Mcl-1 Antisense Therapy Chemosensitizes Human Melanoma in a SCID Mouse Xenotransplantation Model

• Published in: Journal of investigative dermatology Vol. 120; no. 6; pp. 1081 - 1086
• Main Authors: Thallinger, Christiane, Wolschek, Markus F., Wacheck, Volker, Maierhofer, Helmut, Günsberg, Patrick, Polterauer, Peter, Pehamberger, Hubert, Monia, Brett P., Selzer, Edgar, Wolff, Klaus, Jansen, Burkhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2003; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents, Alkylating - therapeutic use; antisense oligonucleotide; Apoptosis; chemoresistance; Dacarbazine - therapeutic use; Drug Synergism; Drug Therapy, Combination; human melanoma; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Mcl-1; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - physiopathology; Mice; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Transplantation; Oligonucleotides, Antisense - pharmacokinetics; Oligonucleotides, Antisense - therapeutic use; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms - drug therapy; Skin Neoplasms - metabolism; Skin Neoplasms - physiopathology; Transplantation, Heterologous; Tumor Cells, Cultured; Mcl-1; apoptosis; chemoresistance; human melanoma; antisense oligonucleotide
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1046/j.1523-1747.2003.12252.x

It is well established that high expression of the antiapoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL can significantly contribute to chemoresistance in a number of human malignancies. Much less is known about the role the more recently described Bcl-2 family member Mcl-1 might play in tumor biology and resistance to chemotherapy. Using an antisense strategy, we here address this issue in melanoma, a paradigm of a treatment-resistant malignancy. After in vitro proof of principle supporting an antisense mechanism of action with specific reduction of Mcl-1 protein as a consequence of nuclear uptake of the Mcl-1 antisense oligonucleotides employed, antisense and universal control oligonucleotides were administered systemically in combination with dacarbazine in a human melanoma SCID mouse xenotransplantation model. Dacarbazine, available now for more than three decades, still remains the most active single agent for treatment of advanced melanoma. Mcl-1 antisense oligonucleotides specifically reduced target protein expression as well as the apoptotic threshold of melanoma xenotransplants. Combined Mcl-1 antisense oligonucleotide plus dacarbazine treatment resulted in enhanced tumor cell apoptosis and led to a significantly reduced mean tumor weight (mean 0.16 g, 95% confidence interval 0.08–0.26) compared to the tumor weight in universal control oligonucleotide plus dacarbazine treated animals (mean 0.35 g, 95% confidence interval 0.2–0.44) or saline plus dacarbazine treated animals (mean 0.39 g, 95% confidence interval 0.25–0.53). We thus show that Mcl-1 is an important factor contributing to the chemoresistance of human melanoma in vivo. Antisense therapy against the Mcl-1 gene product, possibly in combination with antisense strategies targeting other antiapoptotic Bcl-2 family members, appears to be a rational and promising approach to help overcome treatment resistance of malignant melanoma.