Dokument

Zusammenfassung:
Das Schilddrüsenkarzinom ist die häufigste maligne Erkrankung der endokrinen Organsysteme. Während für gut differenzierte Schilddrüsenkarzinome wie das papilläre und follikuläre Karzinom sehr gute Therapieoptionen existieren, die ein 10-Jahresüberleben von bis zu 98 % ermöglichen, versagen diese bei anaplastischen Karzinomen. Das anaplastische Karzinom entspricht dem komplett entdifferenzierten Histiotyp und zählt zu den aggressivsten humanen Karzinomen mit einer Überlebenszeit von wenigen Monaten nach Diagnosestellung. Das Versagen konventioneller Behandlungsansätze erfordert neue innovative Therapiemöglichkeiten. Ein neuer Ansatz der antitumoralen Therapie ist der zielgerichtete Angriff des Ubiquitin-Proteasom Signalwegs durch Pro-teasominhibitoren. In der vorliegenden Arbeit wurde die Wirksamkeit von Bortezomib (PS-341, Velcade®), der erste Proteasominhibitor, der eine klinische Zulassung erreichte, anhand verschiedener Histiotypen des Schilddrüsenkarzinoms in vitro evaluiert. An drei anaplastischen (Hth74, C643, Kat4), einer follikulären (FTC133) und einer papillären (TPC1) Schilddrüsenzelllinie wurden die durch Bortezomibbehandlung in-duzierten antiproliferativen, proapoptotischen und transkriptionalen Effekte in vitro untersucht. Bortezomib inhibierte die Zellproliferation mit IC50-Werten zwischen 4 nM und 12 nM, steigerte die Aktivität der Caspase-3 und induzierte einen Zellzyklusarrest. Die NFkB- Aktivität wurde hingegen verschieden beeinflusst. Durch die vorliegende systematische in vitro Analyse von Bortezomib an den auf-geführten Histiotypen des Schilddrüsenkarzinoms, konnte aufgezeigt werden, dass Bortezomib effektiv in der Behandlung von anaplastischen Schilddrüsenkarzinom-zellen ist. Dies konnte durch eine signifikante Reduktion des Zellwachstums sowie der Apoptoseinduktion verdeutlicht werden. Die Beeinflussung nuklearer Transkription hin-gegen bleibt kontrovers. Bortezomib wird bereits als Erstlinientherapie des Multiplen Myeloms eingesetzt und wurde in verschiedenen präklinischen und klinischen Studien an anderen soliden Tumorentitäten getestet. Die in der vorliegenden Arbeit nachgewiesenen in vitro Effekte von Bortezomib, insbesondere an drei anaplastischen Zelllinien, rechtfertigen eine klinische Evaluation der Bortezomibbehandlung beim anaplastischen Schilddrüsenkarzinom und zeigen, dass diese neue Therapieoption durchaus auch für das anaplastische Schilddrüsenkarzinom vielversprechend sein könnte.

Bibliographie / References

1. Maki, C. G., Huibregtse, J. M., & Howley, P. M. (1996). In vivo ubiquitination and proteasome-mediated degradation of p53(1). Cancer research, 56(11), 2649–54.
2. Tan, C., & Waldmann, T. A. (2002). Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia. Cancer research, 62(4), 1083–6.
3. Nawrocki, S. T., Carew, J. S., Pino, M. S., Highshaw, R. A., Dunner, K., Huang, P., Abbruzzes J. L., McConkey, D. J. (2005b). Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Cancer research, 65(24), 11658–66.
4. Yoshida, T., Shiraishi, T., Nakata, S., Horinaka, M., Wakada, M., Mizutani, Y., Miki T., Sakai, T. (2005). Proteasome inhibitor MG132 induces death receptor 5 through CCAAT/enhancer-binding protein homologous protein. Cancer research, 65(13), 5662–7.
