The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization

Harriet M Kluger,David L Rimm,Gil Mor,Stephan Ariyan,Mario Sznol,Robert L Camp,Mary M Mccarthy,Ayesha B Alvero

doi:10.1186/1479-5876-5-6

Abstract

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.

Highlights

The incidence of cutaneous melanoma in the United States is rising faster than that of any other malignancy, with 62,190 expected new cases diagnosed in 2006 [1,2]
In our large cohort of melanomas and nevi we show significantly higher expression in tumors than in nevi, and X-linked inhibitor of apoptosis protein (XIAP) expression was significantly higher in metastatic specimens than in primary melanomas
Among primary tumors we found an association between high XIAP expression and deep lesions (>2 mm)

Summary

Introduction

The incidence of cutaneous melanoma in the United States is rising faster than that of any other malignancy, with 62,190 expected new cases diagnosed in 2006 [1,2]. This increase in incidence, compounded by the lack of effective therapy once the disease has metastasized, underscores the need for improved methods of treating patients with unresectable melanoma. A number of chemotherapeutic and biological agents have activity in metastatic melanoma, albeit with disappointingly low response rates of less than 25% for any single agent or combination of agents, and none has improved overall survival when compared with observation [3,4,5]. Our understanding of mechanisms of resistance to chemotherapy is limited, as is our ability to overcome resistance, and new, well tolerated agents and approaches are required to sensitize melanoma cells to chemotherapy in order to improve outcome

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