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  • Targeting bacterial energetics to produce new antimicrobials
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-11-02
    Kiel Hards, Gregory M. Cook

    From the war on drug resistance, through cancer biology, even to agricultural and environmental protection: there is a huge demand for rapid and effective solutions to control infections and diseases. The development of small molecule inhibitors was once an accepted “one-size fits all” approach to these varied problems, but persistence and resistance threaten to return society to a pre-antibiotic era. Only five essential cellular targets in bacteria have been developed for the majority of our clinically-relevant antibiotics. These include: cell wall synthesis, cell membrane function, protein and nucleic acid biosynthesis, and antimetabolites. Many of these targets are now compromised through rapidly spreading antimicrobial resistance and the need to target non-replicating cells (persisters). Recently, an unprecedented medical breakthrough was achieved by the FDA approval of the drug bedaquiline (BDQ, trade name Sirturo) for the treatment of multidrug-resistant tuberculosis disease. BDQ targets the membrane-bound F1Fo-ATP synthase, validating cellular energy generating machinery as a new target space for drug discovery. Recently, BDQ and several other FDA-approved drugs have been demonstrated to be respiratory “uncouplers” disrupting transmembrane electrochemical gradients, in addition to binding to enzyme targets. In this review, we summarize the role of bioenergetic systems in mycobacterial persistence and discuss the multi-targeting nature of uncouplers and the place these molecules may have in future drug development.

  • An update on β-lactamase inhibitor discovery and development.
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-11-07
    Jean-Denis Docquier, Stefano Mangani

    Antibiotic resistance, and the emergence of pan-resistant clinical isolates, seriously threatens our capability to treat bacterial diseases, including potentially deadly hospital-acquired infections. This growing issue certainly requires multiple adequate responses, including the improvement of both diagnosis methods and use of antibacterial agents, and obviously the development of novel antibacterial drugs, especially active against Gram-negative pathogens, which represent an urgent medical need.Considering the clinical relevance of both β-lactam antibiotics and β-lactamase-mediated resistance, the discovery and development of combinations including a β-lactamase inhibitor seems to be particularly attractive, despite being extremely challenging due to the enormous diversity, both structurally and mechanistically, of the potential β-lactamase targets. This review will cover the evolution of currently available β-lactamase inhibitors along with the most recent research leading to new β-lactamase inhibitors of potential clinical interest or already in the stage of clinical development.

  • TAK-ing aim at chemoresistance: The emerging role of MAP3K7 as a target for cancer therapy
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-11-03
    Raffaela Santoro, Carmine Carbone, Geny Piro, Paul J. Chiao, Davide Melisi

    Cellular drug resistance remains the main obstacle to the clinical efficacy of cancer chemotherapy. Alterations in key pathways regulating cell cycle checkpoints, apoptosis and Epithelial to Mesenchymal Transition (EMT), such as the Mitogen-activated protein kinase (MAPK) pathway, appear to be closely associated to cancer chemoresistance.Transforming growth factor-β (TGF-β)- activated kinase 1 (TAK1, also known as MAP3K7) is a serine/threonine kinase in the mitogen-activated protein kinase (MAP3K) family. It represents the cellular hub to which IL1, TGF-β and Wnt signaling pathways converge. By regulating the phosphorylation status and activities of transcription factors including Activated Protein-1 (AP-1) and nuclear factor κ-B (NF-κB), TAK1 mediates inflammatory and pro-survival responses. The interest towards the therapeutic targeting of TAK1 is due to its identification as one of the main mediators of both chemoresistance and EMT in several types of tumors, and as the possible target for a subset of treatment-refractory colon cancers exhibiting mutated KRAS or activated WNT pathways. For these reasons, many efforts have been made to design inhibitors of TAK1 kinase activity, which could be used to reverse TAK1-mediated chemoresistance. The activity of these inhibitors, in combination with the most commonly used chemotherapeutic drugs, has been tested in preclinical studies, proving the efficacy of TAK1 inhibition in reducing tumor growth and survival following chemotherapy administration. In the first part of this review, we describe the mechanisms underlying TAK1 regulation such as phosphorylation, ubiquitination and targeting by microRNAs. We then focus on the development of therapeutic small molecule inhibitors of TAK1 kinase activity, as well as preclinical studies supporting the role of TAK1 as a potential target for enhancing the response of tumors to anticancer therapies.

  • 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
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-10-16
    Ilaria Genovese, Andrea Ilari, Yehuda G. Assaraf, Francesco Fazi, Gianni Colotti

    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.

