Increased HRD score in cisplatin resistant penile cancer cells.

Background/introduction: Penile cancer is a rare disease in demand for new therapeutic options. Frequently used combination chemotherapy with 5 fluorouracil (5-FU) and cisplatin (CDDP) in patients with metastatic penile cancer mostly results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance against standard therapy could help to understand molecular mechanisms underlying chemotherapy resistance and to identify candidate treatments for an efficient second line therapy.

Value of c-MET and Associated Signaling Elements for Predicting Outcomes and Targeted Therapy in Penile Cancer.

Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis.

Testing of the Survivin Suppressant YM155 in a Large Panel of Drug-Resistant Neuroblastoma Cell Lines.

The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). Seventy seven (77) cell lines displayed YM155 ICs in the range of clinical YM155 concentrations.

Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen.

Flubendazole was shown to exert anti-leukaemia and anti-myeloma activity through inhibition of microtubule function. Here, flubendazole was tested for its effects on the viability of in total 461 cancer cell lines. Neuroblastoma was identified as highly flubendazole-sensitive cancer entity in a screen of 321 cell lines from 26 cancer entities.

Chemotherapy-associated angiogenesis in neuroblastoma tumors.

The influences of cytotoxic drugs on endothelial cells remain incompletely understood. Herein, we examined the effects of chemotherapeutic agents in experimental angiogenesis models and analyzed vessel densities in clinical neuroblastoma tumor samples. Cisplatin (20 to 500 ng/mL), doxorubicin (4 to 100 ng/mL), and vincristine (0.

Chemoresistance acquisition induces a global shift of expression of aniogenesis-associated genes and increased pro-angogenic activity in neuroblastoma cells.

Background: Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology.

Results: Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated genes significantly differs between chemosensitive and chemoresistant neuroblastoma cells.

Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines.

Artemisinin derivatives are well-tolerated anti-malaria drugs that also exert anti-cancer activity. Here, we investigated artemisinin and its derivatives dihydroartemisinin and artesunate in a panel of chemosensitive and chemoresistant human neuroblastoma cells as well as in primary neuroblastoma cultures. Only dihydroartemisinin and artesunate affected neuroblastoma cell viability with artesunate being more active.

Novel composite hyaluronan/type I collagen/fibrin scaffold enhances repair of osteochondral defect in rabbit knee.

A new composite scaffold containing type I collagen, hyaluronan, and fibrin was prepared with and without autologous chondrocytes and implanted into a rabbit femoral trochlea. The biophysical properties of the composite scaffold were similar to native cartilage. The macroscopic, histological, and immunohistochemical analysis of the regenerated tissue from cell-seeded scaffolds was performed 6 weeks after the implantation and predominantly showed formation of hyaline cartilage accompanied by production of glycosaminoglycans and type II collagen with minor fibro-cartilage production.

Onconase induces caspase-independent cell death in chemoresistant neuroblastoma cells.

The efficacy of Onconase on the growth of a panel of chemosensitive and chemoresistant neuroblastoma cell lines was investigated. Onconase decreased cell viability of chemosensitive (IMR-32, UKF-NB-3) and chemoresistant neuroblastoma cell lines characterised by high expression of P-glycoprotein (P-gp) (UKF-NB-3(r)DOX(20)) or by high P-gp expression in combination with mutated p53 (UKF-NB-3(r)VCR(10), Be(2)-C), in a similar manner. Moreover, Onconase caused cell cycle block in G1 phase and induced caspase-independent cell death.

Anti-cancer effects of bortezomib against chemoresistant neuroblastoma cell lines in vitro and in vivo.

The proteasome inhibitor bortezomib (Velcade) was recently approved for the treatment of therapy-refractive multiple myeloma and is under investigation for numerous other types of cancer. A phase I clinical trial in paediatric patients resulted in tolerable toxicity. Since the emergence of chemoresistance represents one of the major drawbacks in cancer therapy, we investigated the influence of bortezomib on multi-drug resistant human neuroblastoma cell lines characterised by P-glycoprotein expression and p53 mutation.

Increased malignant behavior in neuroblastoma cells with acquired multi-drug resistance does not depend on P-gp expression.

Acquisition of P-gp-mediated multidrug-resistance does not always correlate with observed malignant behavior of NB. To characterize alterations accompanying development of multidrug-resistance in NB we established two neuroblastoma cell sublines resistant to vincristine (UKF-NB-3rVCR10) and doxorubicin (UKF-NB-3rDOX20). UKF-NB-3rVCR10 and UKF-NB-3rDOX20 overexpressed functional P-gp and developed an increased malignant phenotype: presented constitutive phosphorylation of AKT, resistance to gamma-irradiation, and had increased survival in serum-free medium.

Multimutated herpes simplex virus g207 is a potent inhibitor of angiogenesis.

The mode of the antitumoral activity of multimutated oncolytic herpes simplex virus type 1 G207 has not been fully elucidated yet. Because the antitumoral activity of many drugs involves the inhibition of tumor blood vessel formation, we determined if G207 had an influence on angiogenesis. Monolayers of human umbilical vein endothelial cells and human dermal microvascular endothelial cells, but not human dermal fibroblasts, bronchial epithelial cells, and retinal glial cells, were highly sensitive to the replicative and cytotoxic effects of G207.

Increased systemic efficacy of aphidicolin encapsulated in liposomes.

