The Molecular Basis of Cisplatin Resistance in Bladder Cancer Cells

Köberle, Beate; Piée-Staffa, Andrea

doi:10.5772/27073

Cited by 6 publications

(5 citation statements)

References 150 publications

(141 reference statements)

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“…Cisplatin, following activation by aquation, initiates cell death primarily through binding to DNA at the N7 of purine bases, leading to the formation of cross-links inhibiting DNA replication and transcription, triggering cell cycle arrest and apoptosis [ 3 , 4 ]. The most prominent lesions are intrastrand crosslinks, which, unless repaired by nucleotide excision repair [ 5 ], lead to apoptosis [ 4 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Diverse molecular mechanisms underlying cisplatin resistance including decreased cellular uptake, increased cellular efflux, enhanced cellular inactivation, and increased cellular tolerance to DNA damage have been described for different cancer types. Thus, factors contributing to cisplatin resistance are usually categorised as mediating pre-target (transport, metabolism), on-target (DNA-cisplatin adduct formation, DNA-damage response), or post-target (evasion of apoptosis, cell-cycle arrest) resistance [ 6 , 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Further, on-target mechanisms like alterations in DNA damage responses have been observed in cancers. Cisplatin-induced DNA damage is mostly repaired by nucleotide excision (NER) and homologous recombination (HR) repair, or is overcome by translesion synthesis (TLS) [ 6 ]. Specifically, interesting candidates relevant for on-target resistance are ERCC1/2 (NER), MLH1, MSH2 (DNA mismatch repair, MMR), and POLH (TLS) [ 23 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines

Skowron

Melnikova

Roermund

et al. 2018

IJMS

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Therapeutic efficacy of cisplatin-based treatment of late stage urothelial carcinoma (UC) is limited by chemoresistance. To elucidate underlying mechanisms and to develop new approaches for overcoming resistance, we generated long-term cisplatin treated (LTT) UC cell lines, characterised their cisplatin response, and determined the expression of molecules involved in cisplatin transport and detoxification, DNA repair, and apoptosis. Inhibitors of metallothioneins and Survivin were applied to investigate their ability to sensitise towards cisplatin. Cell growth, proliferation, and clonogenicity were examined after cisplatin treatment by MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, EdU (5-ethynyl-2’-deoxyuridine) incorporation assay, and Giemsa staining, respectively. Cell cycle distribution and apoptosis were quantified by flow cytometry. mRNA and protein expressions were measured by real-time quantitative (qRT)-PCR, western blot, or immunofluorescence staining. LTTs recovered rapidly from cisplatin stress compared to parental cells. In LTTs, to various extents, cisplatin exporters and metallothioneins were induced, cisplatin adduct levels and DNA damage were decreased, whereas expression of DNA repair factors and specific anti-apoptotic factors was elevated. Pharmacological inhibition of Survivin, but not of metallothioneins, sensitised LTTs to cisplatin, in an additive manner. LTTs minimise cisplatin-induced DNA damage and evade apoptosis by increased expression of anti-apoptotic factors. The observed diversity among the four LTTs highlights the complexity of cisplatin resistance mechanisms even within one tumour entity, explaining heterogeneity in patient responses to chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines

Skowron

Melnikova

Roermund

et al. 2018

IJMS

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“…27 We therefore fit cellular accumulation rates for both gemcitabine and cisplatin linearly to the IC50 of each cell type, with some modcations. 36,39 …”

Section: Methodsmentioning

confidence: 99%

A Spatiotemporal Model to Simulate Chemotherapy Regimens for Heterogeneous Bladder Cancer Metastases to the Lung

Winner

Costello

2016

Biocomputing 2017

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Tumors are composed of heterogeneous populations of cells. Somatic genetic aberrations are one form of heterogeneity that allows clonal cells to adapt to chemotherapeutic stress, thus providing a path for resistance to arise. In silico modeling of tumors provides a platform for rapid, quantitative experiments to inexpensively study how compositional heterogeneity contributes to drug resistance. Accordingly, we have built a spatiotemporal model of a lung metastasis originating from a primary bladder tumor, incorporating in vivo drug concentrations of first-line chemotherapy, resistance data from bladder cancer cell lines, vascular density of lung metastases, and gains in resistance in cells that survive chemotherapy. In metastatic bladder cancer, a first-line drug regimen includes six cycles of gemcitabine plus cisplatin (GC) delivered simultaneously on day 1, and gemcitabine on day 8 in each 21-day cycle. The interaction between gemcitabine and cisplatin has been shown to be synergistic in vitro, and results in better outcomes in patients. Our model shows that during simulated treatment with this regimen, GC synergy does begin to kill cells that are more resistant to cisplatin, but repopulation by resistant cells occurs. Post-regimen populations are mixtures of the original, seeded resistant clones, and/or new clones that have gained resistance to cisplatin, gemcitabine, or both drugs. The emergence of a tumor with increased resistance is qualitatively consistent with the five-year survival of 6.8% for patients with metastatic transitional cell carcinoma of the urinary bladder treated with a GC regimen. The model can be further used to explore the parameter space for clinically relevant variables, including the timing of drug delivery to optimize cell death, and patient-specific data such as vascular density, rates of resistance gain, disease progression, and molecular profiles, and can be expanded for data on toxicity. The model is specific to bladder cancer, which has not previously been modeled in this context, but can be adapted to represent other cancers.

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“…Chemotherapy is the most important adjuvant treatment for both NMIBC and MIBC. However, after initially favorable response, inferior chemo-sensitivity or even chemo-resistance may arise due to alterations in drug metabolism, DNA repair or apoptotic pathways [ 3 , 4 ]. Hence, relevant studies are urgently needed to further reveal mechanisms of UBC development and optimize current therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Targeting of CCN2 suppresses tumor progression and improves chemo-sensitivity in urothelial bladder cancer

Wang

Gao

et al. 2017

Oncotarget

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Urothelial bladder cancer (UBC) is the most common urinary neoplasm in China. CCN family protein 2 (CCN2), a cysteine-rich matricellular protein, is abnormally expressed in several cancer types and involved in tumor progression or chemo-resistance. However, detailed expression patterns and effects of CCN2 in UBC still remain unknown. We found that down-regulation of CCN2 suppressed proliferation, migration and invasion of UBC cells in vitro and targeting of CCN2 decelerated xenograft growth in vivo. When treated with mitomycin C (MMC), CCN2-scilencing UBC cells showed lower survival and higher apoptotic rates and these effects were probably mediated via inactivation of Akt and Erk pathways. We also demonstrated the clinical significance of CCN2 expression, which was higher in UBC tissues and associated with advanced tumor stage and high pathologic grade. Taken together, our data suggest that CCN2 is an oncogene in UBC and might serve as a matricellular target for improving chemotherapeutic efficacy.

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The Molecular Basis of Cisplatin Resistance in Bladder Cancer Cells

Cited by 6 publications

References 150 publications

Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines

Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines

A Spatiotemporal Model to Simulate Chemotherapy Regimens for Heterogeneous Bladder Cancer Metastases to the Lung

Targeting of CCN2 suppresses tumor progression and improves chemo-sensitivity in urothelial bladder cancer

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