  • Cancer Immunotherapy Getting Brainy: Visualizing the Distinctive CNS Metastatic Niche to Illuminate Therapeutic Resistance
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-10-14
    Mark Owyong, Niloufar Hosseini-Nassab, Gizem Efe, Alexander Honkala, Renske J.E. van den Bijgaart, Vicki Plaks, Bryan Ronain Smith

    The advent of cancer immunotherapy (CIT) and its success in treating primary and metastatic cancer may offer substantially improved outcomes for patients. Despite recent advancements, many malignancies remain resistant to CIT, among which are brain metastases, a particularly virulent disease with no apparent cure. The immunologically unique niche of the brain has prompted compelling new questions in immuno-oncology such as the effects of tissue-specific differences in immune response, heterogeneity between primary tumors and distant metastases, and the role of spatiotemporal dynamics in shaping an effective anti-tumor immune response. Current methods to examine the immunobiology of metastases in the brain are constrained by tissue processing methods that limit spatial data collection, omit dynamic information, and cannot recapitulate the heterogeneity of the tumor microenvironment. In the current review, we describe how high-resolution, live imaging tools, particularly intravital microscopy (IVM), are instrumental in answering these questions. IVM of pre-clinical cancer models enables short- and long-term observations of critical immunobiology and metastatic growth phenomena to potentially generate revolutionary insights into the spatiotemporal dynamics of brain metastasis, interactions of CIT with immune elements therein, and influence of chemo- and radiotherapy. We describe the utility of IVM to study brain metastasis in mice by tracking the migration and growth of fluorescently-labeled cells, including cancer cells and immune subsets, while monitoring the physical environment within optical windows using imaging dyes and other signal generation mechanisms to illuminate angiogenesis, hypoxia, and/or CIT drug expression within the metastatic niche. Our review summarizes the current knowledge regarding brain metastases and the immune milieu, presents the current status of CIT and its prospects in targeting brain metastases to circumvent therapeutic resistance, and proposes avenues to utilize IVM to study CIT drug delivery and therapeutic efficacy in preclinical models that will ultimately facilitate novel drug discovery and innovative combination therapies.

  • Antimicrobial blue light inactivation of pathogenic microbes: state of the art
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-10-13
    Yucheng Wang, Ying Wang, Yuguang Wang, Clinton K. Murray, Michael R. Hamblin, David C. Hooper, Tianhong Dai

    As an innovative non-antibiotic approach, antimicrobial blue light in the spectrum of 400–470 nm has demonstrated its intrinsic antimicrobial properties resulting from the presence of endogenous photosensitizing chromophores in pathogenic microbes and, subsequently, its promise as a counteracter of antibiotic resistance. Since we published our last review of antimicrobial blue light in 2012, there have been a substantial number of new studies reported in this area. Here we provide an updated overview of the findings from the new studies over the past 5 years, including the efficacy of antimicrobial blue light inactivation of different microbes, its mechanism of action, synergism of antimicrobial blue light with other angents, its effect on host cells and tissues, the potential development of resistance to antimicrobial blue light by microbes, and a novel interstitial delivery approach of antimicrobial blue light. The potential new applications of antimicrobial blue light are also discussed.

  • In cancer, A-to-I RNA editing can be the driver, the passenger, or the mechanic
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-10-04
    Nabeel S. Ganem, Noa Ben-Asher, Ayelet T. Lamm

    In recent years, A-to-I RNA modifications performed by the Adenosine Deaminase Acting on RNA (ADAR) protein family were found to be expressed at altered levels in multiple human malignancies. A-to-I RNA editing changes adenosine to inosine on double stranded RNA, thereby changing transcript sequence and structure. Although A-to-I RNA editing have the potential to change essential mRNA transcripts, affecting their corresponding protein structures, most of the human editing sites identified to date reside in non-coding repetitive transcripts such as Alu elements. Therefore, the impact of the hypo- or hyper-editing found in specific cancers remains unknown. Moreover, it is yet unclear whether or not changes in RNA editing and ADAR expression levels facilitate or even drive cancer progression or are just a byproduct of other affected pathways. In both cases, however, the levels of RNA editing and ADAR enzymes can possibly be used as specific biomarkers, as their levels change differently in specific malignancies. More significantly, recent studies suggest that ADAR enzymes can be used to reverse the oncogenic process, suggesting a potential for gene therapies. This review focuses on new findings that suggest that RNA editing by ADARs can affect cancer progression and even formation. We also discuss new possibilities of using ADAR enzymes and RNA editing as cancer biomarkers, indicators of chemotherapeutic drug sensitivity, and even to be themselves potential therapeutic tools.