Aphidicolin, a tetracyclic diterpene antibiotic produced by Cephalosporium aphidicola, is under investigation as anti-cancer drug. Because of its poor solubility in water, it cannot be administered directly in vivo. Systemic application of aphidicolin glycinate or aphidicolin gamma-cyclodextrin complexes resulted in tumour growth inhibition but not in cures.

Valproic acid and interferon-alpha synergistically inhibit neuroblastoma cell growth in vitro and in vivo.

Valproic acid (VPA) as a differentiation inducing anti-neoplastic substance is currently tested in solid tumour and leukaemia patients. Previously, we were able to show that the anti-cancer activity of VPA was synergistically increased by interferon-alpha (IFN-alpha) in Be(2)-C neuroblastoma (NB) cells. Now, we studied the effects of VPA in combination with IFN-alpha on two other NB cell lines.

Valproic acid inhibits angiogenesis in vitro and in vivo.

Valproic acid (VPA) is a widely used antiepileptic agent that is undergoing clinical evaluation for anticancer therapy. We assessed the effects of VPA on angiogenesis in vitro and in vivo. In human umbilical vein endothelial cells, therapeutically relevant concentrations of VPA (0.

Thrombin stimulates IL-6 and IL-8 expression in cytomegalovirus-infected human retinal pigment epithelial cells.

Recently, we reported that thrombin specifically stimulates protease-activated receptor-1 (PAR-1) signaling in RPE entailing inhibition of Sp1 dependent HCMV replication. We now studied whether thrombin modulates the expression of the proinflammatory cytokine/chemokines IL-6 and IL-8 in mock- and cytomegalovirus-infected human retinal pigment epithelial cells (RPE). Our data show that thrombin/PAR-1 stimulates IL-6 and IL-8 gene transcription and protein secretion in both mock- and HCMV-infected RPE.

Effects of S-acetylglutathione in cell and animal model of herpes simplex virus type 1 infection.

Intracellular glutathione (GSH) plays an important regulatory role in the host response to viral infections. Replenishment of intracellular GSH is a desirable yet challenging goal, since systemic GSH supplementation is rather inefficient due to a short half-life of GSH in blood plasma. Further, GSH is not taken up by cells directly, but needs to be broken down into amino acids and resynthesized to GSH intracellularly, this process often being impaired during viral infections.

Sodium valproate facilitates the propagation of granulocytic ehrlichiae (Anaplasma phagocytophilum) in HL-60 cells.

As already shown, some inducers of the differentiation of promyelocytic cells along the granulocytic pathway, such as dimethylsulphoxide (DMSO) or all-trans retinoic acid, can enhance propagation of granulocytic ehrlichiae in HL-60 cell cultures. This study was conducted to prove whether sodium valproate, a salt of di-n-propylacetic acid (VPA) known to trigger cellular differentiation in several solid and hematopoietic malignancies is similarly efficient in ehrlichial cultures. Two cell lines derived from HL-60, that is, low-passage undifferentiated HL-60 (HL-60F) and high-passage HL-60 spontaneously differentiated towards monocytic phenotype (HL-60J) were grown in RPMI 1640 medium supplemented with 10% FBS.

Thrombin induces Sp1-mediated antiviral effects in cytomegalovirus-infected human retinal pigment epithelial cells.

Human cytomegalovirus (HCMV) retinitis causing retinal detachment and destruction of the blood-retina barrier is closely related to retinal hemorrhage/coagulation. However, the effects of procoagulants on HCMV (re)activation in retinal cells have not been investigated yet. Therefore, we studied whether thrombin modulates the expression of HCMV immediate early (IE) and late (L) genes in cultured human retinal pigment epithelial cells (RPE).

Potent oncolytic activity of multimutated herpes simplex virus G207 in combination with vincristine against human rhabdomyosarcoma.

Replication restricted oncolytic viruses such as multimutated herpes simplex virus type 1 (HSV-1) G207 represent a novel and attractive approach for cancer therapy, including pediatric solid tumors. Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood and is often diagnosed already as an advanced disseminated disease. Despite aggressive therapeutic approaches, the prognosis for patients with metastatic rhabdomyosarcoma remains grim.

Development of resistance to vincristine and doxorubicin in neuroblastoma alters malignant properties and induces additional karyotype changes: a preclinical model.

Cytotoxic drug treatment of neuroblastoma often leads to the development of drug resistance and may be associated with increased malignancy. To study the effects of long-term cytotoxic treatment on malignant properties of tumor cells, we established 2 neuroblastoma cell sublines resistant to vincristine (VCR) and doxorubicin (DOX). Both established cell lines (UKF-NB-2(r)VCR(20) and UKF-NB-2(r)DOX(100)) were highly resistant to VCR, DOX and vice-versa but retained their sensitivity to cisplatin.

Expression level of neural cell adhesion molecule (NCAM) inversely correlates with the ability of neuroblastoma cells to adhere to endothelium in vitro.

The precise function of cell adhesion molecules in the hematogenous phase of neuroblastoma metastasis is poorly understood. The aim of this study was to investigate whether neural cell adhesion molecule (NCAM) modulates neuroblastoma cell (NB) adhesion and transendothelial penetration in a coculture model. Our data, assessed on 11 NB cell lines, demonstrate an inverse correlation between NCAM expression and NB cell adhesion.