BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells

SummaryMost forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly overexpress BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC

Cancer stem cell metabolism: A potential target for cancer therapy

© 2016 The Author(s). Cancer Stem cells (CSCs) are a unipotent cell population present within the tumour cell mass. CSCs are known to be highly chemo-resistant, and in recent years, they have gained intense interest as key tumour initiating cells that may also play an integral role in tumour recurrence following chemotherapy. Cancer cells have the ability to alter their metabolism in order to fulfil bio-energetic and biosynthetic requirements. They are largely dependent on aerobic glycolysis for their energy production and also are associated with increased fatty acid synthesis and increased rates of glutamine utilisation. Emerging evidence has shown that therapeutic resistance to cancer treatment may arise due to dysregulation in glucose metabolism, fatty acid synthesis, and glutaminolysis. To propagate their lethal effects and maintain survival, tumour cells alter their metabolic requirements to ensure optimal nutrient use for their survival, evasion from host immune attack, and proliferation. It is now evident that cancer cells metabolise glutamine to grow rapidly because it provides the metabolic stimulus for required energy and precursors for synthesis of proteins, lipids, and nucleic acids. It can also regulate the activities of some of the signalling pathways that control the proliferation of cancer cells. This review describes the key metabolic pathways required by CSCs to maintain a survival advantage and highlights how a combined approach of targeting cellular metabolism in conjunction with the use of chemotherapeutic drugs may provide a promising strategy to overcome therapeutic resistance and therefore aid in cancer therapy

Cancer stem cell metabolism

Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Determining the role of cancer stem cell metabolism in carcinogenesis has become a major focus in cancer research, and substantial efforts are conducted towards discovering clinical targets

Septic Thrombophlebitis Caused by Fusobacterium necrophorum in an Intravenous Drug User

Septic thrombophlebitis is characterized by venous thrombosis, inflammation and bacteremia, that can lead to fatal complications such as sepsis, septic emboli and even death. Though most commonly caused by indwelling catheters, it is also related to intravenous drug users (IVDU) especially those who attempt to inject drugs into more proximal and central veins. Lemierre’s syndrome, also referred to as post-anginal sepsis or necrobacillosis, is a suppurative thrombophlebitis of the internal jugular vein. Primary infection is associated with oropharyngeal and dental infections and the most common causative organism is Fusobacterium necrophorum. We report a case of Lemierre’s syndrome in an IVDU, caused by Fusobacterium necrophorum, which was inoculated at the site of injection, without a history of sore throat or pharyngitis

Alloreactive microenvironment after human hematopoietic cell transplantation induces genomic alterations in epithelium through an ROS-mediated mechanism: In vivo and in vitro study and implications to secondary neoplasia

We hypothesized that chronic tissue stress due to interaction of alloreactive donor cells with host epithelium after allogeneic hematopoietic cell transplantation (allo-HCT) may cause genomic alterations. We therefore analyzed 176 buccal samples obtained from 71 unselected allotransplanted patients for microsatellite instability (MSI). MSI was observed in 52% of allotransplanted patients but never in 31 healthy or autotransplanted controls. The patient age, the donor age, a female-to-male transplantation and a low number of CD34 cells in the graft were significantly correlated with genomic instability. There was a trend for increasing risk of MSI for patients who experienced severe graft-vs-host disease. Secondary malignancy was diagnosed in five (14%) of the MSI and only in one (3%) MSI patient. In an in vitro model of mutation analysis we found significant induction of frameshift mutations and DNA strand breaks in HaCaT keratinocytes co-cultured with mixed lymphocyte cultures (MLCs) but not after their exposure to interferon-γ, tumor necrosis factor-α, transforming growth factor-Β (TGF-Β), MLC supernatant, peripheral blood mononuclear cells (PBMCs) or phytohemagglutinin-stimulated PBMC. A reactive oxygen species-mediated mechanism is implicated. The in vivo and in vitro data of our study show that alloreactions after allo-HCT may induce genomic alterations in epithelium. Progress in understanding DNA damage and repair after allo-HCT can potentially provide molecular biomarkers and therapeutic targets

Pathophysiology and management of Akathisia 70 years after the introduction of the chlorpromazine, the first antipsychotic

OBJECTIVE: Akathisia is among the most troubling effects of psychiatric drugs as it is associated with significant distress on behalf of the patients. and it limits treatment adherence. Though it most commonly presents during treatment with antipsychotic drugs which block dopamine D2 receptors. Akathisia has also been reported during treatment with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), stimulants, mirtazapine, tetrabenazine and other drugs. MATERIALS AND METHODS: This article was designed as a narrative review on akathisia with a focus on its clinical presentation, pathophysiology and management. A PubMed search for akathisia was conducted which returned 8481 articles. RESULTS: Akathisia is experienced as severe restlessness commonly accompanied by dysphoria and purposeless movement which relieves subjective tension. It has been attributed to an imbalance between dopaminergic and noradrenergic neurotransmission in the basal ganglia. Acute akathisia commonly resolves upon treatment discontinuation but tardive and chronic akathisia may persist after the causative agent is withdrawn and prove resistant to pharmacological treatment. Even drugs which induce no other extrapyramidal side effects (such as clozapine, quetiapine, aripiprazole and cariprazine) may induce akathisia. A high index of suspicion should be maintained in patients with motor disabilities, drug-induced parkinsonism and those under mechanical restraint. Propranolol and low-dose mirtazapine are the most thoroughly studied pharmacological interventions for akathisia, though benzodiazepines, voltage- gated calcium channel blockers (gabapentin. pregabalin) and opioids may be effective. CONCLUSIONS: Pharmacological management may pose a challenge in chronic akathisia. Rotation between different pharmacological management strategies may be optimal in resistant cases. Discontinuation of the causative drug and use of b-blockers, mirtazapine, benzo-diazepines or gabapentinoids for symptomatic relief is the basis of management

Pulmonary infection by Rhodococcus equi presenting with positive Ziehl-Neelsen stain in a patient with human immunodeficiency virus: A case report

Introduction: Patients with human immunodeficiency virus carry a significant risk of contracting opportunistic infections. The worldwide increased incidence of tuberculosis has instituted pulmonary tuberculosis as an important diagnostic consideration in patients with human immunodeficiency virus presenting with lower respiratory tract infection. A positive result on the readily-available Ziehl-Neelsen stain usually leads to the initiation of antituberculous treatment, since tuberculosis may exert a rapid and even fatal clinical progress in human immunodeficiency virus coinfection. However, a number of other acid-fast bacteria might be implicated as offending pathogens. This case highlights the importance of broadening the list of pathogens that can account for a positive Ziehl-Neelsen stain in this select group of patients. Case presentation: We describe the case of a 34-year-old, Albanian man with untreated human immunodeficiency virus, presenting with clinical and radiologic signs of pulmonary tuberculosis and a positive Ziehl-Neelsen sputum specimen, who was finally diagnosed with pulmonary infection by Rhodococcus equi. Conclusions: Rhodococcus equi is a rare cause of pulmonary disease, even in patients with human immunodeficiency virus, and a positive Ziehl-Neelsen sputum specimen often misleads clinicians to more common organisms such as mycobacteria. A high index of suspicion, broadening the spectrum of optional pathogens, and effective communication between clinicians and microbiologists can ensure an efficient diagnostic and therapeutic approach. © 2014 Spiliopoulou et al.; licensee BioMed Central Ltd