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1.
Photodiagnosis Photodyn Ther ; 46: 104059, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38548041

ABSTRACT

OBJECTIVE: Herein we describe initial results in a porcine model of a fully implantable device designed to allow closed, repetitive photodynamic treatment of glioblastoma (GBM). METHODS: This implant, Globus Lucidus, is a transparent quartz glass sphere with light-emitting diodes releasing wavelengths of 630 nm (19.5 mW/cm2), 405 nm (5.0 mW/cm2) or 275 nm (0.9 mW/cm2). 5-aminolevulinic acid was the photosensitizing prodrug chosen for use with Globus Lucidus, hence the implants illuminated at 630 nm or 405 nm. An additional 275 nm wavelength-emittance was included to explore the effects of photochemical therapy (PCT) by ultraviolet (UV) light. Twenty healthy domestic pigs underwent right-frontal craniotomies. The Globus Lucidus device was inserted into a surgically created right-frontal lobe cavity. After postoperative recovery, irradiation for up to 30 min daily for up to 14 d, or continuous irradiation for up to 14.6 h was conducted. RESULTS: Surgery, implants, and repeated irradiations using the different wavelengths were generally well tolerated. Social behavior, wound healing, body weight, and temperature remained unaffected. Histopathological analyses revealed consistent leukocyte infiltration around the intracerebral implant sites with no significant differences between experimental and control groups. CONCLUSION: This Globus Lucidus porcine study prepares the groundwork for adjuvant, long-term, repeated PDT of the GBM infiltration zone. This is the first report of a fully implantable PDT/PCT device for the potential treatment of GBM. A preclinical effectivity study of Globus Lucidus PDT/PCT is warranted and in advanced stages of planning.


Subject(s)
Aminolevulinic Acid , Glioblastoma , Photochemotherapy , Photosensitizing Agents , Animals , Glioblastoma/drug therapy , Glioblastoma/therapy , Photochemotherapy/methods , Swine , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Aminolevulinic Acid/therapeutic use , Aminolevulinic Acid/pharmacology , Brain Neoplasms/drug therapy , Brain Neoplasms/therapy , Female
2.
Br J Cancer ; 130(8): 1365-1376, 2024 May.
Article in English | MEDLINE | ID: mdl-38396172

ABSTRACT

BACKGROUND: Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric fields that are continuously delivered to the brain through non-invasive arrays. On a different note, CUSP9v3 represents a drug repurposing strategy that includes 9 repurposed drugs plus metronomic temozolomide. Here, we examined whether TTFields enhance the antineoplastic activity of CUSP9v3 against this disease. METHODS: We performed preclinical testing of a multimodal approach of TTFields and CUSP9v3 in different glioblastoma models. RESULTS: TTFields had predominantly synergistic inhibitory effects on the cell viability of glioblastoma cells and non-directed movement was significantly impaired when combined with CUSP9v3. TTFields plus CUSP9v3 significantly enhanced apoptosis, which was associated with a decreased mitochondrial outer membrane potential (MOMP), enhanced cleavage of effector caspase 3 and reduced expression of Bcl-2 and Mcl-1. Moreover, oxidative phosphorylation and expression of respiratory chain complexes I, III and IV was markedly reduced. CONCLUSION: TTFields strongly enhance the CUSP9v3-mediated anti-glioblastoma activity. TTFields are currently widely used for the treatment of glioblastoma patients and CUSP9v3 was shown to have a favorable safety profile in a phase Ib/IIa trial (NCT02770378) which facilitates transition of this multimodal approach to the clinical setting.


Subject(s)
Antineoplastic Agents , Brain Neoplasms , Electric Stimulation Therapy , Glioblastoma , Humans , Glioblastoma/drug therapy , Drug Repositioning , Metabolic Reprogramming , Temozolomide/pharmacology , Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Combined Modality Therapy
3.
Clin Exp Med ; 23(7): 2979-2996, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37330918

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a medical condition characterized by widespread inflammation in the lungs with consequent proportional loss of gas exchange function. ARDS is linked with severe pulmonary or systemic infection. Several factors, including secretory cytokines, immune cells, and lung epithelial and endothelial cells, play a role in the development and progression of this disease. The present study is based on Pubmed database information (1987-2022) using the words "Acute respiratory distress syndrome", "Interleukin", "Cytokines" and "Immune cells". Cytokines and immune cells play an important role in this disease, with particular emphasis on the balance between pro-inflammatory and anti-inflammatory factors. Neutrophils are one of several important mediators of Inflammation, lung tissue destruction, and malfunction during ARDS. Some immune cells, such as macrophages and eosinophils, play a dual role in releasing inflammatory mediators, recruitment inflammatory cells and the progression of ARDS, or releasing anti-inflammatory mediators, clearing the lung of inflammatory cells, and helping to improve the disease. Different interleukins play a role in the development or inhibition of ARDS by helping to activate various signaling pathways, helping to secrete other inflammatory or anti-inflammatory interleukins, and playing a role in the production and balance between immune cells involved in ARDS. As a result, immune cells and, inflammatory cytokines, especially interleukins play an important role in the pathogenesis of this disease Therefore, understanding the relevant mechanisms will help in the proper diagnosis and treatment of this disease.


