Therapeutic opportunities for counteracting apoptosis resistance in childhood leukaemia

Evasion of apoptosis is a hallmark of human cancers, for example in haematological malignancies. Apoptosis is an intrinsic cell death program that is crucial in maintaining tissue homeostasis, for example in the haematopoietic system where there is a high turnover rate of cells. As a result, a decrease in the rate of apoptosis as well as an increase in proliferation favours tumorigenesis as well as tumour progression. Further, the anti-leukaemic action of current treatment approaches, including chemo-, radio- or immunotherapy, critically relies on intact cell death programs in cancer cells. Therefore, defects in apoptosis pathways are frequently associated with the resistance to anticancer therapies. In recent years, the identification and characterization of the molecules and pathways that are involved in the regulation and execution of cell death in leukaemia and lymphoma cells, for example tumour necrosis factor-related apoptosis inducing ligand (TRAIL), 'inhibitor of apoptosis' (IAP) proteins and Bcl-2, have set the ground for the development of novel diagnostic tools and molecular therapeutics targeting apoptosis pathways in haematological malignancies.     

Dysregulation of apoptosis in hepatocellular carcinoma cells

Hepatocellular carcinoma （HCC） is a major health prob- lem, being the sixth most common cancer world-wide. Dysregulation of the balance between proliferation and cell death represents a pro-tumorigenic principle in hu- man hepatocarcinogenesis. This review updates the recent relevant contributions reporting molecular altera- tions for HCC that induce an imbalance in the regulation of apoptosis. Alterations in the expression and/or activation of p53 are frequent in HCC cells, which confer on them resistance to chemotherapeutic drugs. Many HCCs are also insensitive to apoptosis induced either by death receptor ligands, such as FasL or TRAIL, or by transforming growth factor-beta （TGF-β）. Although the expression of some pro-apoptotic genes is decreased, the balance between death and survival is dysregulated in HCC mainly due to overactivation of anti-apoptotic pathways. Indeed, some molecules involved in counter- acting apoptosis, such as Bcl-X1, Mcl-1, c-IAP1, XIAP or survivin are over-expressed in HCC cells. Furthermore, some growth factors that mediate cell survival are upregulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their pro- forms to an active peptide. The expression and/or activation of the JAK/STAT, PI3K/AKT and RAS/ERKs path- ways are enhanced in many HCC cells, conferring on them resistance to apoptotic stimuli. Finally, recent evi- dence indicates that inflammatory processes, as well as the epithelial-mesenchymal transitions that occur in HCC cells to facilitate their dissemination, are related to cell survival. Therefore, therapeutic strategies to selectively inhibit anti-apoptotic signals in liver tumor cells have the potential to provide powerful tools to treat HCC.     

Cell apoptosis and granulomatous lung diseases

Apoptosis, also known as activation-induced cell death or programmed cell death, is an active suicide mechanism that is involved in normal tissue turnover during embryogenesis and adult life. There are many examples of apoptosis in the immune system, including programmed cell death of T cells during negative intrathymic selection of the TCR repertoire and, in the postthymic phase, death of responsive T cells upon specific activation of the TCR/CD3 complex. Induction of apoptosis assures rapid disappearance of the immune response upon antigenic clearance, avoiding the metabolic costs involved in sustaining a large number of effector cells. The knowledge that failure of immune cells to die is the cause of a number of immune-mediated disorders has opened intriguing new avenues of exploration into the pathogenetic events leading to the accumulation of immunoinflammatory cells at sites of ongoing inflammation in granulomatous disorders, including granulomas initiated by infectious agents, such as Mycobacterium tuberculosis, or in sarcoidosis. In this paper we review recent results obtained in experimental animal models and patients with immune granuloma suggesting that the positive induction by ligands binding to membrane receptors or the induction or loss of intracellular suppressor signals regulates immunoregulatory mechanisms that drive the progressive development of the granulomatous structure. The great advances in understanding how mechanisms for the activation or downregulation of apoptosis have a pathogenetic role in the outcome of granulomatous disorders are also briefly considered.     