  • Immunotherapy for Triple-Negative Breast Cancer: Existing Challenges and Exciting Prospects
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-08-19
    Hongyan Jia, Cristina I. Truica, Bin Wang, Yanhong Wang, Xingcong Ren, Harold A. Harvey, Jianxuan Song, Jin-Ming Yang

    Patients with breast tumors that do not express the estrogen receptor, the progesterone receptor, nor Her-2/neu are hence termed “triple negatives”, and generally have a poor prognosis, with high rates of systemic recurrence and refractoriness to conventional therapy regardless of the choice of adjuvant treatment. Thus, more effective therapeutic options are sorely needed for triple-negative breast cancer (TNBC), which occurs in approximately 20% of diagnosed breast cancers. In recent years, exploiting intrinsic mechanisms of the host immune system to eradicate cancer cells has achieved impressive success, and the advances in immunotherapy have yielded potential new therapeutic strategies for the treatment of this devastating subtype of breast cancer. It is anticipated that the responses initiated by immunotherapeutic interventions will explicitly target and annihilate tumor cells, while at the same time spare normal cells. Various immunotherapeutic approaches have been already developed and tested, which include the blockade of immune checkpoints using neutralizing or blocking antibodies, induction of cytotoxic T lymphocytes (CTLs), adoptive cell transfer-based therapy, and modulation of the tumor microenvironment to enhance the activity of CTLs. One of the most important areas of breast cancer research today is understanding the immune features and profiles of TNBC and devising novel immune-modulatory strategies to tackling TNBC, a subtype of breast cancer notorious for its poor prognosis and its imperviousness to conventional treatments. On the optimal side, one can anticipate that novel, effective, and personalized immunotherapy for TNBC will soon achieve more success and impact clinical treatment of this disease which afflicts approximately 20% of patients with breast cancer. In the present review, we highlight the current progress and encouraging developments in cancer immunotherapy, with a goal to discuss the challenges and to provide future perspectives on how to exploit a variety of new immunotherapeutic approaches including checkpoint inhibitors and neoadjuvant immunotherapy for the treatment of patients with TNBC.

  • New strategies for targeting and treatment of multi-drug resistant Staphylococcus aureus
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-04-06
    L. Mayrink Assis, M. Nedeljković, A. Dessen

    Staphylococcus aureus is a major cause of bacterial infection in humans, and has been notoriously able to acquire resistance to a variety of antibiotics. An example is methicillin-resistant S. aureus (MRSA), which despite having been initially associated with clinical settings, now is one of the key causative agents of community-acquired infections. Antibiotic resistance in S. aureus involves mechanisms ranging from drug efflux to increased expression or mutation of target proteins, and this has required innovative approaches to develop novel treatment methodologies. This review provides an overview of the major mechanisms of antibiotic resistance developed by S. aureus, and describes the emerging alternatives being sought to circumvent infection and proliferation, including new generations of classic antibiotics, synergistic approaches, antibodies, and targeting of virulence factors.

  • Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-05-21
    Maya Bar-Zeev, Yoav D. Livney, Yehuda G. Assaraf

    Intrinsic anticancer drug resistance appearing prior to chemotherapy as well as acquired resistance due to drug treatment, remain the dominant impediments towards curative cancer therapy. Hence, novel targeted strategies to overcome cancer drug resistance constitute a key aim of cancer research. In this respect, targeted nanomedicine offers innovative therapeutic strategies to overcome the various limitations of conventional chemotherapy, enabling enhanced selectivity, early and more precise cancer diagnosis, individualized treatment as well as overcoming of drug resistance, including multidrug resistance (MDR). Delivery systems based on nanoparticles (NPs) include diverse platforms enabling a plethora of rationally designed therapeutic nanomedicines. Here we review NPs designed to enhance antitumor drug uptake and selective intracellular accumulation using strategies including passive and active targeting, stimuli-responsive drug activation or target-activated release, triggered solely in the cancer cell or in specific organelles, cutting edge theranostic multifunctional NPs delivering drug combinations for synergistic therapy, while facilitating diagnostics, and personalization of therapeutic regimens. In the current paper we review the recent findings of the past four years and discuss the advantages and limitations of the various novel NPs-based drug delivery systems. Special emphasis is put on in vivo study-based evidences supporting significant therapeutic impact in chemoresistant cancers. A future perspective is proposed for further research and development of complex targeted, multi-stage responsive nanomedical drug delivery systems for personalized cancer diagnosis and efficacious therapy.

  • Can microbial cells develop resistance to oxidative stress in antimicrobial photodynamic inactivation?
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-07-26
    Nasim Kashef, Michael R. Hamblin

    Infections have been a major cause of disease throughout the history of humans on earth. With the introduction of antibiotics, it was thought that infections had been conquered. However, bacteria have been able to develop resistance to antibiotics at an exponentially increasing rate. The growing threat from multi-drug resistant organisms calls for intensive action to prevent the emergence of totally resistant and untreatable infections. Novel, non-invasive, non-antibiotic strategies are needed that act more efficiently and faster than current antibiotics. One promising alternative is antimicrobial photodynamic inactivation (APDI), an approach that produces reactive oxygen species when dyes and light are combined. So far, it has been questionable if bacteria can develop resistance against APDI. This review paper gives an overview of recent studies concerning the susceptibility of bacteria towards oxidative stress, and suggests possible mechanisms of the development of APDI-resistance that should at least be addressed. Some ways to potentiate APDI and also to overcome future resistance are suggested.

