Not only P-glycoprotein: amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins

The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with anti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated, resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein overexpression, and multidrug resistance (MDR). Clearly however, additional mechanisms such as single nucleotide polymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and of other MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and the wealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vast knowledge from the bench to the bedside has proven to be unexpectedly difficult. Many studies show that upon repeated treatment schedules of cell cultures or tumors with taxenes and anthracyclines as well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genes genomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins may contribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genes contained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed in many cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. This review describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possible connections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1 amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies to overcome cancer MDR

Doxorubicin and other anthracyclines in cancers: activity, chemoresistance and its overcoming

Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by severe side effects and toxicity that occur during or after treatment, including cardiotoxicity. The mode of action of anthracyclines is complex, with several mechanisms proposed. It is possible that their high toxicity is due to the large set of processes involved in anthracycline action. The development of resistance is a major barrier to successful treatment when using anthracyclines. This resistance is based on a series of mechanisms that have been studied and addressed in recent years. This work provides an overview of the anthracyclines used in cancer therapy. It discusses their mechanisms of activity, toxicity, and chemoresistance, as well as the approaches used to improve their activity, decrease their toxicity, and overcome resistance

The central role of gut microbiota in drug metabolism and personalized medicine

The gut microbiota is now considered as a symbiotic organ playing an important role in human health and disease development and has been recently recognized as a modulator of drug metabolism and toxicity. Here, we briefly discuss new findings describing how the gut microbiota is now considered to be a central player in drug metabolism and personalized medicine

Venezuela, la lezione di Allende

La tesi sostenuta qui, consta di due parti. La prima, condivisa da molti marxisti latinoamericani, rileva, fatte le debite proporzioni, le molte analogie esistenti fra gli attacchi dell’imperialismo nordamericano che hanno portato al colpo di Stato in Cile nel 1973, e quelli che hanno portato al golpe contro Hugo Chávez, nel 2002, e che sono proseguiti poi nel contesto delle cosiddette “guerre ibride”, o guerre di IV e V generazione contro il Venezuela. Questa interpretazione mostra anche co..

NMR structure of a non-conjugatable, ADP-ribosylation associated, ubiquitin-like domain from Tetrahymena thermophila polyubiquitin locus

Background: Ubiquitin-like domains (UbLs), in addition to being post-translationally conjugated to the target through the E1-E2-E3 enzymatic cascade, can be translated as a part of the protein they ought to regulate. As integral UbLs coexist with the rest of the protein, their structural properties can differ from canonical ubiquitin, depending on the protein context and how they interact with it. In this work, we investigate T.th-ubl5, a UbL present in a polyubiquitin locus of Tetrahymena thermophila, which is integral to an ADP-ribosyl transferase protein. Only one other co-occurrence of these two domains within the same protein has been reported. Methods: NMR, multiple sequence alignment, MD simulations and SPR have been used to characterize the structure of T.th-ubl5, identify putative binders and experimentally test the interaction, respectively. Results: Molecular dynamics simulations showed that T.th-ubl5 is unable to bind the proteasome like ubiquitin due to the lack of the conserved hydrophobic patch. Of other integral UbLs identified by structural and sequence alignment, T.th-ubl5 showed high structural and sequence resemblance with the Ras-binding epitope of FERM UbLs. SPR experiments confirmed that a strong and specific interaction occurs between T.th-ubl5 and T.th-Ras. Conclusion: Data indicate that T. th-ubl5 does not interact with the proteasome like ubiquitin but acts as a decoy for the recruitment of Ras protein by the ADP-ribosyl transferase domain. General significance: Mono-ADP-ribosylation of Ras proteins is known as a prerogative of bacterial toxins. T.th-ubl5 mediated recruitment of Ras highlights the possibility of an unprecedented post-translational modification with interesting implication for signalling pathways.Peer reviewe

Polytrichadelphus bolivianus una nueva especie de Polytrichaceae para el Noroeste de Argentina

