This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Olie, R. A. Articles by Zangemeister-Wittke, U. Search for Related Content PubMed PubMed Citation Articles by Olie, R. A. Articles by Zangemeister-Wittke, U.

A Novel Antisense Oligonucleotide Targeting Survivin Expression Induces Apoptosis and Sensitizes Lung Cancer Cells to Chemotherapy¹

Division of Oncology, Department of Internal Medicine, University Hospital Zürich, CH-8044 Zürich [R. A. O., A. P. S-W., S. H. L., R. A. S., U. Z-W.]; Institute of Biochemistry, Swiss Federal Institute of Technology, CH-8092 Zürich [B. B.]; and Department of Oncology Research, Novartis Pharma AG, CH-4002 Basel [D. F.], Switzerland

Survivin, an inhibitor of apoptosis protein, deserves attention as a selective target for cancer therapy because it lacks expression in differentiated adult tissues but is expressed in a variety of human tumors. We designed 20-mer phosphorothioate antisense oligonucleotides targeting different regions of survivin mRNA and investigated their ability to down-regulate survivin mRNA and induce apoptosis in the lung adenocarcinoma cell line A549. Oligonucleotide 4003, which targets nucleotides 232–251 of survivin mRNA, was identified as the most potent compound. As measured by real-time PCR, 4003 down-regulated survivin mRNA in a dose-dependent manner with an IC₅₀ of 200 nM. Its maximum effect was achieved at a concentration of 400 nM, at which mRNA was down-regulated by 70%. As revealed by increased caspase-3-like protease activity, nuclear condensation and fragmentation, and trypan blue uptake, treatment with 4003 induced apoptosis and sensitized tumor cells to the chemotherapeutic agent etoposide. Oligonucleotide 4003 did not reduce the viability of normal blood leukocytes with marginal levels of survivin mRNA.

This article has been cited by other articles:

				H. Roca, Z. Varsos, and K. J. Pienta CCL2 Protects Prostate Cancer PC3 Cells from Autophagic Death via Phosphatidylinositol 3-Kinase/AKT-dependent Survivin Up-regulation J. Biol. Chem., September 5, 2008; 283(36): 25057 - 25073. [Abstract] [Full Text] [PDF]

				J. J. Virrey, S. Guan, W. Li, A. H. Schonthal, T. C. Chen, and F. M. Hofman Increased Survivin Expression Confers Chemoresistance to Tumor-Associated Endothelial Cells Am. J. Pathol., August 1, 2008; 173(2): 575 - 585. [Abstract] [Full Text] [PDF]

				X.-F. Wang, J. Kerzerho, O. Adotevi, H. Nuyttens, C. Badoual, G. Munier, S. Oudard, S. Tu, E. Tartour, and B. Maillere Comprehensive Analysis of HLA-DR- and HLA-DP4-Restricted CD4+ T Cell Response Specific for the Tumor-Shared Antigen Survivin in Healthy Donors and Cancer Patients J. Immunol., July 1, 2008; 181(1): 431 - 439. [Abstract] [Full Text] [PDF]

				H. Hu, Y. Shikama, I. Matsuoka, and J. Kimura Terminally differentiated neutrophils predominantly express Survivin-2{alpha}, a dominant-negative isoform of Survivin J. Leukoc. Biol., February 1, 2008; 83(2): 393 - 400. [Abstract] [Full Text] [PDF]

				N. Kindt, A. Menzebach, M. Van de Wouwer, I. Betz, A. De Vriese, and E. M. Conway Protective role of the inhibitor of apoptosis protein, survivin, in toxin-induced acute renal failure FASEB J, February 1, 2008; 22(2): 510 - 521. [Abstract] [Full Text] [PDF]

				Q. Jin, L. Feng, C. Behrens, B. N. Bekele, I. I. Wistuba, W.-K. Hong, and H.-Y. Lee Implication of AMP-Activated Protein Kinase and Akt-Regulated Survivin in Lung Cancer Chemopreventive Activities of Deguelin Cancer Res., December 15, 2007; 67(24): 11630 - 11639. [Abstract] [Full Text] [PDF]