5. Papandreou, C. N., Daliani, D. D., Nix, D., Yang, H., Madden, T., Wang, X., Pien C. S., Millikan R. E., Tu S. M., Pagliaro L., Kim J., Adams J., Elliot P., Esseltine D., Petrusich A., Dieringer P., Perez C., Logothetis, C. J. (2004). Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 22(11), 2108–21.
6. Ling, Y.-H., Liebes, L., Jiang, J.-D., Holland, J. F., Elliott, P. J., Adams, J., Muggia F.M., Perez-Soler, R. (2003). Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clinical cancer research : an official journal of the American Association for Cancer Research, 9(3), 1145–54.
7. Medema, R. H., & Bos, J. L. (1993). The role of p21ras in receptor tyrosine kinase signaling. Critical reviews in oncogenesis, 4(6), 615–61.
8. Kubbutat, M. H., Jones, S. N., & Vousden, K. H. (1997). Regulation of p53 stability by Mdm2. Nature, 387(6630), 299–303.
9. Quiros, R. M., Ding, H. G., Gattuso, P., Prinz, R. A., & Xu, X. (2005). Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer, 103(11), 2261–8.
10. Markovic, S. N., Geyer, S. M., Dawkins, F., Sharfman, W., Albertini, M., Maples, W., Fracasso P. M., Fitch T., Lorusso P., Adjei A. A., Erlichman, C. (2005). A phase II study of bortezomib in the treatment of metastatic malignant melanoma. Cancer, 103(12), 2584–9.
11. Wunderlich, A., Arndt, T., Fischer, M., Roth, S., Ramaswamy, A., Greene, B. H., Brendel C., Hintersseher U., Bartsch D. K., Hoffmann, S. (2011). Targeting the proteasome as a promising therapeutic strategy in thyroid cancer. Journal of surgical oncology, (September).
12. Bortezomib synergizes TRAIL-induced apoptosis in gastric cancer cells. Digestive diseases and sciences, 55(12), 3361–8.
13. Wunderlich, A., Roth, S., Ramaswamy, A., Greene, B. H., Brendel, C., Hinterseher, U., Bartsch D. K., Hoffmann, S. (2012). Combined inhibition of cellular pathways as a future therapeutic option in fatal anaplastic thyroid cancer. Endocrine.
14. Russo, S. M., Tepper, J. E., Baldwin, A. S., Liu, R., Adams, J., Elliott, P., & Cusack, J. C. (2001). Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB. International journal of radiation oncology, biology, physics, 50(1), 183–93.
15. Kondo, T., Ezzat, S., & Asa, S. L. (2006). Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nature reviews. Cancer, 6(4), 292–306.
16. MacLaren, A. P., Chapman, R. S., Wyllie, A. H., & Watson, C. J. (2001). p53- dependent apoptosis induced by proteasome inhibition in mammary epithelial cells. Cell death and differentiation, 8(3), 210–8.
17. Zhu, H., Zhang, L., Dong, F., Guo, W., Wu, S., Teraishi, F., Davis J. J., Chiao P. J., Fang, B. (2005b). Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. Oncogene, 24(31), 4993–9.
18. Pacifico, F., Mauro, C., Barone, C., Crescenzi, E., Mellone, S., Monaco, M., Chiappetta G., Terrazzano G., Liquoro D., Vito P., Consiglio E., Formisano S., Leonardi, A. (2004). Oncogenic and anti-apoptotic activity of NF-kappa B in human thyroid carcinomas. The Journal of biological chemistry, 279(52), 54610–9.
19. Ruschak, A. M., Slassi, M., Kay, L. E., & Schimmer, A. D. (2011). Novel Proteasome Inhibitors to Overcome Bortezomib Resistance. Journal of the National Cancer Institute, 1007–1017.
20. Johnson, T. L., Lloyd, R. V, Thompson, N. W., Beierwaltes, W. H., & Sisson, J. C. (1988). Prognostic implications of the tall cell variant of papillary thyroid carcinoma. The American journal of surgical pathology, 12(1), 22–7.
