The Role of Survivin for Radiation Oncology: Moving Beyond Apoptosis Inhibition

Rödel, Franz; Reichert, Sebastian; Sprenger, Thilo; Gaipl, Udo S.; Mirsch, J.; Liersch, Torsten; Fulda, Simone; Rödel, Claus

doi:10.2174/092986711794088362

Cited by 35 publications

(26 citation statements)

References 110 publications

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“…Interestingly, Survivin/BIRC5 may play a role in DNA-damage repair by interaction with members of DNA-double-strand breaks repair machinery. Rödel et al [34] reported that Survivin/BIRC5 knockdown reduced DNA-PKcs kinase activity. Similar results were obtained by the group of Chen et al [35] concerning the inhibition of the TORC kinases.…”

Section: Discussionmentioning

confidence: 99%

The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances the Antitumoral Activity of Gemcitabine in Human Pancreatic Cancer Cell Lines

Wicht¹

2014

J Integr Oncol

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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors still associated with poor prognosis in advanced stages. Gemcitabine is one of the standard agents for the treatment of PDAC, without having a major impact on the clinical outcome. Combining two compounds acting via different ways of action may result in a better efficacy. Methods:We investigated the effects of gemcitabine in combination with the dual PI3k/mTOR inhibitor BEZ235 in four human pancreatic cancer cell lines (Panc-1, BxPC-3, MiaPaCa-2 and AsPC-1). The cells were analysed with MTT assay for cell viability, FACS-analysis for cell cycle distribution. Real-time RT-PCR and Western blot for survivin/ BIRC5, STAT3, BCl-xL and WNT16 mRNA and protein expression and γH2AX.Results: Application of NVP-BEZ235 or gemcitabine inhibited cell viability of AsPC-1 and BxPC-3 cells while Panc-1 and MiaPaCa-2 remained nearly unaffected. Combined treatment of gemcitabine and BEZ235, however, enhanced the inhibitory effect on cell viability of Panc-1 and MiaPaCa-2 cells of about 80% compared to control cells. This effect was boosted by time-delayed application of the two compounds. The biggest impact on cell growth, viability and downstream gene regulations were achieved by a sequential incubation with gemcitabine followed by BEZ235 24 hours later. Conclusions:Combining gemcitabine with dual PI3K/mTOR inhibitors like NVP-BEZ2235 improved the efficacy on growth inhibition in human pancreatic cell lines especially by sequential application of both agents.

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Section: Discussionmentioning

confidence: 99%

The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances the Antitumoral Activity of Gemcitabine in Human Pancreatic Cancer Cell Lines

Wicht¹

2014

J Integr Oncol

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“…Survivin, in particular, is strongly overexpressed in both alveolar and embryonal RMS cell lines and, moreover, in RMS biopsy specimens. Blocking survivin expression reduces proliferation and viability of RMS xenotransplants, 33,38 increases radiosensitivity through interference with DNA repair, 40 and protects XIAP against ubiquitination 41 and proteasomal degradation. 42 We, therefore, asked whether down-regulation of survivin makes RMS cells more sensitive to a cytotoxic T-cell attack.…”

Section: Discussionmentioning

confidence: 99%

Survivin Blockade Sensitizes Rhabdomyosarcoma Cells for Lysis by Fetal Acetylcholine Receptor–Redirected T Cells