Subject(s)
Endothelial Cells , Respiratory Distress Syndrome , Humans , Endothelial Cells/pathology , Bronchoalveolar Lavage Fluid , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/therapy , Interleukins , Cytokines/metabolism , Inflammation , Anti-Inflammatory Agents
4.
Pharmaceuticals (Basel) ; 14(12)2021 Nov 29.
Article in English | MEDLINE | ID: mdl-34959641

ABSTRACT

BACKGROUND: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1-2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide. METHODS: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort. RESULTS: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells' migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels. CONCLUSIONS: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378).

5.
Cancers (Basel) ; 13(16)2021 Aug 17.
Article in English | MEDLINE | ID: mdl-34439278

ABSTRACT

The purpose of this study was to assess in vitro whether the biological effects of 5-aminolevulinic acid (5-ALA)-based photodynamic therapy are enhanced by inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL in different glioblastoma models. Pre-clinical testing of a microcontroller-based device emitting light of 405 nm wavelength in combination with exposure to 5-ALA (PDT) and the Bcl-2/Bcl-xL inhibitor ABT-263 (navitoclax) was performed in human established and primary cultured glioblastoma cells as well as glioma stem-like cells. We applied cell count analyses to assess cellular proliferation and Annexin V/PI staining to examine pro-apoptotic effects. Western blot analyses and specific knockdown experiments using siRNA were used to examine molecular mechanisms of action. Bcl-2/Bcl-xL inhibition synergistically enhanced apoptosis in combination with PDT. This effect was caspase-dependent. On the molecular level, PDT caused an increased Noxa/Mcl-1 ratio, which was even more pronounced when combined with ABT-263 in a Usp9X-independent manner. Our data showed that Bcl-2/Bcl-xL inhibition increases the response of glioblastoma cells toward photodynamic therapy. This effect can be partly attributed to cytotoxicity and is likely related to a pro-apoptotic shift because of an increased Noxa/Mcl-1 ratio. The results of this study warrant further investigation.

6.
Br J Cancer ; 122(8): 1146-1157, 2020 04.
Article in English | MEDLINE | ID: mdl-32115576

ABSTRACT

BACKGROUND: Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma. METHODS: Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM). RESULTS: ONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM. CONCLUSION: Treatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood-brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy.


Subject(s)
Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , Deoxyglucose/pharmacology , Energy Metabolism/drug effects , Glioblastoma/drug therapy , Imidazoles/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , Animals , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Line, Tumor , Chick Embryo/drug effects , Glioblastoma/metabolism , Glioblastoma/pathology , Glycolysis/drug effects , Humans , Oxidative Phosphorylation
7.
Br J Pharmacol ; 176(18): 3681-3694, 2019 09.
Article in English | MEDLINE | ID: mdl-31222722

ABSTRACT

BACKGROUND AND PURPOSE: Drug repurposing represents a promising approach to safely accelerate the clinical application of therapeutics with anti-cancer activity. In this study, we examined whether inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL enhances the biological effects of the repurposed CUSP9 regimen in an in vitro setting of glioblastoma. EXPERIMENTAL APPROACH: We applied 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays to assess cellular proliferation. Annexin V/propidium iodide and tetramethylrhodamine, ethyl ester staining were used to examine apoptosis. Western blotting, RT-PCR, and specific knockdown experiments using siRNA were employed to examine molecular mechanisms of action. KEY RESULTS: Bcl-2/Bcl-xL inhibition exerted synergistic anti-proliferative effects across established, primary cultured, and stem-like glioblastoma cells when combined with CUSP9 which had been reduced to only one tenth of its proposed original concentration (CUSP9-LD). The combination treatment also led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, CUSP9-LD counteracted ABT263-mediated up-regulation of Mcl-1. Silencing of Mcl-1 enhanced ABT263-mediated apoptosis which indicates that down-regulation of Mcl-1 is crucial for the induction of cell death by the combination treatment. CONCLUSION AND IMPLICATIONS: These data suggest that Bcl-2/Bcl-xL inhibition enhances the susceptibility of glioblastoma cells towards CUSP9, allowing dramatic dose reduction and potentially decreased toxicity when applied clinically. A clinical trial involving the original CUSP doses (CUSP9v3) is currently ongoing in our institution (NCT02770378). The Bcl-2/Bcl-xL inhibitor ABT263 is in clinical trials and might represent a valuable adjunct to the original CUSP.


