Killing Me Softly—Future Challenges in Apoptosis Research

Westhoff, Mike‐Andrew; Brühl, Oliver; Nonnenmacher, Lisa; Karpel‐Massler, Georg; Debatin, Klaus‐Michael

doi:10.3390/ijms15033746

Cited by 25 publications

(33 citation statements)

References 106 publications

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“…43 Derived tumor cells differently interact with ECM, have altered homocellular tumor-tumor and heterocellular tumorstromal interactions, which subsequently contribute to the adhesion-mediated apoptosis resistance. [44][45][46] Shifted balance between MMPs and their inhibitors (increased expression of MMP-1, -11, -14, -16, TIMP-1 and decreased MMP-2) indicates a different matrix remodeling, 47 potentially leading to anoikis resistance in melanoma cells by mechanism similar to the one suggested by Toricelli et al 48 CD-MSC/5FC exerts potent bystander effect in the cells with functional gap junction intercellular communication. 18 Higher expression of connexin-interacting proteins integrins β1 and β3 (ITGB1, ITGB3), α-catenin and β-catenin (CTNA1 and CTNB2) in EGFP-A375/Rel3 cells versus EGFP-A375iv clones may potentially contribute to resistance to apoptosis induction by channel modification.…”

Section: Discussionmentioning

confidence: 80%

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

et al. 2014

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Mesenchymal stromal cells (MSC) can be exploited as cellular delivery vehicles for the enzymes converting non-toxic prodrugs to toxic substances. Because of their inherent chemoresistance, they exert potent bystander and antitumor effect. Here we show that the human adipose tissue-derived MSC expressing fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) in combination with 5-fluorocytosine (5FC) mediated a long-term tumor-free survival in the 83.3% of tumor-bearing animals. CD-MSC/5FC treatment induced cytotoxicity against model human melanoma cells EGFP-A375. Only 4% of the therapeutic CD-MSC cells eliminated >98.5% of the tumor cells in vitro. Long-term tumor-free survival was confirmed in 15 out of the 18 animals. However, repeatedly used CD-MSC/5FC therapeutic regimen generated more aggressive and metastatic variant of the melanoma cells EGFP-A375/Rel3. These cells derived from the refractory xenotransplants exhibited increased resistance to the CD-MSC/5FC treatment, altered cell adhesion, migration, tumorigenic and metastatic properties. However, long-term curative effect was achieved by the augmentation of the CD-MSC/5FC regimen along with the inhibition of c-Met/hepatocyte growth factor signaling axis in this aggressive melanoma derivative. In summary, the CD-MSC/5FC regimen can be regarded as a very effective antitumor approach to achieve long-term tumor-free survival as demonstrated on a mouse model of aggressive human melanoma xenografts.

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Section: Discussionmentioning

confidence: 80%

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

et al. 2014

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“…Despite extensive investigations, a cure for GBM is not currently available. Radiotherapy and chemotherapy work predominantly by inducing apoptosis (19). The unfavorable prognosis for patients with glioblastomas is also due in part to poor knowledge of alterations to the molecular pathways involved.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis-related gene expression in tumor tissue samples obtained from patients diagnosed with glioblastoma multiforme

Blahovcová

Richterová

Kolarovszki

et al. 2015

International Journal of Molecular Medicine

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Tumors of the brain are very diverse in their biological behavior and are therefore considered a major issue in modern medicine. The heterogeneity of gliomas, their clinical presentation and their responses to treatment makes this type of tumor a challenging area of research. Glioblastoma multiforme (GBM) is the most common, and biologically the most aggressive, primary brain tumor in adults. The standard treatment for patients with newly diagnosed GBM consists of surgical resection, radiotherapy and chemotherapy. However, resistance to chemotherapy is a major obstacle to successful treatment. The aim of this study was to examine the changes occurring in the expression levels of apoptosis-associated genes in tumor tissue biopsy samples from 7 patients diagnosed with GBM and compare our results with a human astrocyte cell line (used as a reference) cultured under basic conditions. For molecular analysis, we used a commercial pre-designed microfluidic array to quantify the expression of 93 apoptosis-associated human genes. Significant changes in the expression levels of genes were observed in the tumor tissue samples obtained from patients with GBM. We determined significant changes in gene expression (n=32) in all apoptotic signaling pathways (BCl-2, TNF, Caspases, NF-κB, IAP and CARD), while the most pronounced deregulation (>5-fold) were observed in 46.9% events. The results of this study underline the importance of apoptosis in heterogenous tumor tissue. The identification of the apoptotic gene panel in tissue biopsies from patients with GBM may help improve the effectiveness of treatments for GBM in clinical practice and may broaden our understanding of brain tumor cell metabolism. Recognizing the changes in the expression of pro-apoptotic and anti-apoptotic genes may aid in the development of novel treatment strategies founded on a molecular basis.

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“…Despite considerable progress in research, the survival rate of GB patients has not improved as expected and resistance to clinical therapy is a major obstacle to successful treatment (7,14). Radiotherapy and chemotherapy work predominantly by inducing apoptosis (15). The unfavorable prognosis of patients diagnosed with GB can also be explained by our poor understanding of GB molecular pathway alterations.…”

Section: Microfluidic Profiling Of Apoptosis-related Genes After Treamentioning

confidence: 99%

Microfluidic profiling of apoptosis-related genes after treatment with BH3-mimetic agents in astrocyte and glioblastoma cell lines

et al. 2016

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Glioblastoma (GB) is the most frequent and biologically the most aggressive primary brain tumor in adults. Standard treatment for newly diagnosed GB consists of surgical resection, radiotherapy and chemotherapy. Resistance to therapy is a major obstacle, even with optimal treatment with a survival median of only 12-15 months. The heterogeneity and treatment response of GB makes this tumor type a challenging area of research. The aim of our study was to study the response of normal human astrocyte (HA) and human GB (T98G) cell lines to apoptosis inhibitors in vitro. ABT-737 is an inhibitor of anti-apoptotic proteins Bcl-2, Bcl-xL, Bcl-w, while MIM-1 is an Mcl-1 protein inhibitor. The viability of the cells was assayed biochemically using the cytotoxic methyl thiazolyl tetrazolium (MTT) assay. Changes in the expression of apoptosis-associated genes (n=93) in two human brain cell lines after treatment with the apoptosis inhibitors ABT-737 and MIM-1 (individually), between the apoptosis inhibitor treated group and the control group, were determined using a commercially pre-designed microfluidic array. Significant changes in apoptotic gene expression with more than a 2.0-fold difference in their expression levels were obtained in both cell lines; the most altered genes were in the HA cell line after MIM-1 treatment (n=42). These results contribute to the importance of apoptosis in normal and cancerous brain tissues and provide information on the effect of apoptosis inhibitors on cell viability and gene expression. Despite extensive investigations, a cure for GB is currently not available. The identification of an apoptotic gene panel and determining the sensitivity of normal and GB brain cells to individual apoptosis inhibitors could help to improve clinical practice and increase our understanding of brain tumor cell metabolism and apoptosis inhibitors in GB cells and astrocytes. Recognizing expression changes in pro-apoptotic and anti-apoptotic genes could contribute to the development of new treatments.

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Killing Me Softly—Future Challenges in Apoptosis Research

Cited by 25 publications

References 106 publications

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

Apoptosis-related gene expression in tumor tissue samples obtained from patients diagnosed with glioblastoma multiforme

Microfluidic profiling of apoptosis-related genes after treatment with BH3-mimetic agents in astrocyte and glioblastoma cell lines

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