  • A mechanopharmacology approach to overcome chemoresistance in pancreatic cancer
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-07-24
    Stefano Coppola, Ilaria Carnevale, Erik H.J. Danen, Godefridus J. Peters, Thomas Schmidt, Yehuda G. Assaraf, Elisa Giovannetti

    Pancreatic ductal adenocarcinoma (PDAC) is a highly chemoresistant malignancy. This chemoresistant phenotype has been historically associated with genetic factors. Major biomedical research efforts were concentrated that resulted in the identification of subtypes characterized by specific genetic lesions and gene expression signatures that suggest important biological differences. However, to date, these distinct differences could not be exploited for therapeutic interventions. Apart from these genetic factors, desmoplasia and tumor microenvironment have been recognized as key contributors to PDAC chemoresistance. However, while several strategies targeting tumor-stroma have been explored including drugs against members of the Hedgehog family, they failed to meet the expectations in the clinical setting. These unsatisfactory clinical results suggest that, an important link between genetics and the influence of tumor microenvironment on PDAC chemoresistance remains to be elucidated. In this respect, mechanobiology is an emerging multidisciplinary field that encompasses cell and developmental biology as well as biophysics and bioengineering. Herein we provide a comprehensive overview of the key players in pancreatic cancer chemoresistance from the perspective of mechanobiology, and discuss novel experimental avenues such as elastic micropillar arrays that could provide fresh insights for the development of mechanobiology-targeted therapeutic approaches (know as mechanopharmacology) to overcome anticancer drug resistance in pancreatic cancer.

  • Sensitizing pathogens to antibiotics using the CRISPR-Cas system
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-11-27
    Moran Goren, Ido Yosef, Udi Qimron

    The extensive use of antibiotics over the last century has resulted in a significant artificial selection pressure for antibiotic-resistant pathogens to evolve. Various strategies to fight these pathogens have been introduced including new antibiotics, naturally-derived enzymes/peptides that specifically target pathogens and bacteriophages that lyse these pathogens. A new tool has recently been introduced in the fight against drug-resistant pathogens–the prokaryotic defense mechanism–clustered regularly interspaced short palindromic repeats-CRISPR associated (CRISPR-Cas) system. The CRISPR-Cas system acts as a nuclease that can be guided to cleave any target DNA, allowing sophisticated, yet feasible, manipulations of pathogens. Here, we review pioneering studies that use the CRISPR-Cas system to specifically edit bacterial populations, eliminate their resistance genes and combine these two strategies in order to produce an artificial selection pressure for antibiotic-sensitive pathogens. We suggest that intelligent design of this system, along with efficient delivery tools into pathogens, may significantly reduce the threat of antibiotic-resistant pathogens.

  • Drug-biomarker co-development in oncology – 20 years and counting
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-02-21
    Julianne D. Twomey, Nina N. Brahme, Baolin Zhang

    Predictive biomarkers for oncology are necessary to accurately identify patients who will benefit from anticancer treatment. Recently approved oncology drugs target discrete molecular aberrations or pathways in tumor cells and consequently are active on a subset of patient population, yet clinical studies have shown that not all biomarker-positive patients respond. The advancement of predictive biomarkers needs to detect novel and evolving drug resistance mechanisms, not only to guide the selection of patient subsets for specific treatments, but to identify new therapeutic targets. Going beyond the “one marker, one drug” model to incorporate genomics, transcriptomics, and receptor status assessments during biomarker-drug co-development can aid in the successful application of molecular marker-based cancer therapy. This review provides the latest update of biomarker-based cancer therapeutics approved by the US Food and Drug Administration. We provide case studies of therapeutics selectively targeting HER2, EGFR, or PD-1/PD-L1 signaling pathways. We also discuss the challenges and promising future directions in the co-development of targeted cancer therapeutics and paired predictive biomarkers.

  • Active efflux in dormant bacterial cells – New insights into antibiotic persistence
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-11-29
    Yingying Pu, Yuehua Ke, Fan Bai

    Bacterial persisters are phenotypic variants of an isogenic cell population that can survive antibiotic treatment and resume growth after the antibiotics have been removed. Cell dormancy has long been considered the principle mechanism underlying persister formation. However, dormancy alone is insufficient to explain the full range of bacterial persistence. Our recent work revealed that in addition to ‘passive defense’ via dormancy, persister cells employ ‘active defense’ via enhanced efflux activity to expel drugs. This finding suggests that persisters combine two seemingly contradictory mechanisms to tolerate antibiotic attack. Here, we review the passive and active aspects of persister formation, discuss new insights into the process, and propose new techniques that can facilitate the study of bacterial persistence.