21. Jagannath, S, Barlogie, B., Berenson, J., Siegel, D., Irwin, D., Richardson, P. G., niesvizky R., Alexanian R., Limentani S.A., Alsina M., Adams J., Kauffman M., Esseltine D.L., Schenkein D.P., Anderson, K. C. (2004). A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. British journal of haematology, 127(2), 165–72.
22. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. British journal of haematology, 129(6), 776–83.
23. Shringarpure, R., Catley, L., Bhole, D., Burger, R., Podar, K., Tai, Y.-T., Kessler B., Galardy P., Ploegh H., Tassone P., Hideshima T., Mitsiades C., Munshi N. C., Cauhan D., Anderson, K. C. (2006). Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib. British journal of haematology, 134(2), 145–56.
24. Podar, K., Shringarpure, R., Tai, Y.-T., Simoncini, M., Sattler, M., Ishitsuka, K., Richardson P. G., Hideshima T., Chauhan D., Anderson, K. C. (2004). Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib. Cancer research, 64(20), 7500–6.
25. Lashinger, L. M., Zhu, K., Williams, S. A., Shrader, M., Dinney, C. P. N., & McConkey, D. J. (2005). Bortezomib abolishes tumor necrosis factor-related apoptosis-inducing ligand resistance via a p21-dependent mechanism in human bladder and prostate cancer cells. Cancer research, 65(11), 4902–8.
26. Nawrocki, S. T., Carew, J. S., Dunner, K., Boise, L. H., Chiao, P. J., Huang, P., Abbruzzes J. L., McConkey, D. J. (2005a). Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer research, 65(24), 11510–9.
27. Wang, Y., Rishi, A. K., Puliyappadamba, V. T., Sharma, S., Yang, H., Tarca, A., Dou Q. P., Lonardo F., Ruckdeschel J. C., Pass H. I., Wali, A. (2010). Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines. Cancer chemotherapy and pharmacology, 66(3), 455–66.
28. Hideshima, Teru, Ikeda, H., Chauhan, D., Okawa, Y., Raje, N., Podar, K., Mitsiades C., Munshi N.C., Richardson P.G., Carrasco R.D., Anderson, K. C. (2009). Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood, 114(5), 1046–52.
29. Kondagunta, G. V., Drucker, B., Schwartz, L., Bacik, J., Marion, S., Russo, P., Mazumdar M., Motzer, R. J. (2004). Phase II trial of bortezomib for patients with advanced renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 22(18), 3720–5.
30. Pellegriti, G., Scollo, C., Lumera, G., Regalbuto, C., Vigneri, R., & Belfiore, A. (2004). Clinical behavior and outcome of papillary thyroid cancers smaller than 1.5 cm in diameter: study of 299 cases. The Journal of clinical endocrinology and metabolism, 89(8), 3713–20.
31. Pacini, F., Schlumberger, M., Dralle, H., Elisei, R., Smit, J. W. A., & Wiersinga, W. (2006). European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. European journal of endocrinology / European Federation of Endocrine Societies, 154(6), 787–803.
32. Johnson, D., (2014). The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors. Endocrine-related cancer, March 1-45
33. Rusinek, D., Szpak-Ulczok, S., & Jarzab, B. (2011). Gene expression profile of human thyroid cancer in relation to its mutational status. Journal of molecular endocrinology, 47(3), R91–103.
34. Masdehors, P., Merle-Béral, H., Magdelénat, H., & Delic, J. (2000). Ubiquitin- proteasome system and increased sensitivity of B-CLL lymphocytes to apoptotic death activation. Leukemia & lymphoma, 38(5-6), 499–504.
35. Kim, T. (2012). Bortezomib induces G2-M arrest in human colon cancer cells through ROS-inducible phosphorylation of ATM-CHK1. International Journal of Oncology, 41(1), 76–82.
36. Qin, J.-Z., Ziffra, J., Stennett, L., Bodner, B., Bonish, B. K., Chaturvedi, V., Bennett F., Pollock P. M., trent J. M., Hendrix M. J., Rizzo P., Miele L., Nickoloff, B. J. (2005). Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer research, 65(14), 6282–93.
