In vivo evaluation of intravesical paclitaxel and combined bcl-xL antisense oligodeoxynucleotide treatment for orthotopic urothelial carcinoma

Bolenz, Christian; Weiß, Christel; Wenzel, Melanie; Gabriel, Ute; Steidler, Annette; Becker, Andreas; Herrmann, Edwin; Trojan, Lutz; Michel, Maurice Stephan

doi:10.1007/s00432-008-0500-5

Cited by 4 publications

(4 citation statements)

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“…Furthermore, the inhibitory efficiency of AS-ODNs depended on the sequences and modifications of the constructs as well as on the type of delivery agent (11). However, it was reported in several studies that a treatment of BCa cells with Bcl-xLdirected AS-ODNs alone did not induce significant inhibition of viability, whereas a combination with chemotherapeutics promoted a significant increase of apoptosis in tumor cell lines as evidence for chemosensitization (11,14,17). To improve the efficiency of Bcl-xL-targeted AS-ODNs we systematically designed and characterized new AS-ODNs.…”

Section: Discussionmentioning

confidence: 99%

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Antisense- and siRNA-mediated inhibition of the anti-apoptotic gene Bcl-xL for chemosensitization of bladder cancer cells

Rieger

Huebner

Temme

et al. 2015

International Journal of Oncology

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Bcl-xL is an apoptosis inhibitor that is upregulated in bladder cancer (BCa) and provides an attractive target for molecular therapies. Treatment with specific antisense oligodeoxynucleotides (AS‑ODNs) or small interfering RNAs (siRNAs) were able to sensitize BCa cells to conventional chemotherapeutics. Ten new Bcl‑xL‑targeting AS‑ODNs were systematically designed by using predicting software. AS‑BX2034 and AS‑BX2100 as well as the previously optimized siRNA construct si‑BX713 were selected for further detailed in vitro analysis in the BCa cell lines UM‑UC‑3 and EJ28. Bcl‑xL mRNA and protein expression levels, cell viability and apoptosis were examined 72 h after transfection. A single treatment with AS‑BX2034 or AS‑BX2100 caused only a low inhibition of the Bcl‑xL mRNA expression with the highest reduction of ≤20% in UM‑UC‑3 cells. In contrast, a single treatment with si‑BX713 strongly decreased Bcl‑xL mRNA expression level by ≤69% in UM‑UC‑3 cells and by ≤86% in EJ28 cells. Both gene expression inhibitor types induced a low to moderate reduction of viability. Depending on the cell line, a combined treatment with AS‑BX2100 or si‑BX713 and cisplatin (CDDP) caused an additional inhibition of cell viability by ~33 and 38%, respectively, compared to the respective control construct combined with CDDP. In comparison to the respective control treatment, combinations of AS‑BX2100 and CDDP led to a stronger induction of apoptosis by 57% in UM‑UC‑3 cells and 44% in EJ28 cells, whereas the combination of si‑BX713 and CDDP enhanced apoptosis by 38 and 118% in UM‑UC‑3 and EJ28 cells, respectively. Our comparative studies showed a stronger knockdown of Bcl‑xL by the siRNA construct compared to AS‑ODN treatment in both BCa cell lines. In combinatory treatments, the Bcl‑xL-directed siRNA markedly enhanced the anti-proliferative and apoptotic effects of CDDP and therefore, may serve as suitable tool for chemosensitization of BCa cells.

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Section: Discussionmentioning

confidence: 99%

“…However, the described Bcl-xL-directed AS-ODNs alone did not promote a significant inhibition of viability of BCa cells (11,17,18). For this reason, alternative AS-ODNs with a potentially higher inhibitory efficiency would be preferable.…”

Section: Introductionmentioning

confidence: 95%

Antisense- and siRNA-mediated inhibition of the anti-apoptotic gene Bcl-xL for chemosensitization of bladder cancer cells

Rieger

Huebner

Temme

et al. 2015

International Journal of Oncology

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“…Moreover, Bcl-xL not only inhibits cell apoptosis and boosts survival of cells, but also resists apoptosis mediated by cancer suppressor genes such as P53 and C-myc (16). Research has shown that the Bcl-xL gene was highly expressed in many types of tumor cells (17,18), and that Bcl-xL, which plays a role in the occurrence and development of bladder cancer, may be used for the prognosis and treatment of the relapse of bladder cancer (19,20).…”