  • The importance of breast cancer resistance protein to the kidneys excretory function and chemotherapeutic resistance
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-01-11
    Pedro Caetano-Pinto, Jitske Jansen, Yehuda G. Assaraf, Rosalinde Masereeuw

    The relevance of membrane transporters gained momentum in recent years and it is now widely recognized that transporters are key players in drug disposition and chemoresistance. As such, the kidneys harbor a variety of drug transporters and are one of the main routes for xenobiotic excretion. The breast cancer resistance protein (BCRP/ABCG2) is widely accepted as a key mediator of anticancer drug resistance and is a prominent renal drug transporter. Here, we review the role of BCRP in both processes and present a multitude of variables that can influence its activity. An increasing number of renally cleared chemotherapeutics, including tyrosine kinase inhibitors, described as BCRP substrates can modulate its activity via transcription factors and cellular signaling pathways, such as the phosphoinositide 3-kinase (PI3K) pathway. In addition to pharmacological actions, genetic variations, as well as differences between species and gender can affect BCRP function, which are also discussed. Furthermore, the role of BCRP in light of cancer treatments and the implications for novel therapeutic interventions that take into account renal function are discussed.

  • Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: Contrasting roles in the regulation of chemo/immuno-resistance in cancer
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-01-09
    Stephanie Wottrich, Samantha Kaufhold, Emmanuel Chrysos, Odysseas Zoras, Stavroula Baritaki, Benjamin Bonavida

    Several gene products have been postulated to mediate inherent and/or acquired anticancer drug resistance and tumor metastasis. Among these, the metastasis suppressor and chemo-immuno-sensitizing gene product, Raf Kinase Inhibitor Protein (RKIP), is poorly expressed in many cancers. In contrast, the metastasis inducer and chemo-immuno-resistant factor Yin Yang 1 (YY1) is overexpressed in many cancers. This inverse relationship between RKIP and YY1 expression suggests that these two gene products may be regulated via cross-talks of molecular signaling pathways, culminating in the expression of different phenotypes based on their targets. Analyses of the molecular regulation of the expression patterns of RKIP and YY1 as well as epigenetic, post-transcriptional, and post-translational regulation revealed the existence of several effector mechanisms and crosstalk pathways, of which five pathways of relevance have been identified and analyzed. The five examined cross-talk pathways include the following loops: RKIP/NF-κB/Snail/YY1, p38/MAPK/RKIP/GSK3β/Snail/YY1, RKIP/Smurf2/YY1/Snail, RKIP/MAPK/Myc/Let-7/HMGA2/Snail/YY1, as well as RKIP/GPCR/STAT3/miR-34/YY1. Each loop is comprised of multiple interactions and cascades that provide evidence for YY1’s negative regulation of RKIP expression and vice versa. These loops elucidate potential prognostic motifs and targets for therapeutic intervention. Chiefly, these findings suggest that targeted inhibition of YY1 by specific small molecule inhibitors and/or the specific induction of RKIP expression and activity are potential therapeutic strategies to block tumor growth and metastasis in many cancers, as well as to overcome anticancer drug resistance. These strategies present potential alternatives for their synergistic uses in combination with low doses of conventional chemo-immunotherapeutics and hence, increasing survival, reducing toxicity, and improving quality of life.

  • Novel immune check point inhibiting antibodies in cancer therapy—Opportunities and challenges
    Drug Resist. Updat. (IF 10.906) Pub Date : 2017-02-04
    Yael Diesendruck, Itai Benhar

    Drug resistance of tumor cells to chemotherapy is limiting the therapeutic efficacy of most anticancer drugs and represents a major obstacle in medical oncology. However, treatment of various human malignancies with biologics, mostly monoclonal antibodies (mAbs), is not limited by such chemoresistance mechanisms. However, other resistance or evasion mechanisms limit the efficacy to anticancer therapeutic mAbs that engage tumor-associated antigens on the surface of the malignant cells. Immune checkpoint blocking monoclonal antibodies are heralded as a promising therapeutic approach in clinical oncology. These mAbs do not directly attack the malignant cells as most anticancer mAbs; rather, they enhance the anti-tumor response of the immune system by targeting immune regulatory pathways. Three mAbs targeting immune checkpoint molecules are currently used in the clinic and new mAbs that target other potential inhibitory targets are being actively investigated. This therapeutic approach, while proving as highly beneficial for many patients, is prone to toxicities and side effects of an autoimmune nature. Defining suitable management algorithms and biomarkers that predict therapeutic effects and adverse toxicity are required to provide survival benefit for larger numbers of cancer patients. Overcoming these challenges, along with opportunities for new agents and combinatorial strategies are the main focus of immune checkpoint blockade research today.