Subject(s)
Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Sulfonamides/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Repositioning , Drug Synergism , Humans , Membrane Potential, Mitochondrial/drug effects , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Small Interfering
8.
Cell Oncol (Dordr) ; 42(3): 287-301, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30859392

ABSTRACT

PURPOSE: Anti-apoptotic and pro-migratory phenotypes are hallmarks of neoplastic diseases, including primary brain malignancies. In this work, we examined whether reprogramming of the apoptotic and migratory machineries through a multi-targeting approach would induce enhanced cell death and enhanced inhibition of the migratory capacity of glioblastoma cells. METHODS: Preclinical testing and molecular analyses of combined inhibition of Bcl-2/Bcl-xL and RAC1 were performed in established, primary cultured and stem-like glioblastoma cell systems. RESULTS: We found that the combined inhibition of Bcl-2/Bcl-xL and RAC1 resulted in synergistic pro-apoptotic and anti-migratory effects in a broad range of different glioblastoma cells. At the molecular level, we found that RAC1 inhibition led to a decreased expression of the deubiquitinase Usp9X, followed by a decreased stability of Mcl-1. We also found that the combined inhibition led to a significantly decreased migratory activity and that tumor formation of glioblastoma cells on chorion allantoic membranes of chicken embryos was markedly impaired following the combined inhibition. CONCLUSIONS: Our data indicate that concomitant inhibition of RAC1 and Bcl-2/Bcl-xL induces pro-apoptotic and anti-migratory glioblastoma phenotypes as well as synergistic anti-neoplastic activities. The clinical efficacy of this inhibitory therapeutic strategy warrants further evaluation.


Subject(s)
Aniline Compounds/pharmacology , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis/drug effects , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Sulfonamides/pharmacology , Ubiquitin Thiolesterase/metabolism , rac1 GTP-Binding Protein/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Apoptosis/genetics , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Down-Regulation/drug effects , Glioblastoma/genetics , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA Interference , Signal Transduction/drug effects , Signal Transduction/genetics , Ubiquitin Thiolesterase/genetics , bcl-X Protein/antagonists & inhibitors , bcl-X Protein/genetics , bcl-X Protein/metabolism , rac1 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/metabolism
9.
Curr Med Res Opin ; 32(11): 1839-1848, 2016 11.
Article in English | MEDLINE | ID: mdl-27398628

ABSTRACT

The presence of an aberrantly activated epidermal growth factor receptor (EGFR) in many epithelial tumors, due to its overexpression, activating mutations, gene amplification and/or overexpression of receptor ligands, represent the fundamental basis underlying the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Drugs inhibiting the EGFR have different mechanisms of action; while erlotinib and gefitinib inhibit the intracellular tyrosine kinase, monoclonal antibodies like cetuximab and panitumumab bind the extracellular domain of the EGFR both activating immunomediated anti-cancer effect and inhibiting receptor function. On the other hand, interleukin-8 has tumor promoting as well as neo-angiogenesis enhancing effects and several attempts have been made to inhibit its activity. One of these is based on the use of the old sulfone antibiotic dapsone that has demonstrated several interleukin-8 system inhibiting actions. Erlotinib typically gives a rash that has recently been proven to come out via up-regulated keratinocyte interleukin-8 synthesis with histological features reminiscent of typical neutrophilic dermatoses. In this review, we report experimental evidence that shows the use of dapsone to improve quality of life in erlotinib-treated patients by ameliorating rash as well as short-circuiting a growth-enhancing aspect of erlotinib based on increased interleukin-8 secretion.