Polytrichadelphus bolivianus Herzog, un musgo de los Bosques Montanos de Bolivia es registrado por primera vez para Argentina. Ha sido recolectado en 1997 y 1998 por Schiavone y otros en el norte de la provincia de Salta, pero hasta el momento no había sido identificado. Se presenta una descripción, ilustración y lectotipificación de la especie.Fil: Colotti, Maria T.. Fundación Miguel Lillo; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Suarez, Guillermo Martin. Fundación Miguel Lillo; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; ArgentinaFil: Schiavone, María M.. Fundación Miguel Lillo; Argentina. Universidad Nacional de Tucuman. Facultad de Cs.naturales E Instituto Miguel Lillo. Instituto Miguel Lillo; Argentin

El género Holomitrium (Dicranaceae, Bryophyta), nuevo registro en Argentina y Uruguay

The genus Holomitrium Brid. is recorded for first time from Argentina and Uruguay. Only one species, H. arboreum, is present in the study area. A brief description, photographs and illustrations of the species are provided.El género Holomitrium (Dicranaceae, Bryophyta), nuevo registro en Argentina y Uruguay. El género Holomitrium Brid. es registrado por primera vez en Argentina y Uruguay. Sólo una especie, H. arboreum, está presente en el área de estudio. Se realiza una breve descripción y se proporcionan fotografías e ilustraciones de la especie.Fil: Suarez, Guillermo Martin. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schiavone, Maria M.. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Colotti, Maria T.. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentin

Un sistema di Session Tracking e Threat Evaluation per Applicazioni Web basato su Honeytoken

In questa tesi ho portato avanti lo sviluppo di un sistema di Session Tracking e Threat Evaluation per Applicazioni Web basato su Honeytoken. Il suo compito è quello di mettere a disposizione dei meccanismi che permettano all'amministratore di un sito web di tenere traccia delle azioni che gli utenti effettuano su quest'ultimo, in più deve essere in grado di distinguere delle richieste potenzialmente dannose sfruttando una tecnica di deception come gli Honeytoken a base Web. Per il tracciamento degli utenti è stato deciso, dopo aver consultato lo stato dell'arte in tema di tecniche di Web Tracking, di utilizzare dei cookie di sessione: strumento oggigiorno estremamente diffuso ed utilizzato all'interno di qualsiasi genere di sito web. Dopo aver sviluppato sia il plugin Wordpress che registrerà le richieste degli utenti, sia gli altri sottosistemi che si occuperanno di valutare il livello di minaccia e rappresentare in maniera grafica i dati, sono passato alla fase di testing che mi ha permesso di constatare l'effettiva efficacia del sistema e dei suoi meccanismi proattivi di difesa che permettono di limitare quegli utenti etichettati come pericolosi

Information Transfer in the Penta-EF-hand Protein Sorcin Does Not Operate via the Canonical Structural/Functional Pairing A STUDY WITH SITE-SPECIFIC MUTANTS

Sorcin is a typical penta-EF-hand protein that participates in Ca2+-regulated processes by translocating reversibly from cytosol to membranes, where it interacts with different target proteins in different tissues. Binding of two Ca2+/monomer triggers translocation, although EF1, EF2, and EF3 are potentially able to bind calcium at micromolar concentrations. To identify the functional pair, the conserved bidentate -Z glutamate in these EF-hands was mutated to yield E53Q-, E94A-, and E124A-sorcin, respectively. Limited structural perturbations occur only in E124A-sorcin due to involvement of Glu-124 in a network of interactions that comprise the long D helix connecting EF3 to EF2. The overall affinity for Ca2+ and for two sorcin targets, annexin VII and the ryanodine receptor, follows the order wild-type > E53Q- > E94A- > E124A-sorcin, indicating that disruption of EF3 has the largest functional impact and that disruption of EF2 and EF1 has progressively smaller effects. Based on this experimental evidence, EF3 and EF2, which are not paired in the canonical manner, are the functional EF-hands. Sorcin is proposed to be activated upon Ca2+ binding to EF3 and transmission of the conformational change at Glu-124 via the D helix to EF2 and from there to EF1 via the canonical structural/functional pairing. This mechanism may be applicable to all penta-EF-hand proteins