XIAP expression is an independent prognostic marker in clear-cell renal carcinomas1 1The results of the study are part of the PhD thesis of E. Caliskan.

Ramp, Uwe; Krieg, Thomas; Çalışkan, Ercan; Mahotka, Csaba; Ebert, Thomas; Willers, R.; Gabbert, Helmut E.; Gerharz, Claus Dieter

doi:10.1016/j.humpath.2004.03.011

Cited by 96 publications

(71 citation statements)

References 23 publications

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“…Elevated XIAP expression has been linked to resistance to therapy in diffuse B-cell lymphoma and AML 18 and to more aggressive clinical behavior or higher tumor grade in renal, 19 uterine cervical squamous and endometrial carcinoma (unpublished data). The degree of XIAP staining of tumor cells may be a means of identifying effusions, and possibly their associated solid tumors, most resistant to apoptosis-inducing cancer therapies (ie, those with strong XIAP expression), and in the near future allow additional triaging to XIAP-blocking drugs presently being developed and clinically tested.…”

Section: Discussionmentioning

confidence: 94%

Immunocytochemical detection of XIAP in body cavity effusions and washes

Yuan

Szporn

et al. 2005

Modern Pathology

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Body cavity effusions may be the first manifestation of malignancy or of recurrence or relapse. We surveyed effusions and washes for expression of X-linked inhibitor of apoptosis (XIAP), a potent constituent of the inhibitor of apoptosis (IAP) family of proteins. IAPs prevent apoptosis by blocking the activation of caspases, thereby preventing caspase-mediated cell degradation. Elevated expression of XIAP could be an underpinning of relapse and/or resistance to apoptosis-inducing cancer therapy. We performed an immunocytochemical survey of XIAP expression in cell blocks from benign and malignant body cavity effusions and washes. In all, 116 alcohol-fixed, formalin postfixed paraffin-embedded cell block specimens from 82 pleural effusions, 22 ascites, 11 pelvic/peritoneal washes and one pericardial effusion were evaluated immunocytochemically with monoclonal anti-XIAP (#610763, BD Biosciences, San Jose, USA) 1:250, 41C Â 72 h, and developed using EnVision-Plus reagents (Dako) and diaminobenzidine as chromagen. Particulate cytoplasmic staining was considered positive. The prevalence of staining for specific malignancies varied with the tissue of origin as follows: ovarian (13/13, 100%); lung (9/11, 82%), breast (6/13, 46%); gastric (4/7, 57%), colon (0/4, 0%), pancreas (2/3, 67%), gallbladder (1/1, 100%), fallopian tube (1/3, 33%), endometrial (6/7, 86%), mesothelioma (4/5, 80%), carcinoma of unknown primary (5/5, 100%) and hematopoietic malignancies (3/9, 33%). Overall, 54 out of 81 (67%) malignant effusions displayed XIAP positivity. Benign effusions (n ¼ 35) were virtually XIAP-negative except for two cases (6%) in which histiocytes showed moderate staining. Weak nonspecific staining was sometimes noted in inflammatory cells or histiocytes. XIAP immunostaining, when strong, allows for ready distinction of malignant from benign and reactive cell populations. Strong XIAP staining was most prevalent in ovarian carcinomas and less prevalent in mammary carcinomas. The degree of XIAP staining of tumor cells may be a means of identifying the most therapy-resistant cases (ie, those with strong XIAP expression), and allow additional triaging to XIAP-blocking drugs presently being developed and clinically tested.

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Section: Discussionmentioning

confidence: 94%

Immunocytochemical detection of XIAP in body cavity effusions and washes

Yuan

Szporn

et al. 2005

Modern Pathology

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“…The intensity of XIAP staining, established previously by Ramp et al (2004), was determined for both XIAP and Smac. The intensity was scored as follows: 0, no staining; 3, strong staining comparable with that of convoluted tubule epithelial cells of normal kidney; and 1 and 2, weak and moderate staining, respectively, that is, intermediate between the former two.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis

