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 Zangemeister-Wittke, U. Articles by Stahel, R. A. Search for Related Content PubMed PubMed Citation Articles by Zangemeister-Wittke, U. Articles by Stahel, R. A.

A Novel Bispecific Antisense Oligonucleotide Inhibiting Both bcl-2 and bcl-xL Expression Efficiently Induces Apoptosis in Tumor Cells¹

Division of Oncology, Department of Internal Medicine, University Hospital Zürich, CH-8044 Zürich, Switzerland [U. Z-W., S. H. L., R. A. O., A. P. S-W., O. G., G. H. L., R. A. S.]; Functional Genomics Area, Novartis Pharma AG, CH-4002 Basel, Switzerland [F. N., R. H., P. M., J. H.]; and Novartis Institute for Biomedical Research, Novartis Pharma Inc., Summit, New Jersey 07901-1398 [C. M. N.]

Bcl-2 and Bcl-xL are inhibitors of apoptosis frequently overexpressed in solid tumors. The bcl-2 and bcl-xL mRNAs share a region of homology comprising nucleotides 605–624 and 687–706, respectively, which differs by only three nucleotides. This sequence does not occur in the proapoptotic splice variant bcl-xS. To test the possibility that oligonucleotides targeting this region have the potential to down-regulate bcl-2 and bcl-xL expression simultaneously, three 2'-O-methoxy-ethoxy-modified phosphorothioate oligonucleotides were designed. These oligonucleotides differed in the number of mismatches to bcl-2 and bcl-xL and in the number of nucleotides to which the modifications were made. The effects of these oligonucleotides on bcl-2 and bcl-xL expression, as well as their abilities to induce apoptosis, were assessed in small cell and non-small cell lung cancer cell lines expressing different basal levels of bcl-2 and bcl-xL. Although all oligonucleotides down-regulated bcl-2 and bcl-xL expression, oligonucleotide 4625, which has no mismatching nucleotides to bcl-2 but three to bcl-xL, two of which were modified by 2'-O-methoxy-ethoxy residues, showed the strongest bispecific activity on the transcript and protein level. In all cell lines this bispecific activity induced apoptotic cell death, as demonstrated by increased uptake of propidium iodide, a 10–100-fold increase in caspase-3-like protease activity, and nuclear condensation and fragmentation. This is the first report of a bcl-2/bcl-xL bispecific antisense oligonucleotide that deserves attention as a therapeutic compound in lung cancer and other malignancies in which bcl-2 and/or bcl-xL are overexpressed.

This article has been cited by other articles:

				S. Giorgini, D. Trisciuoglio, C. Gabellini, M. Desideri, L. Castellini, C. Colarossi, U. Zangemeister-Wittke, G. Zupi, and D. Del Bufalo Modulation of bcl-xL in Tumor Cells Regulates Angiogenesis through CXCL8 Expression Mol. Cancer Res., August 1, 2007; 5(8): 761 - 771. [Abstract] [Full Text] [PDF]

				S. Hussain, A. Pluckthun, T. M. Allen, and U. Zangemeister-Wittke Chemosensitization of carcinoma cells using epithelial cell adhesion molecule-targeted liposomal antisense against bcl-2/bcl-xL Mol. Cancer Ther., December 1, 2006; 5(12): 3170 - 3180. [Abstract] [Full Text] [PDF]

				E. Z. Bagci, Y. Vodovotz, T. R. Billiar, G. B. Ermentrout, and I. Bahar Bistability in Apoptosis: Roles of Bax, Bcl-2, and Mitochondrial Permeability Transition Pores Biophys. J., March 1, 2006; 90(5): 1546 - 1559. [Abstract] [Full Text] [PDF]

				K. Yamanaka, P. Rocchi, H. Miyake, L. Fazli, B. Vessella, U. Zangemeister-Wittke, and M. E. Gleave A novel antisense oligonucleotide inhibiting several antiapoptotic Bcl-2 family members induces apoptosis and enhances chemosensitivity in androgen-independent human prostate cancer PC3 cells Mol. Cancer Ther., November 1, 2005; 4(11): 1689 - 1698. [Abstract] [Full Text] [PDF]

