XIAP up-regulation is associated with
chemotherapy resistance.
Phenoxodiol causes XIAP degradation and
chemotherapy sensitization in
ovarian cancer. Here we assessed XIAP expression in
melanomas, using tissue microarrays containing 436
melanomas and 336
nevi by a novel method of automated, quantitative analysis (AQUA). We used S100 to define pixels as
melanoma (
tumor mask) within the array spot, and measured XIAP expression using Cy5-conjugated
antibodies within the mask. XIAP expression was significantly higher in
melanomas than
nevi (P < 0.0001), and higher in metastatic than primary lesions (P < 0.0001). We then assessed a panel of
melanoma cell lines for XIAP expression, and found high expression in all cell lines. Three of the cell lines were assessed for
Phenoxodiol and
Carboplatin sensitivity; all were resistant to
Carboplatin and showed variable sensitivity to
Phenoxodiol. Pre-treating
Phenoxodiol sensitive cells with
Phenoxodiol prior to
Carboplatin resulted in XIAP degradation, associated with
Carboplatin sensitization and apoptosis, whereas exposing
Phenoxodiol resistant cells to
Phenoxodiol resulted in less XIAP degradation and minimal
Carboplatin sensitization. We conclude that XIAP levels in clinical specimens are significantly higher in
melanomas than their benign counterparts, and higher in metastatic than in primary specimens, suggesting an association with malignant progression and disease aggression.
Melanoma resistance to
Carboplatin is possibly due to XIAP over-expression.
Phenoxodiol can sensitize
melanoma cells to
Carboplatin in vitro with corresponding XIAP degradation, although the precise target and mechanism of action of
Phenoxodiol are subject to further assessment. Targeting XIAP warrants additional investigation as a therapeutic approach for metastatic
melanoma.