Subject(s)
Antineoplastic Agents/pharmacology , Dapsone/therapeutic use , ErbB Receptors/antagonists & inhibitors , Erlotinib Hydrochloride/adverse effects , Exanthema/drug therapy , Humans , Interleukin-8/metabolism
10.
J Neurooncol ; 122(1): 21-33, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25524815

ABSTRACT

The poor prognosis of patients with glioblastoma fuels the search for more effective therapeutic compounds. We previously hypothesised that the neuroleptic olanzapine may enhance antineoplastic effects of temozolomide the standard chemotherapeutic agent used in this disease. This study tested this hypothesis. The anti-proliferative effect of olanzapine was examined by MTT assays and cell count analysis. Soft-agar assays were performed to examine colony-forming ability. In addition, the inhibitory effect of olanzapine on the migratory capacity of U87MG and A172 cells was analyzed by Transwell(®) assays. Moreover, staining for annexin V/propidium iodide or carboxyfluorescein succinimidyl ester was performed prior to flow cytometric analysis in order to better understand the subjacent cellular mechanism. Our initial hypothesis that olanzapine may enhance temozolomide's anti-tumor activity could be confirmed in U87MG and A172 glioblastoma cell lines. Moreover, treatment with olanzapine alone resulted in a marked anti-proliferative effect on U87MG, A172 and two glioma stem-like cells with IC50 values ranging from 25 to 79.9 µM. In U87MG cells, anchorage-independent growth was dose-dependently inhibited. In A172 cells, migration was also shown to be inhibited in a dose-dependent manner. In addition, olanzapine was shown to exert a cell line-dependent pleomorphism with respect to the induction of apoptosis, necrosis and/or cytostasis. Our data show that the neuroleptic olanzapine enhances the anti-tumor activity of temozolomide against glioblastoma cell lines. Moreover, this is the first study to show that olanzapine provides on its own anti-cancer activity in glioblastoma and thus may have potential for repurposing.


Subject(s)
Benzodiazepines/pharmacology , Cell Adhesion/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Dacarbazine/analogs & derivatives , Drug Synergism , Glioblastoma/pathology , Antineoplastic Agents, Alkylating/pharmacology , Antipsychotic Agents/pharmacology , Apoptosis/drug effects , Blotting, Western , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Dacarbazine/pharmacology , Glioblastoma/drug therapy , Glioblastoma/metabolism , Humans , Olanzapine , Phosphoproteins/metabolism , Protein Array Analysis , Temozolomide , Tumor Cells, Cultured
11.
Cancers (Basel) ; 4(2): 523-30, 2012 May 08.
Article in English | MEDLINE | ID: mdl-24213322

ABSTRACT

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is almost never curable with the current standard treatment consisting of surgical resection, irradiation and temozolomide. The prognosis remains poor despite undisputable advances in the understanding of this tumor's molecular biology and pathophysiology, which unfortunately has so far failed to translate into a meaningful clinical benefit. Dysregulation and a resulting prominent pathophysiological role of the epidermal growth factor receptor (EGFR) have been identified in several different malignant tumor entities, GBM among them. The EGFR is overexpressed in about 40% of GBM cases, and half of these coexpress a mutant, constitutively activated subtype, EGFRvIII. Unfortunately, recent trials studying with therapeutic approaches targeted against the EGFR and EGFRvIII have failed to meet expectations, with only a minority of patients responding despite evidence of good in vitro and rodent model activity. Having potentially high relevance within this context, epithelial to mesenchymal transition (EMT) is a phenomenon associated with early stages of carcinogenesis, cancer invasion and recurrence. During EMT, epithelial cells lose many of their epithelial characteristics, prominently E-cadherin expression, and acquire properties that are typical for mesenchymal cells such as the expression of vimentin. Epithelial to mesenchymal transition has been specifically demonstrated in GBM. In this review, we summarize the evidence that EMT may precipitate GBM resistance to EGFR-targeted therapy, and may thus be among the principal factors contributing to the clinical failure of targeted therapy against EGFR and EGFRvIII.

12.
Neuroscientist ; 16(3): 308-23, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20479473

ABSTRACT

Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease that is caused by human JC polyomavirus, was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s. The prognosis has remained dismal since then, with discouraging results from clinical trials of various therapeutic approaches, including immunomodulation and/or inhibition of viral replication. PML is caused by reactivation of latent JC virus, and serotonergic 5-HT(2a) receptors have been identified as being critical for viral infection of glial cells. In recent years, immunosuppressive therapeutic antibodies have been associated with an increased incidence rate of PML. Here, the authors review findings on the pathogenesis of PML and the encouraging case reports of novel treatments.


Subject(s)
Immunocompromised Host/immunology , Immunosuppression Therapy/adverse effects , Immunosuppression Therapy/methods , Leukoencephalopathy, Progressive Multifocal/physiopathology , Leukoencephalopathy, Progressive Multifocal/therapy , Humans , Leukoencephalopathy, Progressive Multifocal/drug therapy , Leukoencephalopathy, Progressive Multifocal/virology
16.
J Leukoc Biol ; 85(1): 20-8, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18809733

ABSTRACT

Lithium (as lithium carbonate) is an inexpensive drug, widely used in psychiatry for over 50 years in treatment of mood instability (bipolar disorder) and as an adjunct to antidepressants. Hematological effects of neutrophilia and increased circulating CD34+ cells of marrow origin have long been known. Lithium was at the center of hematological investigations in the 1980s, but no definitive use in hematology has yet emerged. We review evidence that lithium increases G-CSF and augments G-CSF effects. We suggest possible therapeutic uses of lithium in neutropenia. In bone marrow transplantation, preharvest lithium-assisted hematopoietic stem cell mobilization may be useful as well.


