Bcl-xL is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Malignant melanoma is a tumor that responds poorly to a variety of apoptosis-inducing treatment modalities, such as chemotherapy. The expression of genes that regulate apoptotic cell death plays an important role in determining the sensitivity of tumor cells to chemotherapeutic intervention. Bcl-X-L is an antiapoptotic member of the Bcl-2 family and is universally expressed in human melanoma. To evaluate the Bcl-X-L protein as a potential therapeutic target in melanoma, the influence of Bcl-X-L expression levels on the chemoresistance of human melanoma cells was investigated. Overexpression of Bcl-X-L in stably transfected human melanoma Mel Juso cells significantly reduced sensitivity to cisplatin-induced apoptosis (p less than or equal to0.05). In a parallel approach, reduction of Bcl-X-L protein by specific AS oligonucleotide (ISIS 16009) treatment enhanced the chemosensitivity of Mel Juso cells by 62% compared to cells treated with MM control oligonucleotide (ISIS 16967) as well as chemotherapy-induced apoptosis. These data suggest that Bcl-X-L is an important factor contributing to the chemoresistance of human melanoma. Reduction of Bcl-X-L expression by AS oligonucleotides provides a rational and promising approach that may help to overcome chemoresistance in this malignancy. (C) 2002 Wiley-Liss, Inc.