  • The semaphorins and their receptors as modulators of tumor progression
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-08-28
    Gera Neufeld, Yelena Mumblat, Tanya Smolkin, Shira Toledano, Inbal Nir-Zvi, Keren Ziv, Ofra Kessler

    The semaphorins were initially characterized as repulsive axon guidance factors. However, they are currently also recognized as important regulators of diverse biological processes which include regulation of immune responses, angiogenesis, organogenesis, and a variety of additional physiological and developmental functions. The semaphorin family consists of more than 20 genes divided into seven subfamilies, all of which contain the sema domain signature. They usually transduce signals by activation of receptors belonging to the plexin family, either directly, or indirectly following the binding of some semaphorins to receptors of the neuropilin family which subsequently associate with plexins. Additional receptors which form complexes with these primary semaphorin receptors are also frequently involved in semaphorin signalling, and can strongly influence the nature of the biological responses of cells to semaphorins. Recent evidence suggests that semaphorins play important roles in the etiology of multiple forms of cancer. Some semaphorins such as some semaphorins belonging to the class-3 semaphorin subfamily, have been found to function as bona fide tumor suppressors and to inhibit tumor progression by various mechanisms. Because these class-3 semaphorins are secreted proteins, these semaphorins may potentially be used as anti-tumorigenic drugs. Other semaphorins, such as semaphorin-4D, function as inducers of tumor progression and represent targets for the development of novel anti-tumorigenic drugs. The mechanisms by which semaphorins affect tumor progression are diverse, ranging from direct effects on tumor cells to modulation of accessory processes such as modulation of immune responses and inhibition or promotion of tumor angiogenesis and tumor lymphangiogenesis. This review focuses on the diverse mechanisms by which semaphorins affect tumor progression.

  • Plasmid-mediated quinolone resistance: Two decades on
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-09-09
    José Manuel Rodríguez-Martínez, Jesús Machuca, María Eliecer Cano, Jorge Calvo, Luis Martínez-Martínez, Alvaro Pascual

    After two decades of the discovery of plasmid-mediated quinolone resistance (PMQR), three different mechanisms have been associated to this phenomenon: target protection (Qnr proteins, including several families with multiple alleles), active efflux pumps (mainly QepA and OqxAB pumps) and drug modification [AAC(6′)-Ib-cr acetyltransferase]. PMQR genes are usually associated with mobile or transposable elements on plasmids, and, in the case of qnr genes, are often incorporated into sul1-type integrons. PMQR has been found in clinical and environmental isolates around the world and appears to be spreading. Although the three PMQR mechanisms alone cause only low-level resistance to quinolones, they can complement other mechanisms of chromosomal resistance to reach clinical resistance level and facilitate the selection of higher-level resistance, raising a threat to the treatment of infections by microorganisms that host these mechanisms.

  • The rapid spread of carbapenem-resistant Enterobacteriaceae
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-09-19
    Robert F. Potter, Alaric W. D’Souza, Gautam Dantas

    Carbapenems, our one-time silver bullet for multidrug resistant bacterial infections, are now threatened by widespread dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Successful expansion of Enterobacteriaceae clonal groups and frequent horizontal gene transfer of carbapenemase expressing plasmids are causing increasing carbapenem resistance. Recent advances in genetic and phenotypic detection facilitate global surveillance of CRE diversity and prevalence. In particular, whole genome sequencing enabled efficient tracking, annotation, and study of genetic elements colocalized with carbapenemase genes on chromosomes and on plasmids. Improved characterization helps detail the co-occurrence of other antibiotic resistance genes in CRE isolates and helps identify pan-drug resistance mechanisms. The novel β-lactamase inhibitor, avibactam, combined with ceftazidime or aztreonam, is a promising CRE treatment compared to current colistin or tigecycline regimens. To halt increasing CRE-associated morbidity and mortality, we must continue quality, cooperative monitoring and urgently investigate novel treatments.

  • The reduced concentration of citrate in cancer cells: An indicator of cancer aggressiveness and a possible therapeutic target
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-09-21
    Icard Philippe, Lincet Hubert

    Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth. Because citrate is the donor of acetyl-CoA, its reduced production favors a deacetylation state of proteins favoring resistance to apoptosis and epigenetic changes, both processes contributing to tumor aggressiveness. Citrate levels could be monitored as an indicator of cancer aggressiveness (as already shown in human prostate cancer) and/or could serve as a biomarker for response to therapy. Strategies aiming to increase cytosolic citrate should be developed and tested in humans, knowing that experimental studies have shown that administration of citrate and/or inhibition of ACLY arrest tumor growth, inhibit the expression of the key anti-apoptotic factor Mcl-1, reverse cell dedifferentiation and increase sensibility to cisplatin.