In vitro effect of radiation, antibody to epidermal growth factor receptor and Docetaxel in human head and neck squamous carcinoma cells with mutant P53 and over-expressed EGFR

Purpose  Radiotherapy is the most frequently used and cheapest treatment both for curative and palliative purposes in HNSCC. Despite advances in technology and intensive treatments with radiation, only half of the patients are cured. New therapeutic approaches focusing on the molecular mechanism that mediate tumour cell growth or cell death in combination with radiotherapy have been suggested. The effects of radiation, antibody to EGFR and Docetaxel as single treatment or in combinations on HNSCC cells were investigated. Methods  The established HNSCC cells with mutant (mt) P53 and over-expressed normal EGFR was used as the in vitro model. Gene expression profile, cell cycle progression and cell death were used as the indication of treatment outcome. Results  With c-DNA microarray of well-characterised functional genes, massive changes in the genes expression of HNSCC were detected. The alterations of gene expression profiles do not have any correlation neither on tumour cell growth nor cell death. HNSCC cells with mt P53 and over-expressed normal EGFR did not response to radiation, anti-EGFR monoclonal antibody and their combination therapy. Effective treatment could be obtained from single therapy with Docetaxel. No additive effects on cell cycle arrest or cell death were seen in the combination of Docetaxel to anti-EGFR antibody, radiation or anti-EGFR antibody + radiation. Conclusions  The c-DNA microarray analysis does not indicate any specific target or treatment effects of HNSCC with mt P53 and over-expressed normal EGFR. Single therapy, target at microtubules might be the most suitable treatment modulation in this tumour type.     

Involvement of ceramide in cell death responses in the pulmonary circulation

Ceramides are signaling sphingolipids involved in cellular homeostasis but also in pathological processes such as unwanted apoptosis, growth arrest, oxidative stress, or senescence. Several enzymatic pathways are responsible for the synthesis of ceramides, which can be activated in response to exogenous stimuli such as cytokines, radiation, or oxidative stress. Endothelial cells are particularly rich in acid sphingomyelinases, which can be rapidly activated to produce ceramides, both intracellular and at the plasma membrane. In addition, neutral sphingomyelinases, the de novo pathway and the ceramide recycling pathway, may generate excessive ceramides involved in endothelial cell responses. When up-regulated, ceramides trigger signaling pathways that culminate in endothelial cell death, which in murine lungs has been linked to the development of emphysema-like disease. Furthermore, ceramides may be released paracellularly where they are believed to exert paracrine activities. Such effects, along with ceramides released by inflammatory mediators, may contribute to lung inflammation and pulmonary edema, because ceramide-challenged pulmonary endothelial cells exhibit decreased barrier function, independent of apoptosis. Reestablishing the sphingolipid homeostasis, either by modulating ceramide synthesis or by opposing its biological effects through augmentation of the prosurvival sphingosine-1 phosphate, may alleviate acute or chronic pulmonary conditions characterized by vascular endothelial cell death or dysfunction.     

Perspectives on liver failure: past and future

Acute liver failure (ALF) remains a potentially devastating syndrome with a high mortality rate. Much interest continues to center upon the possibility of providing effective liver support through various artificial and bioartificial extracorporeal devices. The development of purpose-designed intensive care units for the treatment of ALF allowed a better understanding of the clinical syndrome and its best management, through the ability to conduct detailed clinical observation and clinical trials of new interventions. Survival rates are substantially improved today compared with the mortality rate that approximated 100% when the syndrome was first described nearly five decades ago. Nonetheless, these have plateaued in recent years, prompting one to consider whether major new advances in disease understanding are needed to further improve the overall outcome. A major challenge to a broader understanding of disease pathogenesis and the ability to direct appropriate therapy remains the substantial number of cases of ALF for which no specific etiology can be identified. Much is now known about the basic molecular mechanisms underlying hepatocyte cell death in ALF and an important issue is whether these cell death pathways can, in the future, be interrupted for therapeutic gain. Such considerations would seem most relevant in the early stages of the clinical course, when damage to the liver is not so severe but perhaps programmed to so evolve. A particular challenge will be to reduce hepatocellular death without inhibiting the liver's regenerative potential, given the pleiotropic functions of some of the molecules involved in both processes.     

Grundlegende Mechanismen der Apoptose in den einfachsten Invertebraten, den Porifera

Sponges (phylum Porifera) represent the oldest metazoan taxon. Through a variety of molecular biological methods the existence of elaborated mechanisms such as programmed cell death was established in those organisms that are regarded today as living fossils. Among the apoptotic proteins identified in sponges are the key molecules of apoptotic pathways, effectors (caspases, death domain proteins) and regulators (Bcl-2 homologues) of programmed cell death. Furthermore, when introduced in vertebrate cells one sponge anti-apoptotic Bcl-2 homologue displayed its pro-survival function in the heterologous system, confirming the conserved character of apoptotic cell death. Comparing apoptotic elements of both the most ancient and the most recent of all metazoans might elucidate the evolution of programmed cell death and processes involved, such as aging.     

