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 Thallinger, C. Articles by Selzer, E. Search for Related Content PubMed PubMed Citation Articles by Thallinger, C. Articles by Selzer, E.

Mcl-1 Is a Novel Therapeutic Target for Human Sarcoma

Synergistic Inhibition of Human Sarcoma Xenotransplants by a Combination of Mcl-1 Antisense Oligonucleotides with Low-Dose Cyclophosphamide

¹ Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, ² Department of Dermatology, Division of General Dermatology, ³ Department of Radiotherapy and Radiobiology, and ⁵ Center of Excellence in Clinical and Experimental Oncology (CLEXO), University of Vienna, Vienna, Austria; ⁴ ISIS Pharmaceuticals, Inc., Carlsbad, California; and ⁶ Prostate Centre and Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada

Purpose: Little is known about the role that Mcl-1, an antiapoptotic Bcl-2 family member, plays in solid tumor biology and susceptibility to anticancer therapy. We observed that the Mcl-1 protein is widely expressed in human sarcoma cell lines of different histological origin (n = 7). Because the expression of antiapoptotic Bcl-2 family proteins can significantly contribute to the chemoresistance of human malignancies, we used an antisense strategy to address this issue in sarcoma.

Experimental Design: SCID mice (n = 6/group) received s.c. injections of SW872 liposarcoma cells. After development of palpable tumors, mice were treated by s.c.-implanted miniosmotic pumps prefilled with saline or antisense or universal control oligonucleotides (20 mg/kg/day for 2 weeks). On days 2, 6, and 10, mice were treated with low-dose cyclophosphamide (35 mg/kg i.p) or saline control. During the experiments, tumor weight was assessed twice weekly by caliper measurements. On day 14, animals were sacrificed. Tumors were weighed and fixed in formalin for immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling analysis.

Results: Mcl-1 antisense oligonucleotides specifically reduced Mcl-1 protein expression but produced no reduction in tumor weight compared with saline-treated control animals. Cyclophosphamide monotreatment caused only modest tumor weight reduction compared with saline control. However, use of Mcl-1 antisense oligonucleotides combined with cyclophosphamide clearly enhanced tumor cell apoptosis and significantly reduced tumor weight by more than two-thirds compared with respective control treatments.

Conclusion: A combination of Mcl-1 antisense oligonucleotides with low-dose cyclophosphamide provides a synergistic antitumor effect and might qualify as a promising strategy to overcome chemoresistance in human sarcoma.

This article has been cited by other articles:

				Q. Ding, L. Huo, J.-Y. Yang, W. Xia, Y. Wei, Y. Liao, C.-J. Chang, Y. Yang, C.-C. Lai, D.-F. Lee, et al. Down-regulation of Myeloid Cell Leukemia-1 through Inhibiting Erk/Pin 1 Pathway by Sorafenib Facilitates Chemosensitization in Breast Cancer Cancer Res., August 1, 2008; 68(15): 6109 - 6117. [Abstract] [Full Text] [PDF]

				Q. Liu, X. Zhao, F. Frissora, Y. Ma, R. Santhanam, D. Jarjoura, A. Lehman, D. Perrotti, C.-S. Chen, J. T. Dalton, et al. FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma Blood, January 1, 2008; 111(1): 275 - 284. [Abstract] [Full Text] [PDF]

				S. Kobayashi, S.-H. Lee, X. W. Meng, J. L. Mott, S. F. Bronk, N. W. Werneburg, R. W. Craig, S. H. Kaufmann, and G. J. Gores Serine 64 Phosphorylation Enhances the Antiapoptotic Function of Mcl-1 J. Biol. Chem., June 22, 2007; 282(25): 18407 - 18417. [Abstract] [Full Text] [PDF]

				Q. Ding, X. He, J.-M. Hsu, W. Xia, C.-T. Chen, L.-Y. Li, D.-F. Lee, J.-C. Liu, Q. Zhong, X. Wang, et al. Degradation of Mcl-1 by {beta}-TrCP Mediates Glycogen Synthase Kinase 3-Induced Tumor Suppression and Chemosensitization Mol. Cell. Biol., June 1, 2007; 27(11): 4006 - 4017. [Abstract] [Full Text] [PDF]

				Q. Ding, X. He, W. Xia, J.-M. Hsu, C.-T. Chen, L.-Y. Li, D.-F. Lee, J.-Y. Yang, X. Xie, J.-C. Liu, et al. Myeloid Cell Leukemia-1 Inversely Correlates with Glycogen Synthase Kinase-3{beta} Activity and Associates with Poor Prognosis in Human Breast Cancer Cancer Res., May 15, 2007; 67(10): 4564 - 4571. [Abstract] [Full Text] [PDF]

				S.-R. A. Hussain, C. M. Cheney, A. J. Johnson, T. S. Lin, M. R. Grever, M. A. Caligiuri, D. M. Lucas, and J. C. Byrd Mcl-1 Is a Relevant Therapeutic Target in Acute and Chronic Lymphoid Malignancies: Down-Regulation Enhances Rituximab-Mediated Apoptosis and Complement-Dependent Cytotoxicity Clin. Cancer Res., April 1, 2007; 13(7): 2144 - 2150. [Abstract] [Full Text] [PDF]

				B. Spankuch, S. Heim, E. Kurunci-Csacsko, C. Lindenau, J. Yuan, M. Kaufmann, and K. Strebhardt Down-regulation of Polo-like Kinase 1 Elevates Drug Sensitivity of Breast Cancer Cells In vitro and In vivo Cancer Res., June 1, 2006; 66(11): 5836 - 5846. [Abstract] [Full Text] [PDF]

				E. S. Henson, X. Hu, and S. B. Gibson Herceptin Sensitizes ErbB2-Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression Clin. Cancer Res., February 1, 2006; 12(3): 845 - 853. [Abstract] [Full Text] [PDF]

				B. M. Erovic, M. Pelzmann, M. Ch. Grasl, J. Pammer, G. Kornek, W. Brannath, E. Selzer, and D. Thurnher Mcl-1, Vascular Endothelial Growth Factor-R2, and 14-3-3{sigma} Expression Might Predict Primary Response against Radiotherapy and Chemotherapy in Patients with Locally Advanced Squamous Cell Carcinomas of the Head and Neck Clin. Cancer Res., December 15, 2005; 11(24): 8632 - 8636. [Abstract] [Full Text] [PDF]

				H. Yasui, T. Hideshima, M. Hamasaki, A. M. Roccaro, N. Shiraishi, S. Kumar, P. Tassone, K. Ishitsuka, N. Raje, Y.-T. Tai, et al. SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma Blood, July 15, 2005; 106(2): 706 - 712. [Abstract] [Full Text] [PDF]