				A. Hachem and R. B. Gartenhaus Oncogenes as molecular targets in lymphoma Blood, September 15, 2005; 106(6): 1911 - 1923. [Full Text] [PDF]

				U. Fischer and K. Schulze-Osthoff New Approaches and Therapeutics Targeting Apoptosis in Disease Pharmacol. Rev., June 1, 2005; 57(2): 187 - 215. [Abstract] [Full Text] [PDF]

				I. M. Ghobrial, T. E. Witzig, and A. A. Adjei Targeting Apoptosis Pathways in Cancer Therapy CA Cancer J Clin, May 1, 2005; 55(3): 178 - 194. [Abstract] [Full Text] [PDF]

				H. Zhu, W. Guo, L. Zhang, J. J. Davis, F. Teraishi, S. Wu, X. Cao, J. Daniel, W. R. Smythe, and B. Fang Bcl-XL small interfering RNA suppresses the proliferation of 5-fluorouracil-resistant human colon cancer cells Mol. Cancer Ther., March 1, 2005; 4(3): 451 - 456. [Abstract] [Full Text] [PDF]

				M. G. Friedrich, D. J. Weisenberger, J. C. Cheng, S. Chandrasoma, K. D. Siegmund, M. L. Gonzalgo, M. I. Toma, H. Huland, C. Yoo, Y. C. Tsai, et al. Detection of Methylated Apoptosis-Associated Genes in Urine Sediments of Bladder Cancer Patients Clin. Cancer Res., November 15, 2004; 10(22): 7457 - 7465. [Abstract] [Full Text] [PDF]

				M. Milella, D. Trisciuoglio, T. Bruno, L. Ciuffreda, M. Mottolese, A. Cianciulli, F. Cognetti, U. Zangemeister-Wittke, D. Del Bufalo, and G. Zupi Trastuzumab Down-Regulates Bcl-2 Expression and Potentiates Apoptosis Induction by Bcl-2/Bcl-XL Bispecific Antisense Oligonucleotides in HER-2Gene-Amplified Breast Cancer Cells Clin. Cancer Res., November 15, 2004; 10(22): 7747 - 7756. [Abstract] [Full Text] [PDF]

				P. J. Real, Y. Cao, R. Wang, Z. Nikolovska-Coleska, J. Sanz-Ortiz, S. Wang, and J. L. Fernandez-Luna Breast Cancer Cells Can Evade Apoptosis-Mediated Selective Killing by a Novel Small Molecule Inhibitor of Bcl-2 Cancer Res., November 1, 2004; 64(21): 7947 - 7953. [Abstract] [Full Text] [PDF]

				B. Chandrasekar, K. Vemula, R. M. Surabhi, M. Li-Weber, L. B. Owen-Schaub, L. E. Jensen, and S. Mummidi Activation of Intrinsic and Extrinsic Proapoptotic Signaling Pathways in Interleukin-18-mediated Human Cardiac Endothelial Cell Death J. Biol. Chem., May 7, 2004; 279(19): 20221 - 20233. [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]

				S. Kumar Biswas, J. Huang, S. Persaud, and A. Basu Down-regulation of Bcl-2 is associated with cisplatin resistance in human small cell lung cancer H69 cells Mol. Cancer Ther., March 1, 2004; 3(3): 327 - 334. [Abstract] [Full Text]

				R. L. Hayward, J. S. Macpherson, J. Cummings, B. P. Monia, J. F. Smyth, and D. I. Jodrell Enhanced oxaliplatin-induced apoptosis following antisense Bcl-xl down-regulation is p53 and Bax dependent: Genetic evidence for specificity of the antisense effect Mol. Cancer Ther., February 1, 2004; 3(2): 169 - 178. [Abstract] [Full Text] [PDF]