Mechanisms of Cancer Cell Killing by the Adenovirus E4orf4 Protein

During adenovirus (Ad) replication the Ad E4orf4 protein regulates progression from the early to the late phase of infection. However, when E4orf4 is expressed alone outside the context of the virus it induces a non-canonical mode of programmed cell death, which feeds into known cell death pathways such as apoptosis or necrosis, depending on the cell line tested. E4orf4-induced cell death has many interesting and unique features including a higher susceptibility of cancer cells to E4orf4-induced cell killing compared with normal cells, caspase-independence, a high degree of evolutionary conservation of the signaling pathways, a link to perturbations of the cell cycle, and involvement of two distinct cell death programs, in the nucleus and in the cytoplasm. Several E4orf4-interacting proteins including its major partners, protein phosphatase 2A (PP2A) and Src family kinases, contribute to induction of cell death. The various features of E4orf4-induced cell killing as well as studies to decipher the underlying mechanisms are described here. Many explanations for the cancer specificity of E4orf4-induced cell death have been proposed, but a full understanding of the reasons for the different susceptibility of cancer and normal cells to killing by E4orf4 will require a more detailed analysis of the complex E4orf4 signaling network. An improved understanding of the mechanisms involved in this unique mode of programmed cell death may aid in design of novel E4orf4-based cancer therapeutics.     

Acute liver failure: mechanisms of hepatocyte injury and regeneration

Acute liver failure (ALF) occurs when the extent of hepatocyte death exceeds the liver's regenerative capacity. Despite vast differences in causes, the mode of cell death typically follows one of two patterns: necrosis or apoptosis. Necrosis and apoptosis have traditionally been considered separate entities within various etiologies of ALF; however, there is increasing evidence that they are alternative outcomes of the same initiating factors and signaling pathways, a process known as necroapoptosis. Here we review mechanisms of liver cell injury in ALF, including evolving knowledge of pathways leading to apoptosis, necrosis, and necroapoptosis, as well as how these pathways are potential therapeutic targets in ALF. We also discuss hepatic regeneration and the cytokines and growth factors involved in both the replication of differentiated hepatocytes as well as activation of intrahepatic progenitor cells, two pathways of hepatocyte regeneration that are dependent on the type and extent of hepatic insult in ALF.     

Constitutive neutrophil apoptosis: mechanisms and regulation

Neutrophil constitutive death is a critical cellular process for modulating neutrophil number and function, and it plays an essential role in neutrophil homeostasis and the resolution of inflammation. Neutrophils die due to programmed cell death or apoptosis. In this article, we review recent studies on the mechanism of neutrophil apoptosis. The involvement of caspase, calpain, reactive oxygen species, cellular survival/death signaling pathways, mitochondria, and BCL-2 family member proteins are discussed. The fate of neutrophils can be influenced within the inflammatory microenvironment. We summarize the current understanding regarding the modulation of neutrophil apoptotic death by various extracellular stimuli such as proinflammatory cytokines, cell adhesion, phagocytosis, red blood cells, and platelets. The involvement of neutrophil apoptosis in infectious and inflammatory diseases is also addressed.     

Gastric cancer in the era of molecularly targeted agents: current drug development strategies

Gastric cancer is the second most common cause of cancer death worldwide with approximately one million cases diagnosed annually. Despite considerable improvements in surgical techniques, innovations in clinical diagnostics and the development of new chemotherapy regimens, the clinical outcome for patients with advanced gastric cancer and cancer of the GEJ is generally poor with 5-year survival rates ranging between 5 and 15%. The understanding of cancer relevant events has resulted in new therapeutic strategies, particularly in developing of new molecular targeted agents. These agents have the ability to target a variety of cancer relevant receptors and downstream pathways including the epidermal growth factor receptor (EGFR), the vascular endothelial growth factor receptor (VEGFR), the insulin-like growth factor receptor (IGFR), the c-Met pathway, cell-cycle pathways, and down-stream signalling pathways such as the Akt-PI3k-mTOR pathway. In the era of new molecularly targeted agents this review focuses on recent developments of targeting relevant pathways involved in gastric cancer and cancer of the GEJ.     

Cell death pathways in pancreatitis and pancreatic cancer.

The understanding of the regulation of apoptosis and necrosis, the two principal cell death pathways, is becoming exceedingly important in investigations of the pathogenesis and treatment of pancreatitis and pancreatic cancer. For example, in acute pancreatitis significant amounts of pancreatic necrosis are associated with increased morbidity and mortality. Thus, determining the key steps regulating necrosis should provide insights into potential therapeutic strategies for improving outcome in these patients. On the other hand, in pancreatic cancer various survival mechanisms act to prevent cell death, resulting in promotion of tumor growth and metastasis. Resistance of pancreatic cancer to apoptosis is the key factor preventing responses to therapies. Investigations of the regulation of cell death mechanisms specific to pancreatic cancer should lead to improvements in our current therapies for this disease. The present review is designed to provide information about cell death pathways in pancreatitis and pancreatic cancer with reference to areas that need further investigation, as well as to provide measurement techniques adapted to pancreatic tissue and cells.     