37. Rayet, B., & Gélinas, C. (1999). Aberrant rel/nfkb genes and activity in human cancer. Oncogene, 18(49), 6938–47.
38. Köhrle, J. (2004). Guard your master: thyroid hormone receptors protect their gland of origin from thyroid cancer. Endocrinology, 145(10), 4427–9.
39. Nickeleit, I., Zender, S., Sasse, F., Geffers, R., Brandes, G., Sörensen, I., Steinmetz H., Kubicka S., Carlomagno T., Menche D., Gütgemann I., Buer J., Gossler A., Manns M. P., Kalesse M., Frank R., Malek, N. P. (2008). Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition. Cancer cell, 14(1), 23–35.
40. Köhler, A., Cascio, P., Leggett, D. S., Woo, K. M., Goldberg, A. L., & Finley, D. (2001). The Axial Channel of the Proteasome Core Particle Is Gated by the Rpt2 ATPase and Controls Both Substrate Entry and Product Release. Molecular Cell, 7(6), 1143–1152.
41. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 28(34), 5101–9.
42. Mateos, M.-V., Richardson, P. G., Schlag, R., Khuageva, N. K., Dimopoulos, M. A., Shpilberg, O., Kropff M., Spicka I., Petrucci M.T., Palumbo A., Samoilova O. S., Dmoszynska A., Abdulkadryov K.M., Schots R., Jiang B., Esseltine D. L., liu K., Cakana A., van de Velde H., San Miguel, J. F. (2010). Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 28(13), 2259–66.
43. Voortman, J., Smit, E. F., Honeywell, R., Kuenen, B. C., Peters, G. J., van de Velde, H., & Giaccone, G. (2007). A parallel dose-escalation study of weekly and twice- weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 13(12), 3642– 51.
44. Richardson, P. G., Barlogie, B., Berenson, J., Singhal, S., Jagannath, S., Irwin, D., Rajkumar S. V., Srkalovic G., Alsina M., Alexanian R., Siegel D., Orlowski R. Z., Kuter D., Limentani S. A., Lee S., Hideshima T., Esseltine D. L., Kauffman M., Adams J., Schenkein D. P., Anderson, K. C. (2003a). A phase 2 study of bortezomib in relapsed, refractory myeloma. The New England journal of medicine, 348(26), 2609–17.
45. Mitsiades, C. S., Hayden, P., Kotoula, V., McMillin, D. W., McMullan, C., Negri, J., Delmore J.E., Poulaki V., Mitsiades, N. (2007). Bcl-2 overexpression in thyroid carcinoma cells increases sensitivity to Bcl-2 homology 3 domain inhibition. The Journal of clinical endocrinology and metabolism, 92(12), 4845–52.
46. Mitsiades, N., Mitsiades, C. S., Poulaki, V., Chauhan, D., Richardson, P. G., Hideshima, T., Munshi N., Treon S. P., Anderson, K. C. (2002). Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood, 99(11), 4079–86.
47. Yang, C. H., Gonzalez-Angulo, A. M., Reuben, J. M., Booser, D. J., Pusztai, L., Krishnamurthy, S., Esseltine D., Stec J., Broglio K. R., Islam R., Hortobagyi G. N.,Cristofanilli, M. (2006). Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 17(5), 813–7.
48. Xing, M. (2007). BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocrine reviews, 28(7), 742–62.
49. Williams, S., Pettaway, C., Song, R., Papandreou, C., Logothetis, C., & McConkey, D. J. (2003b). Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts. Molecular cancer therapeutics, 2(9), 835–43.
50. Wang, H.-Q., Du, Z.-X., Zhang, H.-Y., & Gao, D.-X. (2007). Different induction of GRP78 and CHOP as a predictor of sensitivity to proteasome inhibitors in thyroid cancer cells. Endocrinology, 148(7), 3258–70.