Simon-Keller

Paschen

Hombach

et al. 2013

The American Journal of Pathology

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Cellular immunotherapy may provide a strategy to overcome the poor prognosis of metastatic and recurrent rhabdomyosarcoma (RMS) under the current regimen of polychemotherapy. Because little is known about resistance mechanisms of RMS to cytotoxic T cells, we investigated RMS cell lines and biopsy specimens for expression and function of immune costimulatory receptors and anti-apoptotic molecules by RT-PCR, Western blot analysis, IHC, and cytotoxicity assays using siRNA or transfection-modified RMS cell lines, together with engineered RMS-directed cytotoxic T cells specific for the fetal acetylcholine receptor. We found that costimulatory CD80 and CD86 were consistently absent from all RMSs tested, whereas inducible T-cell co-stimulator ligand (ICOS-L; alias B7H2) was expressed by a subset of RMSs and was inducible by tumor necrosis factor a in two of five RMS cell lines. Anti-apoptotic survivin, along with other inhibitor of apoptosis (IAP) family members (cIAP1, cIAP2, and X-linked inhibitor of apoptosis protein), was overexpressed by RMS cell lines and biopsy specimens. Down-regulation of survivin by siRNA or pharmacologically in RMS cells increased their susceptibility toward a T-cell attack, whereas induction of ICOS-L did not. Treatment of RMS-bearing Rag À/À mice with fetal acetylcholine receptorespecific chimeric T cells delayed xenograft growth; however, this happened without definitive tumor eradication. Combined blockade of survivin and application of chimeric T cells in vivo suppressed tumor proliferation during survivin inhibition. In conclusion, survivin blockade provides a strategy to sensitize RMS cells for T-celle based therapy. (Am J Pathol 2013, 182: 2121e2131; http://dx

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“…Analogous results with higher rates of acute toxicity have also been reported in several other studies (Table 2). Therefore, clinical characteristics and additional biomarkers, for example, survivin, are required for risk stratification in rectal cancer patients [37,38].…”

Section: Discussionmentioning

confidence: 99%

Gender-Specific Acute Organ Toxicity during Intensified Preoperative Radiochemotherapy for Rectal Cancer

et al. 2011

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Learning Objectives After completing this course, the reader will be able to: Describe present strategies of treatment of locally advanced rectal cancer and ongoing clinical trials, including neoadjuvant radiochemotherapy with 50.4 Gy and concomitant 5-FU +/− oxaliplatin.Define the basic clinical parameters, with special emphasis on gender and BMI, correlating with radiochemotherapy-associated side effects in rectal cancer patients and differences in severity of toxicity. CME This article is available for continuing medical education credit at CME.TheOncologist.com Patients with locally advanced rectal cancer (cUICC stages II/III) are typically treated with preoperative 5-fluorouracil–based (5-FU–based) radiochemotherapy (RCT). However, trials are currently being conducted to improve the complete remission rates and the systemic control by combining 5-FU with oxaliplatin. The primary objective was to identify the subgroups of rectal cancer patients who were at risk for high-grade toxicity. All 196 patients who were included in the present study were treated with 50.4 Gy and chemotherapy that included either 5-FU (n = 115) or 5-FU+oxaliplatin (n = 81). The preoperative RCT was followed by a total mesorectal excision and adjuvant chemotherapy. Acute toxicity was monitored weekly and a toxicity grade ≥3 (Common Toxicity Criteria) for a skin reaction, cystitis, proctitis, or enteritis was defined as high-grade acute organ toxicity. After RCT with 5-FU+oxaliplatin, complete tumor remission was achieved in 13.6% of the patients and in 11.3% after RCT with 5-FU alone. Complete irradiation dosages of 50.4 Gy were given to 99% (5-FU) and 95% (5-FU+oxaliplatin) of the patients. Concomitant chemotherapy was fully administered in 95% of the patients treated with 5-FU compared with the 84% of patients treated with 5-FU+oxaliplatin. A significantly higher proportion of acute organ toxicity was found in the patients who were treated with 5-FU+oxaliplatin compared with those who were treated with 5-FU. Additionally, women with a low body mass index were at the highest risk for acute organ toxicity. These results suggest that there are basic clinical parameters, such as gender and body mass index, that may be potential markers for generating individual risk profiles of RCT-induced toxicity.

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The Role of Survivin for Radiation Oncology: Moving Beyond Apoptosis Inhibition

Cited by 35 publications

References 110 publications

The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances the Antitumoral Activity of Gemcitabine in Human Pancreatic Cancer Cell Lines

The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances the Antitumoral Activity of Gemcitabine in Human Pancreatic Cancer Cell Lines

Survivin Blockade Sensitizes Rhabdomyosarcoma Cells for Lysis by Fetal Acetylcholine Receptor–Redirected T Cells

Gender-Specific Acute Organ Toxicity during Intensified Preoperative Radiochemotherapy for Rectal Cancer

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