Section: Discussionmentioning

confidence: 99%

β-elemene acts as an antitumor factor and downregulates the expression of survivin, Bcl-xL and Mta-1

et al. 2012

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Abstract. β-elemene, a non-cellular antineoplastic agent, may be used to effectively inhibit the growth and proliferation of various types of tumor cells by inhibiting the nucleic acid synthesis or inducing their apoptosis and differentiation. The aim of this study was to investigate the expression, as well as the effects, of Mta-1, survivin and Bcl-xL in T24 bladder cancer cells following β-elemene treatment. The expression of the three proteins in T24 cells following β-elemene treatment was analyzed by immunocytochemistry staining and western blot analysis. The survival rate and apoptosis of T24 cells following β-elemene treatment was detected by MTT assay and TUNEL staining. We analyzed the internal corelations between apoptosis-associated genes, tumor metastasis-associated genes (cancer genes) and cell apoptosis, and investigated the mechanism of action by which β-elemene induces the apoptosis of T24 cells at a molecular level. These results provide scientific evidence for further study on the anticancer effect of β-elemene in carcinoma of the urinary bladder. In this study, it is shown that β-elemene downregulates the expression of survivin, Bcl-xL and Mta-1 in tumor cells. The apoptosis of T24 cells is dependent on the dosage and length of incubation time of β-elemene.

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“…Although Bcl-2 was not overexpressed frequently in UC of urinary bladder (Kirsh et al , 1998), Bcl-xL is expressed at a high frequency (Lebedeva et al , 2001; Korkolopoulou et al , 2002), therefore, it might become the target of treatment in UC. Several studies have evaluated the prognostic role of Bcl-xL protein expression in bladder carcinoma, especially for superficial bladder carcinoma (Gabriel et al , 2008; Bolenz et al , 2009). However, the status of Bcl-xL expression in UTUC tissues and its prognostic significance are unclear.…”

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confidence: 99%

Prognostic significance of Bcl-xL expression and efficacy of Bcl-xL targeting therapy in urothelial carcinoma

et al. 2013

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Background:Bcl-xL has an important role in the control of cell death through its inhibition of apoptosis. The aim of this study was to investigate the clinicopathological significance of Bcl-xL in upper urinary tract urothelial carcinoma (UTUC) and the therapeutic effect of targeting Bcl-xL protein in urothelial carcinoma (UC) cells.Methods:We evaluated the immunohistochemical expression of Bcl-xL in 175 UTUC patients to determine the clinical role of Bcl-xL expression in clinical outcome. We used bafilomycin A1 (BMA) as a specific inhibitor of Bcl-xL to examine the biological effects in UC cells in vitro and in vivo.Results:Immunohistochemical analysis of Bcl-xL expression revealed that patients with a high Bcl-xL score had a significantly lower 5-year cancer-specific survival (CSS) rate (53.2%) than those with a low Bcl-xL score (77.2%) (P=0.0011). Multivariate analysis indicated that a high Bcl-xL score was an independent prognostic factor of CSS (P=0.023). BMA inhibited UMUC-3 cell proliferation in vitro by induction of apoptosis. Treatment with BMA significantly inhibited tumour growth in UMUC-3 tumours in this mouse xenograft model accompanied by an elevated apoptosis induction.Conclusion:Bcl-xL appears to be a significant molecular marker for the prognosis of UTUCs. Targeting Bcl-xL may be a promising therapeutic strategy for patients with UC.

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In vivo evaluation of intravesical paclitaxel and combined bcl-xL antisense oligodeoxynucleotide treatment for orthotopic urothelial carcinoma

Abstract: We present an in vivo evaluation of intravesical treatment with paclitaxel and combined bcl-xL AS-ODNs. Despite efficient tumor size reduction, no gain was observed when adding bcl-xL AS-ODNs in this experimental setting.

Cited by 4 publications

References 31 publications

Antisense- and siRNA-mediated inhibition of the anti-apoptotic gene Bcl-xL for chemosensitization of bladder cancer cells

Antisense- and siRNA-mediated inhibition of the anti-apoptotic gene Bcl-xL for chemosensitization of bladder cancer cells

β-elemene acts as an antitumor factor and downregulates the expression of survivin, Bcl-xL and Mta-1

Prognostic significance of Bcl-xL expression and efficacy of Bcl-xL targeting therapy in urothelial carcinoma

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