Subject(s)
Antidepressive Agents/therapeutic use , Antimanic Agents/therapeutic use , Hematopoiesis/drug effects , Lithium Carbonate/therapeutic use , Neutropenia/drug therapy , Anemia, Aplastic/drug therapy , Animals , Antidepressive Agents/adverse effects , Antidepressive Agents/pharmacology , Antimanic Agents/adverse effects , Antimanic Agents/pharmacology , Bone Marrow Transplantation/methods , Dendritic Cells/drug effects , Dendritic Cells/pathology , Granulocyte Colony-Stimulating Factor/metabolism , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cells/drug effects , Humans , Lithium Carbonate/adverse effects , Lithium Carbonate/pharmacology , Megakaryocytes/drug effects , Megakaryocytes/pathology , Monocytes/drug effects , Monocytes/pathology , Neutrophils/drug effects , Neutrophils/pathology
18.
J Leukoc Biol ; 84(2): 331-7, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18511574

ABSTRACT

G-CSF is routinely used to mobilize hematopoietic stem cells (HSCs) from bone marrow (BM) into peripheral blood before aphaeresis, but HSC harvesting can be suboptimal. On the other hand, transplanted HSCs sometimes fail to engraft a recipient BM microenvironment when G-CSF is used after transplantation, as pushing-CSF will push HSCs away from marrow. So, G-CSF action needs to be potentiated by other drugs. Marrow stromal cells establish a local CXCL12 concentration gradient that is the primary homing signal for HSCs. Pharmacological interventions that modify this gradient, therefore, have potential to help HSC mobilization (by decreasing CXCL12) and engraftment (by increasing CXCL12). CXCL12 inactivation is primarily mediated by dipeptidyl peptidase-IV. We review here the currently available drugs affecting this enzyme that could be used in the clinic to achieve phase-specific help for G-CSF.


Subject(s)
Adenosine Deaminase/metabolism , Dipeptidyl Peptidase 4/metabolism , Hematopoietic Stem Cell Mobilization , Lymphokines/pharmacology , Animals , Blood Component Removal , Bone Marrow Cells/physiology , Chemokine CXCL12/physiology , Humans , Receptors, CXCR4/physiology
19.
JOP ; 9(3): 350-3, 2008 May 08.
Article in English | MEDLINE | ID: mdl-18469453

ABSTRACT

Interleukin-18 (IL-18) is one of the mediators of both pancreas damage and systemic complications like hypotension and multi-organ dysfunction during acute pancreatitis. IL-18 is generated intracellularly from pro-IL-18 by caspase-1 mediated proteolysis. Active caspase-1 itself is generated intracellularly by the action of the inflammasome, autocatalysis and other stimuli. The anti-retroviral drug ritonavir inhibits conversion of inactive pro-caspase-1 to active caspase-1. Since ritonavir is well tolerated in short-term use it may therefore prove useful in treating acute pancreatitis by lowering caspase-1 mediated IL-18 formation and the many inflammatory mediators downstream from that. The alcoholism treatment drug disulfiram has been in continuous use since the 1950s. It likewise has a low risk profile. Disulfiram inhibits several human proteases, among them caspase-1. Given the current morbidity and mortality of pancreatitis, research should be directed to ritonavir and disulfiram as treatment options for illnesses like pancreatitis where excessive IL-18 contributes to pathology. The first clinically used angiotensin converting enzyme inhibitor, captopril, has shown potent caspase-1 inhibiting activity as well and should be investigated in rodent models of human pancreatitis.


Subject(s)
Disulfiram/pharmacology , Interleukin-18/blood , Pancreatitis/drug therapy , Ritonavir/pharmacology , Acute Disease , Animals , Antihypertensive Agents/pharmacology , Captopril/pharmacology , Caspase Inhibitors , Disulfiram/administration & dosage , Drug Synergism , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Humans , Interleukin-18/metabolism , Interleukin-18/physiology , Models, Biological , Pancreatitis/blood , Pancreatitis/etiology , Remission Induction , Ritonavir/administration & dosage , Time Factors
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