51. Peters, J. M., Franke, W. W., & Kleinschmidt, J. a. (1994). Distinct 19 S and 20 S subcomplexes of the 26 S proteasome and their distribution in the nucleus and the cytoplasm. The Journal of biological chemistry, 269(10), 7709–18.
52. Smith, D. M., Chang, S.-C., Park, S., Finley, D., Cheng, Y., & Goldberg, A. L. (2007). Docking of the proteasomal ATPases' carboxyl termini in the 20S proteasome's alpha ring opens the gate for substrate entry. Molecular cell, 27(5), 731–44.
53. Reiners, C., Geling, M., Luster, M., Farahati, J., & Mäder, U. (2005). Epidemiologie des Schilddrüsenkarzinoms. Der Onkologe, 11(1), 11–19.
54. Marques, A. R., Espadinha, C., Catarino, A. L., Moniz, S., Pereira, T., Sobrinho, L. G., & Leite, V. (2002). Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. The Journal of clinical endocrinology and metabolism, 87(8), 3947–52.
55. Landowski, T. H., Megli, C. J., Nullmeyer, K. D., Lynch, R. M., & Dorr, R. T. (2005). Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines. Cancer research, 65(9), 3828–36.
56. Zavrski, I., Jakob, C., Kaiser, M., Fleissner, C., Heider, U., & Sezer, O. (2007). Molecular and clinical aspects of proteasome inhibition in the treatment of cancer. Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer, 176, 165–76.
57. Oerlemans, R., Franke, N. E., Assaraf, Y. G., Cloos, J., van Zantwijk, I., Berkers, C. R., Scheffler G. L., Debipersad K., Vojtekova K., Lemos C., van der Heijden J. W., Ylstra B., Peters G. J., Kaspers G. L., Dijkmans B. A., Scheper R. J., Jansen, G. (2008). Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood, 112(6), 2489–99.
58. McCarthy, R. P., Wang, M., Jones, T. D., Strate, R. W., & Cheng, L. (2006). Molecular evidence for the same clonal origin of multifocal papillary thyroid carcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research, 12(8), 2414–8.
59. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood, 101(4), 1530–4.
60. Ricarte-Filho, J. C., Ryder, M., Chitale, D. A., Rivera, M., Heguy, A., Ladanyi, M., Janakiraman M., Solit D., Knauf J. A., Tuttle R. M., Ghossein R. A., Fagin, J. A. (2009). Mutational profile of advanced primary and metastatic radioactive iodine- refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer research, 69(11), 4885–93.
61. Karin, M., Cao, Y., Greten, F. R., & Li, Z.-W. (2002). NF-kappaB in cancer: from innocent bystander to major culprit. Nature reviews. Cancer, 2(4), 301–10.
62. Sunwoo, J. B., Chen, Z., Dong, G., Yeh, N., Crowl Bancroft, C., Sausville, E., Adams J., Elliott P., Van Waes, C. (2001). Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 7(5), 1419–28.
63. Oda, E., Ohki, R., Murasawa, H., Nemoto, J., Shibue, T., Yamashita, T., Tokino T., Taniquchi T., Tanaka, N. (2000). Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science (New York, N.Y.), 288(5468), 1053–8.
64. Loercher, A., Lee, T. L., Ricker, J. L., Howard, A., Geoghegen, J., Chen, Z., Sunwoo J.B., Sitcheran R., Chuang E.Y., Mitchell J.B., Baldwin A.S.,Van Waes, C. (2004). Nuclear factor-kappaB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer research, 64(18), 6511–23.
65. Ludwig, L., Kessler, H., Wagner, M., Hoang-Vu, C., Dralle, H., Adler, G., Böhm B.O., Schmid, R. M. (2001). Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation. Cancer research, 61(11), 4526–35.
66. Orlowski, R. Z., Voorhees, P. M., Garcia, R. A., Hall, M. D., Kudrik, F. J., Allred, T., Johri A. R., Jones P. E., Ivanova A., Van deventer H. W., Gabriel D. A., Shea T. C., Mitchell B. S., Adams J., Esseltine D. L., Trehu E. G., Green M., Lehman M. J., Natoli S., Collins J.M., Lindley C. M., Dees, E. C. (2005). Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood, 105(8), 3058–65.
