Assessment of the tumourigenic and metastatic properties of SK-MEL28 melanoma cells surviving electrochemotherapy with bleomycin

Todorović, Vesna; Serša, Gregor; Mlakar, Vid; Glavač, Damjan; Čemažar, Maja

doi:10.2478/v10019-012-0010-6

Cited by 12 publications

(6 citation statements)

References 53 publications

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“…In previous studies, the intrinsic susceptibility of the cells to bleomycin was an important predictive factor for the antitumour effectiveness. Several studies have demonstrated the differences in cell sensitivity to electrochemotherapy . However, the results of the present study demonstrated that other factors, related to the tumour micro‐environment, also influence the tumour response to electrochemotherapy.…”

Section: Discussioncontrasting

confidence: 45%

Vascularization of the tumours affects the pharmacokinetics of bleomycin and the effectiveness of electrochemotherapy

Groselj

Kranjc

Bošnjak

et al. 2018

Basic Clin Pharma Tox

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Pre-clinical and clinical data indicate differences in the responses of melanoma and carcinoma tumours to electrochemotherapy. The purpose of this study was to investigate the origin of this difference, whether it is due to the intrinsic difference in tumour cell susceptibility to the chemotherapeutic, or due to the tumour micro-environment. For this purpose, we performed a pre-clinical study in B16F1 melanoma and TS/A carcinoma tumours in mice, in which the antitumour effectiveness of electrochemotherapy with bleomycin, the intrinsic sensitivity of tumour cells in vitro, the pharmacokinetics of bleomycin in plasma and tumours, and the vascularization of tumours in vivo were evaluated. The results of the treatment show that carcinoma was significantly more responsive to electrochemotherapy than melanoma. This effect cannot be ascribed to the intrinsic sensitivity of these cells, as melanoma cells were more sensitive than carcinoma cells in vitro. The difference in responses could be ascribed to differences in the pharmacokinetics of bleomycin; at the time of electroporation in carcinomas, more bleomycin was accumulated. This effect could be due to differences in tumour vascularization, as carcinoma tumours had numerous well-distributed, small blood vessels, while melanomas were less vascularized, exhibiting predominantly larger vessels. In conclusion, this study provides evidence on the importance of the tumour micro-environment, particularly the tumour vasculature, in the responses of the tumours to bleomycin electrochemotherapy. Vasculature is important for the pharmacokinetics of bleomycin, influencing drug accumulation and drug distribution in tumours, and might be used as a predictive factor for the tumour response to electrochemotherapy.

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Section: Discussioncontrasting

confidence: 45%

Vascularization of the tumours affects the pharmacokinetics of bleomycin and the effectiveness of electrochemotherapy

Groselj

Kranjc

Bošnjak

et al. 2018

Basic Clin Pharma Tox

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“…The knowledge of the cell death mechanisms and tumorigenic properties of the cells, and development of advanced therapies is therefore a key to successful treatment 18,19…”