et al. 2008

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Renal cell carcinoma (RCC) is known to be resistant to chemo-and radiotherapy due to a high apoptotic threshold. Smac and XIAP (X-linked inhibitor of apoptosis protein) proteins were detected in all RCC cell lines and tissue samples examined. We modulated the function of XIAP, either through its constitutional downregulation with an shRNA vector or by applying a Smac-mimicking peptide. Among RCC cell lines, Caki1 expresses the highest levels of XIAP. We transfected Caki1 with XIAP-targeting shRNA vector and generated stable clones. XIAP was knocked down by RNA interference in clone no. 14 by 81.6% and in clone no. 19 by 85.3%. Compared to the parental and mock-transfected cells, neither clone was more sensitive to conventional chemotherapeutic agents, but both clones were more susceptible to Fas stimulation (Po0.0001) and to pharmacological Bcl-2 inhibition (Po0.0001), as well as to a combination of the two (Po0.0001). Mature Smac binds to XIAP via the N-terminal residues, disrupting its interaction with caspases and promoting their activity. We determined that exposure of Caki1 cells to Smac-N7 peptide (AVPIAQK) resulted in a slight but significant decrease in viability (P ¼ 0.0031) and potentiated cisplatin's effect (P ¼ 0.0027). In contrast with point targeting of XIAP by shRNA, Smac-N7 peptide is active against several IAP (inhibitor of apoptosis protein) family members, which can explain its role in sensitising cells to cisplatin. Our results suggest that multiple targeting of both Bcl-2 and XIAP or, alternatively, of several IAP family members by the Smac-N7 peptide is a potent way to overcome resistance of RCC to apoptosis-triggering treatment modalities, and might be a new tool for molecular targeted therapy.

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“…Thus, it can antagonise both the mitochondrial regulated (intrinsic) and death-receptormediated (extrinsic) apoptotic pathways (Hengartner, 2000). In clinical investigations, the protein has been shown to be overexpressed in a number of different tumours relative to normal tissue (Hofmann et al, 2002;Krajewska et al, 2003;Shiraki et al, 2003) and high expression is often associated with poor patient outcome (Tamm et al, 2000(Tamm et al, , 2004Ramp et al, 2004;Yan et al, 2004) and resistance to chemotherapy (Parton et al, 2002).…”

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Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP

et al. 2005

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The inhibitor of apoptosis protein, XIAP, is frequently overexpressed in chemoresistant human tumours. An antisense oligonucleotide (AEG 35156/GEM 640) that targets XIAP has recently entered phase I trials in the UK. Method validation data are presented on three pharmacodynamic assays that will be utilised during this trial. Quantitative RT-PCR was based on a Taqman assay and was confirmed to be specific for XIAP. Assay linearity extended over four orders of magnitude. MDA-MB-231/U6-E1 cells and clone X-G4 stably expressing an RNAi vector against XIAP were chosen as high and low XIAP expression quality controls (QCs). Within-day and between-day coefficients of variation (CVs) in precision for cycle threshold (CT) and delta CT values (employing GAPDH and beta 2 microglobulin as housekeepers) were always less than 10%. A Western blotting technique was validated using a GST -XIAP fusion protein as a standard and HeLa cells and SF268 (human glioblastoma) cells as high and low XIAP expression QCs. Specificity of the final choice of antibody for XIAP was evaluated by analysing a panel of cell lines including clone X-G4. The assay was linear over a 29-fold range of protein concentration and between-day precision was 29% for the low QC and 23% for the high QC when normalised to GAPDH. XIAP protein was also shown to be stable at À801C for at least 60 days. M30-Apoptosenset plasma Elisa detects a caspase-cleaved fragment of cytokeratin 18 (CK18), believed to be a surrogate marker for tumour cell apoptosis. Generation of an independent QC was achieved through the treatment of X-G4 cells with staurosporine and collection of media. Measurements on assay precision and kit-to-kit QC were always less than 10%. The M30 antigen (CK18-Asp 396 ) was stable for 3 months at À801C, while at 371C it had a half-life of 80 -100 h in healthy volunteer plasma. Results from the phase I trial are eagerly awaited.

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XIAP expression is an independent prognostic marker in clear-cell renal carcinomas1 1The results of the study are part of the PhD thesis of E. Caliskan.

Cited by 96 publications

References 23 publications

Immunocytochemical detection of XIAP in body cavity effusions and washes

Immunocytochemical detection of XIAP in body cavity effusions and washes

Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis

Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP

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