  • Heparanase: From basic research to therapeutic applications in cancer and inflammation
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-10-06
    Israel Vlodavsky, Preeti Singh, Ilanit Boyango, Lilach Gutter-Kapon, Michael Elkin, Ralph D. Sanderson, Neta Ilan

    Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. In contrast, knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination; this is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. In fact, much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. The repertoire of the physio-pathological activities of heparanase is expanding. Specifically, heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance; but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase is upregulated in response to chemotherapy in cancer patients and the surviving cells acquire chemoresistance, attributed, at least in part, to autophagy. Consequently, heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase neutralizing monoclonal antibodies are being evaluated in pre-clinical studies, and heparanase-inhibiting small molecules are being developed based on the recently resolved crystal structure of the heparanase protein. Collectively, the emerging premise is that heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy.

  • Molecular mechanisms and clinical implications of bacterial persistence
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-10-15
    Joran Elie Michiels, Bram Van den Bergh, Natalie Verstraeten, Jan Michiels

    Any bacterial population harbors a small number of phenotypic variants that survive exposure to high concentrations of antibiotic. Importantly, these so-called ‘persister cells’ compromise successful antibiotic therapy of bacterial infections and are thought to contribute to the development of antibiotic resistance. Intriguingly, drug-tolerant persisters have also been identified as a factor underlying failure of chemotherapy in tumor cell populations. Recent studies have begun to unravel the complex molecular mechanisms underlying persister formation and revolve around stress responses and toxin–antitoxin modules. Additionally, in vitro evolution experiments are revealing insights into the evolutionary and adaptive aspects of this phenotype. Furthermore, ever-improving experimental techniques are stimulating efforts to investigate persisters in their natural, infection-associated, in vivo environment. This review summarizes recent insights into the molecular mechanisms of persister formation, explains how persisters complicate antibiotic treatment of infections, and outlines emerging strategies to combat these tolerant cells.

  • New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-10-29
    Alberto A. Gabizon, Yogita Patil, Ninh M. La-Beck

    We herein review various pharmacological and clinical aspects of pegylated liposomal doxorubicin (PLD), the first nanomedicine to be approved for cancer therapy, and discuss the gap between its potent antitumor activity in preclinical studies and its comparatively modest achievements in clinical studies and limited use in clinical practice. PLD is a complex formulation of doxorubicin based on pharmaceutical nanotechnology with unique pharmacokinetic and pharmacodynamic properties. Its long circulation time with stable retention of the payload and its accumulation in tumors with high vascular permeability both result in important advantages over conventional chemotherapy. The ability of PLD to buffer a number of undesirable side effects of doxorubicin, including a major risk reduction in cardiac toxicity, is now well-established and confers a major added value in a number of disease conditions. PLD is approved for the treatment of ovarian cancer, breast cancer, multiple myeloma, and Kaposi sarcoma. In addition, clinically significant antitumor activity of PLD has been reported in a number of other cancer types, including lymphomas and soft tissue sarcomas. In spite of this, PLD has not replaced conventional doxorubicin in common applications such as the adjuvant and neoadjuvant treatment of breast cancer, and its use in the clinic has not become as widespread as one may have predicted. Exploiting the unique pharmacology of PLD, analyzing its selective biodistribution and homing to tumors in cancer patients with proper theranostic tools, and harnessing its complex interaction with the immune system, will lead to a more selective and rational use of PLD that may have great impact on future clinical results and may help realize its largely untapped potential.

  • The bad seed: Cancer stem cells in tumor development and resistance
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-06-25
    Elle Koren, Yaron Fuchs

    Over the past two decades cancer stem cells (CSCs) have emerged as essential players in the pathogenesis of cancer, with the capacity to initiate, maintain and repopulate different tumors. Within the tumor bulk, CSCs represent a small subpopulation, bestowed with the capacity to self-renew and yield heterogeneous lineages of cancer cells. In many scenarios, CSCs exhibit increased resistance toward irradiation and chemotherapy, and given their spectacular ability to replenish the tumor, they constitute a substantial therapeutic challenge. In this review, we provide a brief overview of the concept of CSCs and the experimental methodology utilized for identifying and isolating these unique cells. We discuss how CSCs are regulated within the tumor microenvironment as well as the role they portray in seeding fresh tumors. Finally, we explore the mechanisms that enable CSCs to evade modern therapeutic approaches and the possible strategies that can be utilized to prevent CSCs from resurrecting the disease.

