ISSN: 2008-2258

Cell death in drug design

Richard A. Lockshin

Gastroenterology and Hepatology from Bed to Bench, , 27 July 2009

Cell death is a major factor separating healthy physiology from pathology and is rightly the target of considerable attention in the development of new therapies. Most of the effort has been directed at the activation of key effectors of apoptosis and the molecules that regulate this activation. This approach may be valid to address cancer, but otherwise, while efforts are making progress, they miss an important point that addresses cells that die too soon or inappropriately. In these situations, the stress on the cell often derives from an external source, and ultimately this stress must be relieved. If it is not, the cell is still likely to die, though perhaps not by apoptosis. Controlled autophagy, in which specific organelles are removed, begins to give us clues by which we may learn to understand how organelles are targeted.

Mechanisms of Bax/Bak activation: Is there any light at the end of the tunnel?

Sandra Vogel, Thomas Kiefer, Nina Raulf, Kai Sterz, Anand Manoharan, Christoph Borner

Gastroenterology and Hepatology from Bed to Bench, , 27 July 2009

In this review we summarize the current knowledge on the mechanisms by which the pore-forming Bcl-2 family members Bax and Bak are activated on the mitochondrial outer membrane (MOM) in apoptotic cells. We compare the two major working models and conclude that they are both insufficient to explain reality. Instead, we need to identify novel binding partners and posttranslational modifications of Bcl-2 family proteins to fully understand their

modi operandi in healthy and apoptotic cells.

Prohibitins are chaperone proteins highly conserved among eukaryotes. Many different functions have been attributed to Prohibitins depending on their tissue expression and sub-cellular localization. Prohibitins play a major role in mitochondrial physiology, regulating the stability and the processing of both respiratory chain complex subunits and OPA1, a mitochondrial fusion regulating protein. Prohibitins are also involved in the control of proliferation, apoptosis, transcription and signal transduction by interacting with important regulators of these processes located either in mitochondria or in other subcellular sites, such as nucleus, cytosol, plasma membrane. Here, I will review recent experimental data linking the impairment of the different functions of Prohibitins with the onset of important human pathologies, such as cancer, chronic inflammation and drug-induced toxicity. These data highlight how Prohibitins could represent promising candidate targets for the development of novel therapeutic approaches.

Autophagy is a cellular process mediating degradation of bulk cytoplasm, long-lived proteins and entire organelles. In this process, double-membrane vesicles, the autophagosomes, wrap around portions of cytosol and transport them to the lysosome for degradation. Several molecules participate in autophagosome nucleation and elongation, including various components of the class III PI3K complex, such as Beclin 1 and Ambra1 (


Activating Molecule in Beclin 1-Regulated Autophagy), which has been recently characterized in our laboratory (1, 2). Any genetic or pharmacological alteration in this process impairs the cell survival rate or cell metabolism, thereby affecting tissue homeostasis (3). Many neurodegenerative conditions, for example, can be traced back to defective autophagy and autophagy has also been identified as a crucial process in oncogenesis and cancer progression. Several autophagy-related proteins have tumor suppressor activity (Beclin 1, Atg5, Bif-1, Atg4C, UVRAG) and some autophagy gene mutations can lead to an accumulation of DNA damage and genome instability. Manipulation of autophagy regulation or of expression and/or function of autophagy genes is therefore of the highest importance in biomedicine. For this reason, the development of molecules, which interfere specifically with autophagy signaling or action, could be useful in the treatment of human disorders. We discuss here the strategies used to manipulate autophagy in several pathological conditions, focussing on the use of small peptides or peptidomimetic molecules in this context.

Marine cytotoxins: callers for the various dances of death

Florence Folmer, Marcel Jaspars, Mario Dicato, Marc Diederich

Gastroenterology and Hepatology from Bed to Bench, , 27 July 2009

Programmed cell death, which can be classified into apoptosis, autophagy, and oncosis, based on the cellular signalling
pathways involved in the process, plays a critical role in cellular house-keeping. Aberrant cell death regulation leads to
body malformations, as well as to numerous diseases. Here, we describe the effects of cytototoxins isolated from marine
organisms on the various programmed cell death pathways, and we discuss the current and future applications of marine
natural products in the fields of biomedicine and of biotechnology.

