Mcl-1 antisense therapy chemosensitizes human melanoma in a SCID mouse xenotransplantation model.
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.
Thallinger
Christiane
C
Department of Clinical Pharmacology, Section of Experimental Oncology, University of Vienna, Austria.
Wolschek
Markus F
MF
Wacheck
Volker
V
Maierhofer
Helmut
H
Günsberg
Patrick
P
Polterauer
Peter
P
Pehamberger
Hubert
H
Monia
Brett P
BP
Selzer
Edgar
E
Wolff
Klaus
K
Jansen
Burkhard
B
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D017209:Apoptosis; D003606:Dacarbazine / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D003606:Dacarbazine