Section: Discussionmentioning

confidence: 99%

Staurosporine induces different cell death forms in cultured rat astrocytes

Simenc¹,

Lipnik‐Štangelj²

2012

Radiology and Oncology

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BackgroundAstroglial cells are frequently involved in malignant transformation. Besides apoptosis, necroptosis, a different form of regulated cell death, seems to be related with glioblastoma genesis, proliferation, angiogenesis and invasion. In the present work we elucidated mechanisms of necroptosis in cultured astrocytes, and compared them with apoptosis, caused by staurosporine.Materials and methodsCultured rat cortical astrocytes were used for a cell death studies. Cell death was induced by different concentrations of staurosporine, and modified by inhibitors of apoptosis (z-vad-fmk) and necroptosis (nec-1). Different forms of a cell death were detected using flow cytometry.ResultsWe showed that staurosporine, depending on concentration, induces both, apoptosis as well as necroptosis. Treatment with 10−7 M staurosporine increased apoptosis of astrocytes after the regeneration in a staurosporine free medium. When caspases were inhibited, apoptosis was attenuated, while necroptosis was slightly increased. Treatment with 10−6 M staurosporine induced necroptosis that occurred after the regeneration of astrocytes in a staurosporine free medium, as well as without regeneration period. Necroptosis was significantly attenuated by nec-1 which inhibits RIP1 kinase. On the other hand, the inhibition of caspases had no effect on necroptosis. Furthermore, staurosporine activated RIP1 kinase increased the production of reactive oxygen species, while an antioxidant BHA significantly attenuated necroptosis.ConclusionStaurosporine can induce apoptosis and/or necroptosis in cultured astrocytes via different signalling pathways. Distinction between different forms of cell death is crucial in the studies of therapy-induced necroptosis.

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“…Trypsinized B16.F10 mouse melanoma cells were suspended in electroporation buffer and pDNA added as described previously. 62 Aliquots were transferred to cuvettes or pipetted between 2 mm gap steel electrodes. Two different pulse types were used, eight square wave electric pulses at an amplitude over distance ratio 600 V/cm, a pulse duration of 5 ms, and a frequency 1 Hz (EP), and six square wave electric pulses at an amplitude over distance ratio 1,300 V/cm, a pulse duration of 100 µs, and a frequency of 4 Hz (EP1) electric pulses were generated by an in-house built electroporator (GT-01, Faculty of Electrical Engineering, University of Ljubljana, Slovenia) or with a T820 Electrosquare porator (BTX Molecular Delivery Systems, Holliston, MA).…”

Section: Methodsmentioning

confidence: 99%

Cytosolic DNA Sensor Upregulation Accompanies DNA Electrotransfer in B16.F10 Melanoma Cells

Žnidar

Bošnjak

Čemažar

et al. 2016

Molecular Therapy - Nucleic Acids

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In several preclinical tumor models, antitumor effects occur after intratumoral electroporation, also known as electrotransfer, of plasmid DNA devoid of a therapeutic gene. In mouse melanomas, these effects are preceded by significant elevation of several proinflammatory cytokines. These observations implicate the binding and activation of intracellular DNA-specific pattern recognition receptors or DNA sensors in response to DNA electrotransfer. In tumors, IFNβ mRNA and protein levels significantly increased. The mRNAs of several DNA sensors were detected, and DAI, DDX60, and p204 tended to be upregulated. These effects were accompanied with reduced tumor growth and increased tumor necrosis. In B16.F10 cells in culture, IFNβ mRNA and protein levels were significantly upregulated. The mRNAs for several DNA sensors were present in these cells; DNA-dependent activator of interferon regulatory factor (DAI), DEAD (Asp-Glu-Ala-Asp) box polypeptide 60 (DDX60), and p204 were significantly upregulated while DDX60 protein levels were coordinately upregulated. Upregulation of DNA sensors in tumors could be masked by the lower transfection efficiency compared to in vitro or to dilution by other tumor cell types. Mirroring the observation of tumor necrosis, cells underwent a significant DNA concentration-dependent decrease in proliferation and survival. Taken together, these results indicate that DNA electrotransfer may cause the upregulation of several intracellular DNA sensors in B16.F10 cells, inducing effects in vitro and potentially in vivo.

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Assessment of the tumourigenic and metastatic properties of SK-MEL28 melanoma cells surviving electrochemotherapy with bleomycin

Cited by 12 publications

References 53 publications

Vascularization of the tumours affects the pharmacokinetics of bleomycin and the effectiveness of electrochemotherapy

Vascularization of the tumours affects the pharmacokinetics of bleomycin and the effectiveness of electrochemotherapy

Staurosporine induces different cell death forms in cultured rat astrocytes

Cytosolic DNA Sensor Upregulation Accompanies DNA Electrotransfer in B16.F10 Melanoma Cells

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