Gossypol: from contraceptive for men to antitumoral activity

Maryam Mehrpour, Patrice Codogno, Quan Chen

Gastroenterology and Hepatology from Bed to Bench, , 27 July 2009

It is widely thought that Bcl-2 family proteins regulate commitment to apoptosis primarily through their capacity tocontrol the permeability of the mitochondrial outer membrane permeabilization (MOMP) triggers the release of multipleapoptogenic factors into the cytosol and, thereby apoptosis. Various Bcl-2 family members affect this key event of theapoptotic cascade in different ways, determining their pro- or anti-apoptotic status. The Bcl-2-type proteins inhibitMOMP, thereby preserving cell viability. In contrast, Bax-type proteins and the diverse group of BH3-only proteinsfacilitate MOMP and thus promote cell death. Recently, several drugs that act as BH3 mimetics have been identified,including Gossypol. This review revisits the proprieties of gossypol family, their using as anticancer agents for cancertherapy.

Connective tissue and diseases: from morphology to proteomics towards the development of new therapeutic approaches

Daniela Quaglino, Federica Boraldi, Giulia Annovi, Deanna Guerra, Ivonne Ronchetti

Gastroenterology and Hepatology from Bed to Bench, , 27 July 2009

Connective tissue consists of cells separated by the extracellular matrix, whose composition and amount vary accordingto age, to functional requirements, and to the presence of pathologic conditions. Within this non-randommacromolecular assembly, collagens, elastin, proteoglycans and structural glycoproteins are mutually interdependentand modifications of one component, by extrinsic (environmental) and/or intrinsic (systemic, genetic, age-related)factors, may have consequences on the tissue as a whole. Since decades, different microscopical techniques have beenapplied mainly for diagnostic purposes and for detailed descriptions of changes occurring in cells and in matrixcomponents. More recently, in order to dissect the molecular complexity of the matrix network, to analyse theinteractions between cells and matrix and to look for modulators of cell phenotype, histomorphologic investigationshave been implemented with proteomic studies that allow to identify possible diagnostic markers, and to betterunderstand patho-mechanisms enabling the design of novel therapeutic strategies. Therefore, the progressivelyexpanding, although incomplete, knowledge on connective tissue biology, sheds new light on the pathogenesis ofdiseases affecting single molecules (i.e. collagenopathies, mucopolysaccharidoses, elastinopathies) and discloses theimportance of matrix components as fundamental regulators of cell phenotype, in relation, for instance, to the agingprocess and/or to cancer development and progression. Few examples will be presented demonstrating the promises ofproteomics as a technique leading to the discovery of new therapies and possibly to the development of individualizedtreatments for a better patient care.

Vital functions of Apoptosis Inducing Factor (AIF)

Emilie Hangen, Guido Kroemer, Nazanine Modjtahedi

Gastroenterology and Hepatology from Bed to Bench, , 27 July 2009

In many models of programmed cell death, the mitochondrial protein AIF translocates to the nucleus, where it inducesthe chromatin condensation and DNA degradation. However, today it is well established that this flavoprotein isbifunctional. In addition to its lethal function in the nucleus of dying cells, AIF plays a vital bioenergetic role in healthyones by regulating mainly the activity of the mitochondrial respiratory chain complex I. Hypomorphic or deletionmutants of AIF have led to the generation of the first reliable mouse model of complex I deficiency syndrome, whichleads to progressive ataxia and blindness due to neuronal degeneration, as well as a dilated cardiomyopathy, skeletalmuscle atrophy and metabolic dysfunction. Here, we discuss recent progress in the quest to understand AIF’sinvolvement in cell survival and in the regulation of mitochondrial respiratory chain complex I.


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