Cell cycle arrest and apoptosis in <i>TP53</i> subtypes of bladder carcinoma cell lines treated with cisplatin and gemcitabine

Silva, Glenda Nicioli da; Marcondes, João Paulo de Castro; Camargo, Elaine Aparecida de; Júnior, Geraldo Aleixo da Silva Passos; Sakamoto-Hojo, Elza T.; Salvadori, Daisy Maria Fávero

doi:10.1258/ebm.2010.009322

Cited by 41 publications

(45 citation statements)

References 51 publications

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“…20,21 However, our results show that the status of p53 gene might be an important factor to determine the sensitivity of different cell lines to apoptosis caused by PLK1 inhibitors. Although increased caspase-3 activity was detected for all inhibitors, the level of cell death was significantly higher in 5637 and T24 cells which are p53-deficient, and RT4 cells were particularly unaffected by exposure to BI 2536.…”

mentioning

confidence: 76%

In vitro targeting of Polo-like kinase 1 in bladder carcinoma

Brassesco

Pezuk

Morales

et al. 2013

Cancer Biology & Therapy

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mentioning

confidence: 76%

In vitro targeting of Polo-like kinase 1 in bladder carcinoma

Brassesco

Pezuk

Morales

et al. 2013

Cancer Biology & Therapy

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“…Cisplatin is an effective antitumor agent owing to its ability to induce intra-and inter-strand DNA cross-links (2). Cisplatin-based combination chemotherapy is currently the primary treatment strategy for patients with advanced bladder cancer, however, its clinical use as an anti-cancer agent is predominantly limited by its association with a high incidence of chemoresistance (3,4).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects of cisplatin and proteasome inhibitor bortezomib on human bladder cancer cells

et al. 2015

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Abstract. The proteasome inhibitor bortezomib is a promising novel agent in bladder cancer therapy; however, inducible cytoprotective mechanisms may limit its potential efficacy. To date, the cellular and molecular effects of proteasome inhibitors on bladder cancer cells have been poorly characterized. Despite the consistent rate of initial responses, cisplatin treatment typically results in the development of chemoresistance, leading to therapeutic failure. Therefore, the present study aimed to characterize the molecular mechanisms underlying the anti-proliferative effects of cisplatin and bortezomib combination therapy on the human T24 bladder cancer cell line, by analyzing the protein expression levels of apoptotic genes. Cytotoxic effects were measured using a water-soluble tetrazolium salt-1 assay, and the apoptosis-associated molecules were examined using western blot analysis and ELISA. It was observed that combined administration of cisplatin and bortezomib induced upregulation of caspase-3, -8 and -9, B-cell lymphoma-2 (Bcl-2)-like 11 and Bcl-2-interacting killer, but downregulated Bcl-2 and Bcl-extra large protein expression levels in T24 cells in a dose-dependent manner. Furthermore, enhanced protein expression of caspase-8 and -9, in line with the significantly increased caspase-3 activation, was detected when the cells were treated with a combination of cisplatin and bortezomib, compared with that of either agent alone. Bortezomib appeared to synergize with cisplatin to promote apoptosis via the extrinsic and intrinsic apoptotic pathways. Taken together, the results of the current study provide the preclinical framework for additional evaluation of the effects of combining bortezomib with other agents to induce apoptosis in bladder cancer cells.

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“…The 5637 cells, obtained from a moderately differentiated tumor, contain a TP53 allele carrying two mutations: one at codon 280 (Arg>Thr) and the second at codon 72 (Arg>Pro) (Cooper et al, 1994;Sanchez-Carbayo et al, 2007). The cells were cultured according to a previously described protocol (Da Silva et al, 2010). The antineoplastic drugs gemcitabine (dFdC, Gemzar) and cisplatin (CDDP) were obtained from Eli Lilly Laboratory (Eli Lilly and Company, Indianapolis, IN, USA) and Sigma-Aldrich, respectively.…”

Section: Cell Lines and Chemicalsmentioning

confidence: 99%

No Relationship between the Amount of DNA Damage and the Level of hMLH1 and RASSF1A Gene Expression in Bladder Cancer Cells Treated with Cisplatin and Gemcitabine

Camargo

Silva²,

Gobette³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Tumor response to antineoplastic drugs is not always predictable. This is also true for bladder carcinoma, a highly recurrent neoplasia. Currently, the combination of cisplatin and gemcitabine is well accepted as a standard protocol for treating bladder carcinoma. However, in some cases, this treatment protocol causes harmful side effects. Therefore, we investigated the roles of the genes TP53, RASSF1A (a tumor suppressor gene) and hMLH1 (a gene involved in the mismatch repair pathway) in cell susceptibility to cisplatin/gemcitabine treatment. Two bladder transitional carcinoma cell (TCC) lines, RT4 (wild-type TP53) and 5637 (mutated TP53), were used in this study. First, we evaluated whether the genotoxic potential of cisplatin/gemcitabine was dependent on TP53 status. Then, we evaluated whether the two antineoplastic drugs modulated RASSF1A and hMLH1 expression in the two cell lines. Increased DNA damage was observed in both cell lines after treatment with cisplatin or gemcitabine and with the two drugs simultaneously, as depicted by the comet assay. A lack of RASSF1A expression and hypermethylation of its promoter were observed before and after treatment in both cell lines. On the other hand, hMLH1 downregulation, unrelated to methylation status, was observed in RT4 cells after treatment with cisplatin or with cisplatin and gemcitabine simultaneously (wild-type TP53); in 5637 cells, hMLH1 was upregulated only after treatment with gemcitabine. In conclusion, the three treatment protocols were genotoxic, independent of TP53 status. However, cisplatin was the most effective, causing the highest level of DNA damage in both wild-type and mutated TP53 cells. Gemcitabine was the least genotoxic agent in both cell lines. Furthermore, no relationship was observed between the amount of DNA damage and the level of hMLH1 and RASSF1A expression. Therefore, other alternative pathways might be involved in cisplatin and gemcitabine genotoxicity in these two bladder cancer cell lines.

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Cell cycle arrest and apoptosis in TP53 subtypes of bladder carcinoma cell lines treated with cisplatin and gemcitabine

Cited by 41 publications

References 51 publications

In vitro targeting of Polo-like kinase 1 in bladder carcinoma

In vitro targeting of Polo-like kinase 1 in bladder carcinoma

Synergistic effects of cisplatin and proteasome inhibitor bortezomib on human bladder cancer cells

No Relationship between the Amount of DNA Damage and the Level of hMLH1 and RASSF1A Gene Expression in Bladder Cancer Cells Treated with Cisplatin and Gemcitabine

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