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

Abstract

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 < 0.05). 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.

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

“…Most melanoma cells were shown to express Bcl-2, Bcl-xL, and Mcl-1 (37,38). Additional studies have correlated the resistance of melanoma cells to Fas-mediated apoptosis, mainly with the expression levels of proapoptotic Bax and antiapoptotic Bcl-2 proteins (24-26), whereas expression of Bcl-xL has been largely associated with their drug resistance (39)(40)(41). The melanoma cell lines used in our study express Bcl-2 and Bcl-xL; however, only Mcl-1 expression was decreased after cycloheximide treatment.…”

Reduced Apaf-1 expression in human cutaneous melanomas

“…For example, survivin, a member of the inhibitor of apoptosis protein (IAP) family, was strongly expressed in human melanomas but not in normal melanocytes, and overexpression of survivin in the sentinel lymph nodes from melanoma patients was inversely correlated with patient survival (Grossman et al, 1999;Gradilone et al, 2003). X L , and Mcl-1, may also contribute to melanoma progression and chemoresistance as antisense oligos against these genes can induce death of melanoma cells (Jansen et al, 1998;Heere-Ress et al, 2002;Thallinger et al, 2003). However, the implication of Bcl-2 antiapoptotic proteins as melanoma progression factors is controversial.…”

Strategies for reversing drug resistance

“…As the clinical data demonstrating a correlation between chemoresistance and Bcl-2 levels are more persuasive than that showing Bcl-2 as a mechanism of acquired resistance, one would predict that this strategy would be most successful if employed in the initial therapy of tumors, rather than in drug-refractory malignancies. A similar rationale supports the development of ASOs targeting the functional and structural homolog of Bcl-2, Bcl-X L (Heere-Ress et al, 2002). It remains to be established if a strategy that targets both Bcl-2 or Bcl-X L using either individual or bispecific ASOs will be more effective (Miyake et al, 2000;ZangemeisterWittke et al, 2000).…”