67. Shah, M. H., Young, D., Kindler, H. L., Webb, I., Kleiber, B., Wright, J., & Grever, M. (2004). Phase II study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 10(18 Pt 1), 6111–8.
68. Iqbal, M., Chatterjee, S., Kauer, J. C., Mallamo, J. P., Messina, P. A., Reiboldt, A., & Siman, R. (1996). Potent α-ketocarbonyl and boronic ester derived inhibitors of proteasome. Bioorganic & Medicinal Chemistry Letters, 6(3), 287–290.
69. Proteasome inhibition: a new therapeutic strategy to cancer treatment. Cancer letters, 293(1), 15–22.
70. Saulle, E., Petronelli, A., Pasquini, L., Petrucci, E., Mariani, G., Biffoni, M., Ferretti G., Scambia G., Benedetti-Panici P., Cognetti F., Humphreys R., Peschle C., Testa, U. (2007). Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis. Apoptosis : an international journal on programmed cell death, 12(4), 635–55.
71. Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65(1), 55–63.
72. Ling, Y.-H., Liebes, L., Zou, Y., & Perez-Soler, R. (2003). Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. The Journal of biological chemistry, 278(36), 33714–23.
73. Poulaki, V., Mitsiades, C. S., Kotoula, V., Tseleni-Balafouta, S., Ashkenazi, A., Koutras, D. A., & Mitsiades, N. (2002). Regulation of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells. The American journal of pathology, 161(2), 643–54.
74. Karin, M., Yamamoto, Y., & Wang, Q. M. (2004). The IKK NF-kappa B system: a treasure trove for drug development. Nature reviews. Drug discovery, 3(1), 17–26.
75. Rivett, A. J. (1989). The multicatalytic proteinase. Multiple proteolytic activities. The Journal of biological chemistry, 264(21), 12215–9.
76. Zong, W. X., Edelstein, L. C., Chen, C., Bash, J., & Gélinas, C. (1999). The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis. Genes & development, 13(4), 382–7.
77. Voorhees, P. M., Dees, E. C., Neil, B. O., & Orlowski, R. Z. (2003). The Proteasome as a Target for Cancer Therapy The Proteasome as a Target for Cancer Therapy. Clinical Cancer Research, 6316–6325.
78. Pérez-Galán, P., Roué, G., Villamor, N., Montserrat, E., Campo, E., & Colomer, D. (2006). The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood, 107(1), 257–64.
79. Teicher, B. A., Ara, G., Herbst, R., Palombella, V. J., & Adams, J. (1999). The Proteasome Inhibitor PS-341 in Cancer Therapy. Clinical Cancer Research, 5(September), 2638–2645.
80. Shie N., Vescio R.A., Berenson, J. R. (2003). The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clinical cancer research : an official journal of the American Association for Cancer Research, 9(3), 1136–44.
81. Orlowski, R. Z., Eswara, J. R., Lafond-walker, A., Dang, C. V, Grever, M. R., & Orlowski, M. (1998). Tumor Growth Inhibition Induced in a Murine Model of Human Burkitt ' s Lymphoma by a Proteasome Inhibitor Tumor Growth Inhibition Induced in a Murine Model of Human Burkitt ' s Lymphoma by a Proteasome Inhibitor1. Cancer, 4342–4348.
82. Pickart, C. M., & Eddins, M. J. (2004). Ubiquitin: structures, functions, mechanisms. Biochimica et biophysica acta, 1695(1-3), 55–72.
83. Markovina, S., Callander, N. S., O'Connor, S. L., Kim, J., Werndli, J. E., Raschko, M., Leith C. P., Kahl B. S., Kim K., Miyamoto, S. (2008). Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells. Molecular cancer research : MCR, 6(8), 1356–64.
84. Richardson, P. G., Hideshima, T., & Anderson, K. C. (2003b). Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer control : journal of the Moffitt Cancer Center, 10(5), 361–9.
