissues. FEBS Lett 431:167–169PubMedCrossRefGoogle Scholar
  49. 49.
    Liang Y, Yan C, Schor NF (2001) Apoptosis in the absence of caspase 3. Oncogene 20:6570–6578PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Danny Rogers
    • 1
  • Karen D. Nylander
    • 2
  • Zhiping Mi
    • 1
  • Tong Hu
    • 1
  • Nina F. Schor
    • 1
    • 3
  1. 1.Departments of Pediatrics, Neurology & Neurobiology and AnatomyUniversity of Rochester Medical CenterRochesterUSA
  2. 2.Pediatric Center for NeuroscienceChildren’s Hospital of PittsburghPittsburghUSA
  3. 3.Department of PediatricsUniversity of Rochester Medical Center, Golisano Children’s Hospital at StrongRochesterUSA

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