				M. H. Andersen, I. M. Svane, J. C. Becker, and P. t. Straten The Universal Character of the Tumor-Associated Antigen Survivin Clin. Cancer Res., October 15, 2007; 13(20): 5991 - 5994. [Abstract] [Full Text] [PDF]

				M. Grube, S. Moritz, E. C. Obermann, K. Rezvani, A. Mackensen, R. Andreesen, and E. Holler CD8+ T cells Reactive to Survivin Antigen in Patients with Multiple Myeloma Clin. Cancer Res., February 1, 2007; 13(3): 1053 - 1060. [Abstract] [Full Text] [PDF]

				A. Charalambous, M. Oks, G. Nchinda, S. Yamazaki, and R. M. Steinman Dendritic Cell Targeting of Survivin Protein in a Xenogeneic Form Elicits Strong CD4+ T Cell Immunity to Mouse Survivin J. Immunol., December 15, 2006; 177(12): 8410 - 8421. [Abstract] [Full Text] [PDF]

				X.-F. Che, C.-L. Zheng, S. Owatari, M. Mutoh, T. Gotanda, H.-C. Jeung, T. Furukawa, R. Ikeda, M. Yamamoto, M. Haraguchi, et al. Overexpression of survivin in primary ATL cells and sodium arsenite induces apoptosis by down-regulating survivin expression in ATL cell lines Blood, June 15, 2006; 107(12): 4880 - 4887. [Abstract] [Full Text] [PDF]

				H. Kojima, M. Iida, Y. Yaguchi, R. Suzuki, N. Hayashi, H. Moriyama, and Y. Manome Enhancement of Cisplatin sensitivity in squamous cell carcinoma of the head and neck transfected with a survivin antisense gene. Arch Otolaryngol Head Neck Surg, June 1, 2006; 132(6): 682 - 685. [Abstract] [Full Text] [PDF]

				N. Zhu, L. Gu, H. W. Findley, C. Chen, J.-T. Dong, L. Yang, and M. Zhou KLF5 Interacts with p53 in Regulating Survivin Expression in Acute Lymphoblastic Leukemia J. Biol. Chem., May 26, 2006; 281(21): 14711 - 14718. [Abstract] [Full Text] [PDF]

				B. Z. Carter, D. H. Mak, W. D. Schober, M. Cabreira-Hansen, M. Beran, T. McQueen, W. Chen, and M. Andreeff Regulation of survivin expression through Bcr-Abl/MAPK cascade: targeting survivin overcomes imatinib resistance and increases imatinib sensitivity in imatinib-responsive CML cells Blood, February 15, 2006; 107(4): 1555 - 1563. [Abstract] [Full Text] [PDF]

				F. Paduano, R. Villa, M. Pennati, M. Folini, M. Binda, M. G. Daidone, and N. Zaffaroni Silencing of survivin gene by small interfering RNAs produces supra-additive growth suppression in combination with 17-allylamino-17-demethoxygeldanamycin in human prostate cancer cells Mol. Cancer Ther., January 1, 2006; 5(1): 179 - 186. [Abstract] [Full Text] [PDF]

				Z. Wang, J. Sampath, S. Fukuda, and L. M. Pelus Disruption of the Inhibitor of Apoptosis Protein Survivin Sensitizes Bcr-abl-Positive Cells to STI571-Induced Apoptosis Cancer Res., September 15, 2005; 65(18): 8224 - 8232. [Abstract] [Full Text] [PDF]

				Y. Jiang, A. de Bruin, H. Caldas, J. Fangusaro, J. Hayes, E. M. Conway, M. L. Robinson, and R. A. Altura Essential Role for Survivin in Early Brain Development J. Neurosci., July 27, 2005; 25(30): 6962 - 6970. [Abstract] [Full Text] [PDF]

				D. A. Fennell Caspase Regulation in Non-Small Cell Lung Cancer and its Potential for Therapeutic Exploitation Clin. Cancer Res., March 15, 2005; 11(6): 2097 - 2105. [Abstract] [Full Text] [PDF]