85. Németh, Z. H., Wong, H. R., Odoms, K., Deitch, E. A., Szabó, C., Vizi, E. S., & Haskó, G. (2004). Proteasome inhibitors induce inhibitory kappa B (I kappa B) kinase activation, I kappa B alpha degradation, and nuclear factor kappa B activation in HT-29 cells. Molecular pharmacology, 65(2), 342–9.
86. Shah, S. a, Potter, M. W., McDade, T. P., Ricciardi, R., Perugini, R. a, Elliott, P. J., Adams J., Callery, M. P. (2001). 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. Journal of cellular biochemistry, 82(1), 110–22.
87. Pallares, J., Martínez-Guitarte, J. L., Dolcet, X., Llobet, D., Rue, M., Palacios, J., Prat J., Matias-Guiu, X. (2004). Abnormalities in the NF-kappaB family and related proteins in endometrial carcinoma. The Journal of pathology, 204(5), 569–77.
88. Mitsiades, C. S., McMillin, D., Kotoula, V., Poulaki, V., McMullan, C., Negri, J., Fanourakis G., Tseleni-Balafouta S., Ain K. B., Mitsiades, N. (2006). Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro. The Journal of clinical endocrinology and metabolism, 91(10), 4013–21.
89. Pal, T., Vogl, F. D., Chappuis, P. O., Tsang, R., Brierley, J., Renard, H., Sanders K., Kantemiroff T., Bagha S., Goldgar D. E., Narod S. A., Foulkes, W. D. (2001). Increased risk for nonmedullary thyroid cancer in the first degree relatives of prevalent cases of nonmedullary thyroid cancer: a hospital-based study. The Journal of clinical endocrinology and metabolism, 86(11), 5307–12.
90. Richardson, P. G., Sonneveld, P., Schuster, M. W., Irwin, D., Stadtmauer, E. A., Facon, T., Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San- Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson, K. C. (2005). Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. The New England journal of medicine, 352(24), 2487–98.
91. U.S. Department of Health & Human Services. U.S. Food and Drug Administration United States Food and drug Administration Approval Summary: Bortezomib for the Treatment of Progressive Multiple Myeloma after One Prior Therapy (2006) [Internet] Zitiert am: 17.10.2013 URL: http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsan dtobacco/cder/ucm103300.pdf U.S. National Institutes of Health (2012) ClinicalTrials.gov [Internet] Zitiert am: 17.10.2012
92. Lopes, U. G., Erhardt, P., Yao, R., & Cooper, G. M. (1997). p53-dependent induction of apoptosis by proteasome inhibitors. The Journal of biological chemistry, 272(20), 12893–6
93. Zwickl, P. (1999). An Archaebacterial ATPase, Homologous to ATPases in the Eukaryotic 26 S Proteasome, Activates Protein Breakdown by 20 S Proteasomes. Journal of Biological Chemistry, 274(37), 26008–26014.
94. Schneider, A. B., & Sarne, D. H. (2005). Long-term risks for thyroid cancer and other neoplasms after exposure to radiation. Nature clinical practice. Endocrinology & metabolism, 1(2), 82–91.
95. Mujtaba, T., & Dou, Q. P. (2011). Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discovery medicine, 12(67), 471–80.
96. Apoptosis induction resulting from proteasome inhibition. The Biochemical journal, 317 ( Pt 2, 385–8.
97. Mitsiades, N., Mitsiades, C. S., Poulaki, V., Chauhan, D., Fanourakis, G., Gu, X., Bailey C., Joseph M., Libermann T.A., Treon S.P., MUnshi N. C., Richardson P. G., Hideshima T., Anderson, K. C. (2002). Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proceedings of the National Academy of Sciences of the United States of America, 99(22), 14374–9.
98. Zhu, H., Guo, W., Zhang, L., Wu, S., Teraishi, F., Davis, J. J., Dong F., Fang, B. (2005a). Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. Cancer biology & therapy, 4(7), 781–6.