				D. J. Waxman and P. S. Schwartz Harnessing Apoptosis for Improved Anticancer Gene Therapy Cancer Res., December 15, 2003; 63(24): 8563 - 8572. [Abstract] [Full Text] [PDF]

				M. GLEAVE and B. JANSEN Clusterin and IGFBPs as Antisense Targets in Prostate Cancer Ann. N.Y. Acad. Sci., December 1, 2003; 1002(1): 95 - 104. [Abstract] [Full Text] [PDF]

				G. Stassi, M. Todaro, M. Zerilli, L. Ricci-Vitiani, D. Di Liberto, M. Patti, A. Florena, F. Di Gaudio, G. Di Gesu, and R. De Maria Thyroid Cancer Resistance to Chemotherapeutic Drugs via Autocrine Production of Interleukin-4 and Interleukin-10 Cancer Res., October 15, 2003; 63(20): 6784 - 6790. [Abstract] [Full Text] [PDF]

				G. Tortora, R. Caputo, V. Damiano, R. Caputo, T. Troiani, B. M. Veneziani, S. De Placido, A. R. Bianco, U. Zangemeister-Wittke, and F. Ciardiello Combined Targeted Inhibition of bcl-2, bcl-XL, Epidermal Growth Factor Receptor, and Protein Kinase A Type I Causes Potent Antitumor, Apoptotic, and Antiangiogenic Activity Clin. Cancer Res., February 1, 2003; 9(2): 866 - 871. [Abstract] [Full Text] [PDF]

				B. Jahrsdorfer, R. Jox, L. Muhlenhoff, K. Tschoep, A. Krug, S. Rothenfusser, G. Meinhardt, B. Emmerich, S. Endres, and G. Hartmann Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN J. Leukoc. Biol., July 1, 2002; 72(1): 83 - 92. [Abstract] [Full Text] [PDF]

				W. R. Smythe, I. Mohuiddin, M. Ozveran, and X. X. Cao Antisense therapy for malignant mesothelioma with oligonucleotides targeting the bcl-xl gene product J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1191 - 1198. [Abstract] [Full Text] [PDF]

				O. E. Pardo, A. Arcaro, G. Salerno, S. Raguz, J. Downward, and M. J. Seckl Fibroblast Growth Factor-2 Induces Translational Regulation of Bcl-XL and Bcl-2 via a MEK-dependent Pathway. CORRELATION WITH RESISTANCE TO ETOPOSIDE-INDUCED APOPTOSIS J. Biol. Chem., March 29, 2002; 277(14): 12040 - 12046. [Abstract] [Full Text] [PDF]

				A. S. Jun, S. H. Liu, E. H. Koo, D. V. Do, W. J. Stark, and J. D. Gottsch Microarray Analysis of Gene Expression in Human Donor Corneas Arch Ophthalmol, November 1, 2001; 119(11): 1629 - 1634. [Abstract] [Full Text] [PDF]

				M. S. Rieber, U. Zangemeister-Wittke, and M. Rieber p53-independent Induction of Apoptosis in Human Melanoma Cells by a bcl-2/bcl-xL Bispecific Antisense Oligonucleotide Clin. Cancer Res., May 1, 2001; 7(5): 1446 - 1451. [Abstract] [Full Text]

				O. Gautschi, S. Tschopp, R. A. Olie, S. H. Leech, A. P. Simoes-Wust, A. Ziegler, B. Baumann, B. Odermatt, J. Hall, R. A. Stahel, et al. Activity of a Novel bcl-2/bcl-xL-Bispecific Antisense Oligonucleotide Against Tumors of Diverse Histologic Origins J Natl Cancer Inst, March 21, 2001; 93(6): 463 - 471. [Abstract] [Full Text] [PDF]

				I. Lebedeva, R. Rando, J. Ojwang, P. Cossum, and C. A. Stein Bcl-xL in Prostate Cancer Cells: Effects of Overexpression and Down-Regulation on Chemosensitivity Cancer Res., November 1, 2000; 60(21): 6052 - 6060. [Abstract] [Full Text]