				J. Wu, X. Ling, D. Pan, P. Apontes, L. Song, P. Liang, D. C. Altieri, T. Beerman, and F. Li Molecular Mechanism of Inhibition of Survivin Transcription by the GC-rich Sequence-selective DNA Binding Antitumor Agent, Hedamycin: EVIDENCE OF SURVIVIN DOWN-REGULATION ASSOCIATED WITH DRUG SENSITIVITY J. Biol. Chem., March 11, 2005; 280(10): 9745 - 9751. [Abstract] [Full Text] [PDF]

				P.-C. Kuo, H.-F. Liu, and J.-I Chao Survivin and p53 Modulate Quercetin-induced Cell Growth Inhibition and Apoptosis in Human Lung Carcinoma Cells J. Biol. Chem., December 31, 2004; 279(53): 55875 - 55885. [Abstract] [Full Text] [PDF]

				M. E. Johnson and E. W. Howerth Survivin: A Bifunctional Inhibitor of Apoptosis Protein Vet. Pathol., November 1, 2004; 41(6): 599 - 607. [Abstract] [Full Text] [PDF]

				A. D. Schimmer Inhibitor of Apoptosis Proteins: Translating Basic Knowledge into Clinical Practice Cancer Res., October 15, 2004; 64(20): 7183 - 7190. [Abstract] [Full Text] [PDF]

				M. Pennati, M. Binda, M. De Cesare, G. Pratesi, M. Folini, L. Citti, M. G. Daidone, F. Zunino, and N. Zaffaroni Ribozyme-mediated down-regulation of survivin expression sensitizes human melanoma cells to topotecan in vitro and in vivo Carcinogenesis, July 1, 2004; 25(7): 1129 - 1136. [Abstract] [Full Text] [PDF]

				F. Altznauer, S. Martinelli, S. Yousefi, C. Thurig, I. Schmid, E. M. Conway, M. H. Schoni, P. Vogt, C. Mueller, M. F. Fey, et al. Inflammation-associated Cell Cycle-independent Block of Apoptosis by Survivin in Terminally Differentiated Neutrophils J. Exp. Med., May 17, 2004; 199(10): 1343 - 1354. [Abstract] [Full Text] [PDF]

				M. B. Einarson, E. Cukierman, D. A. Compton, and E. A. Golemis Human Enhancer of Invasion-Cluster, a Coiled-Coil Protein Required for Passage through Mitosis Mol. Cell. Biol., May 1, 2004; 24(9): 3957 - 3971. [Abstract] [Full Text] [PDF]

				X. Ling, R. J. Bernacki, M. G. Brattain, and F. Li Induction of Survivin Expression by Taxol (Paclitaxel) Is an Early Event, Which Is Independent of Taxol-mediated G2/M Arrest J. Biol. Chem., April 9, 2004; 279(15): 15196 - 15203. [Abstract] [Full Text] [PDF]

				L. V. July, E. Beraldi, A. So, L. Fazli, K. Evans, J. C. English, and M. E. Gleave Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo Mol. Cancer Ther., March 1, 2004; 3(3): 223 - 232. [Abstract] [Full Text]

				Z. Song, S. Liu, H. He, N. Hoti, Y. Wang, S. Feng, and M. Wu A Single Amino Acid Change (Asp 53-> Ala53) Converts Survivin from Anti-apoptotic to Pro-apoptotic Mol. Biol. Cell, March 1, 2004; 15(3): 1287 - 1296. [Abstract] [Full Text] [PDF]

				A. Martinez, B. Bellosillo, F. Bosch, A. Ferrer, S. Marce, N. Villamor, G. Ott, E. Montserrat, E. Campo, and D. Colomer Nuclear Survivin Expression in Mantle Cell Lymphoma Is Associated with Cell Proliferation and Survival Am. J. Pathol., February 1, 2004; 164(2): 501 - 510. [Abstract] [Full Text] [PDF]

				N. C. Kirkiles-Smith, K. Mahboubi, J. Plescia, J. M. McNiff, J. Karras, J. S. Schechner, D. C. Altieri, and J. S. Pober IL-11 Protects Human Microvascular Endothelium from Alloinjury In Vivo by Induction of Survivin Expression J. Immunol., February 1, 2004; 172(3): 1391 - 1396. [Abstract] [Full Text] [PDF]

