Biomedical subjects

Claus Belka

Publications and source records attributed to Claus Belka.

42 records · Page 3Linked to original sources

PubMed2003

Guardians of cell death: the Bcl-2 family proteins.

Apoptosis is mediated through at least three major pathways that are regulated by (i) the death receptors, (ii) the mitochondria and (iii) the ER (endoplasmic reticulum). In most cells, these pathways are controlled by the Bcl-2 family of proteins that can be divided into anti-apoptotic and pro-apoptotic members. Although the overall amino acid sequence homology between the family members is relatively low, they contain highly conserved domains, referred to as BH (Bcl-2 homology) domains (BH1-4), that are essential for homo- and hetero-complex formation, as well as for their cell-death-inducing capacity. Structural and functional analyses revealed that the pro-apoptotic homologues can be subdivided into the Bax subfamily and the growing BH3-only subfamily. Recent data indicate that BH3-only proteins act as mediators that link various upstream signals, including death receptors and DNA damage signalling, to the mitochondrial and the ER pathway. This review discusses recent structural and functional insights into how these subfamilies promote or inhibit cell-death signals, and how these properties may be utilized for development of apoptosis-promoting small molecules, e.g. in cancer therapy.

Animals↗

PubMed2003

Apoptotic response of Chang cells to infection with Pseudomonas aeruginosa strains PAK and PAO-I: molecular ordering of the apoptosis signaling cascade and role of type IV pili.

Pseudomonas aeruginosa is a gram-negative facultative opportunistic pathogen associated with severe infections in immunocompromised hosts and in patients with cystic fibrosis. P. aeruginosa strains show divergent pathogenicity in vivo and trigger apoptosis of and/or are internalized into human host cells. In the present study, we studied the molecular ordering of apoptosis signaling upon infection of human conjunctiva epithelial Chang cells with P. aeruginosa PAK as well as the role of bacterial pili in the response to the infection. Our results show that CD95 up-regulation is followed by early activation of caspase-8 and -3 and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase. The data also demonstrate release of apoptosis inducing factor into the cytosol of infected cells. Induction of mitochondrial alterations, i.e., mitochondrial depolarization and release of cytochrome c, as well as cleavage of caspase-9, -7, and -1 occurred only at later time points. In addition, our results demonstrate that pili are required for P. aeruginosa-induced apoptosis of human epithelial cells. While the two piliated P. aeruginosa strains, PAO-I and PAK, induced apoptosis of Chang cells within 3 h of infection, the pilus-deficient P. aeruginosa mutants PAK Delta pilA and PAK Delta pilA Delta all were without effect. The pilus-deficient mutants failed to induce a significant up-regulation of CD95 on the cell surface and to trigger mitochondrial alterations or activation of caspase-8, -3, and -7. In addition, only the piliated wild-type strains induced caspase-1-mediated activation of interleukin-1 beta. Thus, pili are necessary for distinct infection-induced cellular responses of human epithelial cells.

Apoptosis↗

PubMed2003

Novel chemotherapeutic agents for the treatment of glioblastoma multiforme.

During the last few decades, the discovery of novel targets for therapeutic intervention led to the development of chemotherapeutic agents that specifically interfere with altered cellular functions of tumour cells. Genetic alterations in glioblastoma affect cell proliferation and cell cycle control, as well as invasive and metastatic growth. Therefore, innovative therapeutic strategies have been based on drugs targeting cellular proliferation, invasion, angiogenesis, metastasis and differentiation of tumour cells. Furthermore, disruption of cell-death pathways also contributes to the pathogenesis of glioblastoma and may result in resistance to chemotherapy and radiation. Therefore, additional treatment strategies that target intracellular survival and/or apoptotic pathways are under current laboratory investigation. The progress in the understanding of glioblastoma tumour biology and the refined diagnosis of individual patients together with the exploration of targeted drugs may allow a risk-adapted, individualised therapeutic strategy and will hopefully improve prognosis of glioblastoma patients in the future.

Angiogenesis Inhibitors↗

PubMed2003

Death receptor ligands: new strategies for combined treatment with ionizing radiation.

The major goal of modern radiation oncology is the achievement of a maximal tumor control with minimal normal tissue damage. However, normal tissue tolerance may preclude the application of tumoricidal radiation doses. In order to overcome this limitation, strategies either to increase normal tissue tolerance or to reduce the radiation dose required may prove beneficial. In this regard, attempts to minimize the required radiation dose by reducing the number of malignant clonogenic cells are promising. Therefore, therapies which induce programmed cell death (apoptosis) in tumor cells, may prove to be suitable approaches. TRAIL (TNFalpha-related apoptosis inducing ligand)/Apo2L is a very promising member of the family of death ligands. The ligand preferentially induces apoptotic cell death in a wide range of tumor cells but not in normal cells. TRAIL/Apo2L triggers apoptosis even in cells not undergoing apoptosis in response to radiation, since ionizing radiation induce apoptosis by a different pathway as death ligands although an overlapping set of molecules is involved. Combination of both modalities has been shown to induce additive or synergistic apoptotic effects and eradication of clonogenic tumor cells thereby increasing the therapeutic efficacy. The present article reviews this novel biological strategy for optimized radiotherapy based on the combination of ionizing irradiation and death receptor triggered cell death.

Animals↗

PubMed2003

Disruption of cell death signaling in cancer: impact on disease prognosis and response to therapy.

Disruption of cell cycle and apoptosis signaling pathways are key events during tumorigenesis, tumor progression and development of resistance against anticancer therapies. Thus, the analysis of functional alterations within these signaling cascades is of utmost importance for the understanding of resistance mechanisms, clinical outcome and risk-adapted treatment strategies. Key signaling pathways involved in the treatment resistance include the p53/p14ARF signaling complex and the mitochondrial apoptosis machinery. Apart from the direct genetic events, these signaling cascades are subject to epigenetic modulations implied by the tumor microenvironment.

Animals↗

PubMed2002

CT-guided percutaneous drainage of intra-abdominal abscesses: APACHE III score stratification of 1-year results. Acute Physiology, Age, Chronic Health Evaluation.

Our objective was to evaluate the clinical success rates of percutaneously drained intra-abdominal abscesses using a risk stratification score for severely ill patients (APACHE III; Acute Physiology, Age, Chronic Health Evaluation). In 75 patients CT-guided percutaneous abscess drainage was performed to treat intra-abdominal abscesses. The clinical success rate based on a 1-year follow-up was correlated with abscess etiology, size, and structure, as well as with the initial APACHE III score. Clinical success, i.e., the complete removal of the abscess without surgical treatment, was observed in 62 of 75 patients (83%). Abscess size (<200 cm(3)) and abscesses with a simple structure correlated with higher clinical success rates. Patients presenting with APACHE III scores below 30 were treated by percutaneous abscess drainages (PAD) alone significantly more often than patients presenting with higher APACHE scores. The percutaneous drainage of intra-abdominal abscesses shows good long-term results as long as abscesses are singular, small (<200 cm(3)), and located in well accessible regions in combination with low APACHE scores (<30).

Abdominal Abscess↗