Molecular pathogenesis of chronic myeloid leukemia: implications for new therapeutic strategies

 With an annual incidence of about ten in 1,000,000 people, chronic myeloid leukemia (CML) accounts for most cases of myeloproliferative disease and for 20% of all leukemias. While novel therapies such as treatment with interferon-α or bone marrow transplantation have successively improved the outcome of CML treatment, hope for future progress in the therapy of CML lies in an almost unique feature of this hematological malignancy. In contrast to many other forms or subforms of leukemias which display a great diversity in chromosomal alterations, most cases (>95%) of CML seem to be caused by an almost invariably found cytogenetic aberration, the so-called Philadelphia chromosome (Ph), resulting in the bcr-abl fusion gene. Its gene product, p210^bcr-abl (Bcr-Abl), is believed to be essential for hematopoietic cell transformation and seems to exert its effects by interfering with cellular signal transduction pathways, normally involved in the control of cell death and proliferation. Several partially interacting pathways have been shown to be induced by Bcr-Abl. The role of most of them is still unclear and, as understanding their biological functions should lead to novel therapeutic strategies on a molecular basis, much effort is spent on identifying their precise roles in CML. This review focuses on our current understanding of Bcr-Abl-induced signal transduction and outlines its importance for the biological effects of Bcr-Abl. Received: July 7, 1998 / Accepted: November 26, 1998     

Apoptosis in the vascular wall and atherosclerosis

Apoptosis, programmed cell death, has emerged as a key element in the complex pathophysiology underlying the development as well as the progression of atherosclerosis. A number of recent reports provided evidence for both in vivo and in vitro occurrence of apoptotic cell death of vascular cells, namely endothelial cells, macrophages, and vascular smooth muscle cells. In addition, functional studies in disease models underscore the relevance of these findings for the understanding of processes which lead to lesion development, plaque rupture, and thrombus formation. Pathomechanistic in vitro investigations provided an increasingly detailed picture of the involved intracellular signaling pathways that regulate onset and execution of apoptosis. These insights offer the potential of therapeutic interventions targeted to interfere with the molecular processes involving apoptotic cell death in the vascular wall. Received: 18 August 2000, Returned for revision: 30 August 2000, Revision received: 11 September 2000, Accepted: 13 September 2000     

Combating pancreatic cancer chemoresistance by triggering multiple cell death pathways

Pancreatic cancer is the fourth most common cause of cancer-associated death in western countries, where the incidence and number of deaths are increasing every year. Intrinsic or acquired resistance of tumor cells to chemotherapy agents is the major reason for failure of traditional cancer treatment. Several factors are implicated in this impressive resistance; however, of these, it is important to highlight the extensive cellular heterogeneity of these tumors. This heterogeneity is linked to a wide range of sensitivity that different clones in the same tumor display to chemotherapeutic agents. Accordingly, recent findings in this field have discovered new therapeutic targets in order to develop new combinatory treatments, as well as to induce several cell death pathways and reduce therapy-threshold and likelihood of future resistance. Accordingly, recent research has focused on targeting mitochondria, an organelle with key roles regulating cell death signaling pathways, such as apoptosis, necroptosis, autophagy, ferroptosis, or parthanatos. These findings — identifying new compounds, alone or in combination, that can target pancreatic ductal adenocarcinoma cell resistance — could be the key to future treatments.     

Genomics and signaling pathways in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of death among cirrhotic patients and has become a major health problem in developed countries. There is an elemental understanding of the genes and signaling pathways involved in the initiation and progression of this neoplasm. The current hypothesis of the HCC cell origin includes both somatic cells (hepatocytes) and stem cells/progenitor cells. Unlike that in other malignancies such as breast, brain, or hematopoietic cancers, the implication of cancer stem cells in HCC pathogenesis is not yet supported by consistent data. Analysis of somatic genetic alterations and gene expression profiles in HCC samples has provided relevant information on the genes involved in hepatocarcinogenesis, pinpointing a seminal molecular classification of the disease. Nonetheless, a comprehensive genomic analysis of HCC samples using high-resolution platforms in precisely annotated HCCs is clearly needed. Recent data have identified different signaling pathways in liver carcinogenesis (e.g., Wnt-betaCatenin, Hedgehog, tyrosine kinase receptor-related pathways), providing an important potential source of novel molecular targets for new therapies. This review summarizes the most relevant information regarding structural and functional alterations in HCC and describes some of the key signaling pathways implicated in hepatocarcinogenesis.