				Z.-X. Xu, R.-X. Zhao, T. Ding, T. T. Tran, W. Zhang, P. P. Pandolfi, and K.-S. Chang Promyelocytic Leukemia Protein 4 Induces Apoptosis by Inhibition of Survivin Expression J. Biol. Chem., January 16, 2004; 279(3): 1838 - 1844. [Abstract] [Full Text] [PDF]

				S. Fulda and K.-M. Debatin Sensitization for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by the Chemopreventive Agent Resveratrol Cancer Res., January 1, 2004; 64(1): 337 - 346. [Abstract] [Full Text] [PDF]

				S. Fukuda, C. R. Mantel, and L. M. Pelus Survivin regulates hematopoietic progenitor cell proliferation through p21WAF1/Cip1-dependent and -independent pathways Blood, January 1, 2004; 103(1): 120 - 127. [Abstract] [Full Text] [PDF]

				M. Fornaro, J. Plescia, S. Chheang, G. Tallini, Y.-M. Zhu, M. King, D. C. Altieri, and L. R. Languino Fibronectin Protects Prostate Cancer Cells from Tumor Necrosis Factor-{alpha}-induced Apoptosis via the AKT/Survivin Pathway J. Biol. Chem., December 12, 2003; 278(50): 50402 - 50411. [Abstract] [Full Text] [PDF]

				B. Z. Carter, S. M. Kornblau, T. Tsao, R.-Y. Wang, W. D. Schober, M. Milella, H.-G. Sung, J. C. Reed, and M. Andreeff Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis Blood, December 1, 2003; 102(12): 4179 - 4186. [Abstract] [Full Text] [PDF]

				S. P. Tu, X. H. Jiang, M. C. M. Lin, J. T. Cui, Y. Yang, C. T. Lum, B. Zou, Y. B. Zhu, S. H. Jiang, W. M. Wong, et al. Suppression of Survivin Expression Inhibits in Vivo Tumorigenicity and Angiogenesis in Gastric Cancer Cancer Res., November 15, 2003; 63(22): 7724 - 7732. [Abstract] [Full Text] [PDF]

				M. Kappler, M. Kotzsch, F. Bartel, S. Fussel, C. Lautenschlager, U. Schmidt, P. Wurl, M. Bache, H. Schmidt, H. Taubert, et al. Elevated Expression Level of Survivin Protein in Soft-Tissue Sarcomas Is a Strong Independent Predictor of Survival Clin. Cancer Res., March 1, 2003; 9(3): 1098 - 1104. [Abstract] [Full Text] [PDF]

				S. Wittmann, P. Bali, S. Donapaty, R. Nimmanapalli, F. Guo, H. Yamaguchi, M. Huang, R. Jove, H. G. Wang, and K. Bhalla Flavopiridol Down-Regulates Antiapoptotic Proteins and Sensitizes Human Breast Cancer Cells to Epothilone B-induced Apoptosis Cancer Res., January 1, 2003; 63(1): 93 - 99. [Abstract] [Full Text] [PDF]

				N. R. Wall, D. S. O'Connor, J. Plescia, Y. Pommier, and D. C. Altieri Suppression of Survivin Phosphorylation on Thr34 by Flavopiridol Enhances Tumor Cell Apoptosis Cancer Res., January 1, 2003; 63(1): 230 - 235. [Abstract] [Full Text] [PDF]

				M. Zhou, L. Gu, F. Li, Y. Zhu, W. G. Woods, and H. W. Findley DNA Damage Induces a Novel p53-Survivin Signaling Pathway Regulating Cell Cycle and Apoptosis in Acute Lymphoblastic Leukemia Cells J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 124 - 131. [Abstract] [Full Text] [PDF]

				S. Fukuda, R. G. Foster, S. B. Porter, and L. M. Pelus The antiapoptosis protein survivin is associated with cell cycle entry of normal cord blood CD34+ cells and modulates cell cycle and proliferation of mouse hematopoietic progenitor cells Blood, September 18, 2002; 100(7): 2463 - 2471. [Abstract] [Full Text] [PDF]

				C. Xia, Z. Xu, X. Yuan, K. Uematsu, L. You, K. Li, L. Li, F. McCormick, and D. M. Jablons Induction of Apoptosis in Mesothelioma Cells by Antisurvivin Oligonucleotides Mol. Cancer Ther., July 1, 2002; 1(9): 687 - 694. [Abstract] [Full Text] [PDF]

