The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization.
The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization.
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DOI：
10.1186/1479-5876-5-6
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发表时间：
2007-01-26
影响因子：
7.4
通讯作者：
Mor, Gil
中科院分区：
文献类型：
--
作者：
Kluger, Harriet M.;McCarthy, Mary M.;Alvero, Ayesha B.;Sznol, Mario;Ariyan, Stephan;Camp, Robert L.;Rimm, David L.;Mor, Gil
XIAP上调与化疗耐药性相关。酚氧二醇导致卵巢癌中XIAP降解和化疗增敏。在这里，我们评估XIAP表达的黑色素瘤，使用组织微阵列包含436个黑色素瘤和336痣的自动化，定量分析（AQUA）的新方法。我们使用S100将像素定义为阵列点内的黑素瘤（肿瘤掩模），并使用掩模内的Cy 5缀合抗体测量XIAP表达。XIAP在黑色素瘤中的表达显著高于痣（P < 0.0001），在转移灶中的表达显著高于原发灶（P < 0.0001）。然后，我们评估了一组黑色素瘤细胞系的XIAP表达，并发现在所有细胞系中的高表达。评估了三种细胞系的酚氧二醇和卡铂敏感性;所有细胞系均对卡铂耐药，并对酚氧二醇显示出不同的敏感性。在卡铂之前用苯氧二醇预处理苯氧二醇敏感性细胞导致XIAP降解，与卡铂敏化和细胞凋亡相关，而将苯氧二醇抗性细胞暴露于苯氧二醇导致较少的XIAP降解和最小的卡铂敏化。我们的结论是，XIAP水平在临床标本中显着高于黑色素瘤比他们的良性同行，并在转移性高于原发性标本，这表明与恶性进展和疾病的侵略。黑色素瘤对卡铂的耐药性可能是由于XIAP过表达。在体外，酚氧二醇可以使黑素瘤细胞对卡铂敏感，并伴有相应的XIAP降解，尽管酚氧二醇的精确靶点和作用机制有待进一步评估。靶向XIAP作为转移性黑色素瘤的治疗方法需要额外的研究。
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.
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影响因子：
8.8
作者：
Cummings, J;Ward, TH;LaCasse, E;Lefebvre, C;St-Jean, M;Durkin, J;Ranson, M;Dive, C
通讯作者：
Dive, C
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
45.3
作者：
Chapman, PB;Einhorn, LH;Kirkwood, JM
通讯作者：
Kirkwood, JM
影响因子：
11.2
作者：
Frank, NY;Margaryan, A;Frank, MH
通讯作者：
Frank, MH
DOI：
10.1097/00000421-199304000-00015
发表时间：
1993-04-01
影响因子：
2.6
作者：
CHANG, A;HUNT, M;SMITH, TJ
通讯作者：
SMITH, TJ