99. Li, B., & Dou, Q. P. (2000). Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. Proceedings of the National Academy of Sciences of the United States of America, 97(8), 3850–5.
100. Obeng, E. A., Carlson, L. M., Gutman, D. M., Harrington, W. J., Lee, K. P., & Boise, L. H. (2006). Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood, 107(12), 4907–16.
101. Sherman, S. I. (2003). Thyroid carcinoma. Lancet, 361(9356), 501–11.
102. Nikiforov, M. A., Riblett, M., Tang, W.-H., Gratchouck, V., Zhuang, D., Fernandez, Y., Verhaegen M., Varambally S., Chinnaiyan A. M., Jakubowiak A. J., Soengas, M. S. (2007). Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proceedings of the National Academy of Sciences of the United States of America, 104(49), 19488–93.
103. Willis, M. S., Townley-Tilson, W. H. D., Kang, E. Y., Homeister, J. W., & Patterson, C. (2010). Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. Circulation research, 106(3), 463–78.
104. Seki, N., Toh, U., Sayers, T. J., Fujii, T., Miyagi, M., Akagi, Y., Kusukawa J., Kage M., Shirouzu K., Yamana, H. (2010). Bortezomib sensitizes human esophageal squamous cell carcinoma cells to TRAIL-mediated apoptosis via activation of both extrinsic and intrinsic apoptosis pathways. Molecular cancer therapeutics, 9(6), 1842–51.
105. Saeki, Y., & Tanaka, K. (2012). Assembly and function of the proteasome. Methods in molecular biology (Clifton, N.J.), 832, 315–37.
106. Kumar, S. K., Flinn, I., Noga, S. J., Hari, P., Rifkin, R., Callander, N., Bhandari M., Wolf J.L., Gasparetto C., Krishnan A., Grosman D., Glass J., Sahovic E.A., Shi H., Webb I.J., Richardson P.G., Rajkumar, S. V. (2010). Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 24(7), 1350–6.
107. Smith, A. J., Dai, H., Correia, C., Takahashi, R., Lee, S.-H., Schmitz, I., & Kaufmann, S. H. (2011). Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells. The Journal of biological chemistry, 286(20), 17682–92.
108. Hock, A. K., Vigneron, A. M., Carter, S., Ludwig, R. L., & Vousden, K. H. (2011). Regulation of p53 stability and function by the deubiquitinating enzyme USP42. The EMBO journal, 30(24), 4921–30.
109. Tsuruta, F., Sunayama, J., Mori, Y., Hattori, S., Shimizu, S., Tsujimoto, Y., Yoshioka K., Masuyama N., Gotoh, Y. (2004). JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. The EMBO journal, 23(8), 1889–99.
110. Towbin, H., Staehelin, T., & Gordon, J. (1992). Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. 1979. Biotechnology (Reading, Mass.), 24(9), 145–9.
111. Wu, X., & Levine, A. J. (1994). p53 and E2F-1 cooperate to mediate apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 91(9), 3602–6.
112. Kuerbitz, S. J., Plunkett, B. S., Walsh, W. V, & Kastan, M. B. (1992). Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proceedings of the National Academy of Sciences of the United States of America, 89(16), 7491–5.
113. Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling. Cancer science, 95(2), 176– 80.
114. Kisselev, a F., & Goldberg, a L. (2001). Proteasome inhibitors: from research tools to drug candidates. Chemistry & biology, 8(8), 739–58.
115. Yoshiba, S., Iwase, S., Kurihara, S., Satorou, S., (2011) Proteasome inhibitor sensitizes oral squamous cell carcinoma cells to TRAIL-mediated apoptosis. Oncology reports, 25 (3), 645-52
116. Stenner, F., Liewen, H., Zweifel, M., Weber, A., Tchinda, J., Bode, B., Saamaras P., Bauer S., Knuth A., Renner, C. (2008). Targeted therapeutic approach for an anaplastic thyroid cancer in vitro and in vivo. Cancer science, 99(9), 1847–52.

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