				C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone Apoptosis: Target of Cancer Therapy Clin. Cancer Res., July 1, 2002; 8(7): 2024 - 2034. [Abstract] [Full Text] [PDF]

				F. Guo, R. Nimmanapalli, S. Paranawithana, S. Wittman, D. Griffin, P. Bali, E. O'Bryan, C. Fumero, H. G. Wang, and K. Bhalla Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis Blood, May 1, 2002; 99(9): 3419 - 3426. [Abstract] [Full Text] [PDF]

				A. Chakravarti, E. Noll, P. McL. Black, D. F. Finkelstein, D. M. Finkelstein, N. J. Dyson, and J. S. Loeffler Quantitatively Determined Survivin Expression Levels Are of Prognostic Value in Human Gliomas J. Clin. Oncol., February 15, 2002; 20(4): 1063 - 1068. [Abstract] [Full Text] [PDF]

				P. Fortugno, N. R. Wall, A. Giodini, D. S. O'Connor, J. Plescia, K. M. Padgett, S. Tognin, P. C. Marchisio, and D. C. Altieri Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function J. Cell Sci., January 2, 2002; 115(3): 575 - 585. [Abstract] [Full Text] [PDF]

				J. R. Kanwar, W.-P. Shen, R. K. Kanwar, R. W. Berg, and G. W. Krissansen Effects of Survivin Antagonists on Growth of Established Tumors and B7-1 Immunogene Therapy J Natl Cancer Inst, October 17, 2001; 93(20): 1541 - 1552. [Abstract] [Full Text] [PDF]

				S. Fukuda and L. M. Pelus Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34+ cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis Blood, October 1, 2001; 98(7): 2091 - 2100. [Abstract] [Full Text] [PDF]

				M. Mesri, M. Morales-Ruiz, E. J. Ackermann, C. F. Bennett, J. S. Pober, W. C. Sessa, and D. C. Altieri Suppression of Vascular Endothelial Growth Factor-Mediated Endothelial Cell Protection by Survivin Targeting Am. J. Pathol., May 1, 2001; 158(5): 1757 - 1765. [Abstract] [Full Text] [PDF]

				C. S. Detweiler, D. B. Cunanan, and S. Falkow Host microarray analysis reveals a role for the Salmonella response regulator phoP in human macrophage cell death PNAS, April 18, 2001; (2001) 91110098. [Abstract] [Full Text]

				A. O'Brate, M. Tarón, D. Gandara, and R. Rosell Sharing New Approaches to Translational Research in Non-Small Cell Lung Cancer Oncologist, December 1, 2000; 5(6): 514 - 519. [Full Text]

				D. P. Banks, J. Plescia, D. C. Altieri, J. Chen, S. H. Rosenberg, H. Zhang, S.-C. Ng;, E. M. Conway, D. Collen, and A. Schuh Survivin does not inhibit caspase-3 activity Blood, December 1, 2000; 96(12): 4002 - 4003. [Full Text] [PDF]

				G. M. Kasof and B. C. Gomes Livin, a Novel Inhibitor of Apoptosis Protein Family Member J. Biol. Chem., January 26, 2001; 276(5): 3238 - 3246. [Abstract] [Full Text] [PDF]

				W. H. Hoffman, S. Biade, J. T. Zilfou, J. Chen, and M. Murphy Transcriptional Repression of the Anti-apoptotic survivin Gene by Wild Type p53 J. Biol. Chem., January 25, 2002; 277(5): 3247 - 3257. [Abstract] [Full Text] [PDF]

				C. S. Detweiler, D. B. Cunanan, and S. Falkow Host microarray analysis reveals a role for the Salmonella response regulator phoP in human macrophage cell death PNAS, May 8, 2001; 98(10): 5850 - 5855. [Abstract] [Full Text] [PDF]

				D. Grossman, P. J. Kim, J. S. Schechner, and D. C. Altieri Inhibition of melanoma tumor growth in vivo by survivin targeting PNAS, January 16, 2001; 98(2): 635 - 640. [Abstract] [Full Text] [PDF]