  • Multidrug efflux pumps as main players in intrinsic and acquired resistance to antimicrobials
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-06-30
    Sara Hernando-Amado, Paula Blanco, Manuel Alcalde-Rico, Fernando Corona, Jose A. Reales-Calderón, María B. Sánchez, José L. Martínez

    Multidrug efflux pumps constitute a group of transporters that are ubiquitously found in any organism. In addition to other functions with relevance for the cell physiology, efflux pumps contribute to the resistance to compounds used for treating different diseases, including resistance to anticancer drugs, antibiotics or antifungal compounds. In the case of antimicrobials, efflux pumps are major players in both intrinsic and acquired resistance to drugs currently in use for the treatment of infectious diseases. One important aspect not fully explored of efflux pumps consists on the identification of effectors able to induce their expression. Indeed, whereas the analysis of clinical isolates have shown that mutants overexpressing these resistance elements are frequently found, less is known on the conditions that may trigger expression of efflux pumps, hence leading to transient induction of resistance in vivo, a situation that is barely detectable using classical susceptibility tests. In the current article we review the structure and mechanisms of regulation of the expression of bacterial and fungal efflux pumps, with a particular focus in those for which a role in clinically relevant resistance has been reported.

  • The pharmacogenomics of drug resistance to protein kinase inhibitors
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-07-05
    Nancy K. Gillis, Howard L. McLeod

    Dysregulation of growth factor cell signaling is a major driver of most human cancers. This has led to development of numerous drugs targeting protein kinases, with demonstrated efficacy in the treatment of a wide spectrum of cancers. Despite their high initial response rates and survival benefits, the majority of patients eventually develop resistance to these targeted therapies. This review article discusses examples of established mechanisms of drug resistance to anticancer therapies, including drug target mutations or gene amplifications, emergence of alternate signaling pathways, and pharmacokinetic variation. This reveals a role for pharmacogenomic analysis to identify and monitor for resistance, with possible therapeutic strategies to combat chemoresistance.

  • Folylpoly-γ-glutamate synthetase: A key determinant of folate homeostasis and antifolate resistance in cancer
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-07-04
    Shachar Raz, Michal Stark, Yehuda G. Assaraf

    Mammalians are devoid of autonomous biosynthesis of folates and hence must obtain them from the diet. Reduced folate cofactors are B9-vitamins which play a key role as donors of one-carbon units in the biosynthesis of purine nucleotides, thymidylate and amino acids as well as in a multitude of methylation reactions including DNA, RNA, histone and non-histone proteins, phospholipids, as well as intermediate metabolites. The products of these S-adenosylmethionine (SAM)-dependent methylations are involved in the regulation of key biological processes including transcription, translation and intracellular signaling. Folate-dependent one-carbon metabolism occurs in several subcellular compartments including the cytoplasm, mitochondria, and nucleus. Since folates are essential for DNA replication, intracellular folate cofactors play a central role in cancer biology and inflammatory autoimmune disorders. In this respect, various folate-dependent enzymes catalyzing nucleotide biosynthesis have been targeted by specific folate antagonists known as antifolates. Currently, antifolates are used in drug treatment of multiple human cancers, non-malignant chronic inflammatory disorders as well as bacterial and parasitic infections. An obligatory key component of intracellular folate retention and intracellular homeostasis is (anti)folate polyglutamylation, mediated by the unique enzyme folylpoly-γ-glutamate synthetase (FPGS), which resides in both the cytoplasm and mitochondria. Consistently, knockout of the FPGS gene in mice results in embryonic lethality. FPGS catalyzes the addition of a long polyglutamate chain to folates and antifolates, hence rendering them polyanions which are efficiently retained in the cell and are now bound with enhanced affinity by various folate-dependent enzymes. The current review highlights the crucial role that FPGS plays in maintenance of folate homeostasis under physiological conditions and delineates the plethora of the molecular mechanisms underlying loss of FPGS function and consequent antifolate resistance in cancer.

  • Old drugs, novel ways out: Drug resistance toward cytotoxic chemotherapeutics
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-07-16
    Ruud H. Wijdeven, Baoxu Pang, Yehuda G. Assaraf, Jacques Neefjes

    Efficacy of chemotherapy in the treatment of distinct malignancies is often hampered by drug resistance arising in the tumor. Understanding the molecular basis of drug resistance and translating this knowledge into personalized treatment decisions can enhance therapeutic efficacy and even curative outcome. Over the years, multiple drug resistance mechanisms have been identified that enable tumors to cope with the damage instigated by a specific drug or group of anti-tumor agents. Here we provide an overview of the molecular pathways leading to resistance against conventional anti-cancer drugs, with emphasis on the utility of these pathways for rational selection of treatments for individual cancer patients. We further complement the review by discussing the pitfalls and difficulties in translating these findings into novel treatment strategies for cancer patients.

  • Antibiotic resistance in Burkholderia species
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-07-30
    Katherine A. Rhodes, Herbert P. Schweizer

    The genus Burkholderia comprises metabolically diverse and adaptable Gram-negative bacteria, which thrive in often adversarial environments. A few members of the genus are prominent opportunistic pathogens. These include Burkholderia mallei and Burkholderia pseudomallei of the B. pseudomallei complex, which cause glanders and melioidosis, respectively. Burkholderia cenocepacia, Burkholderia multivorans, and Burkholderia vietnamiensis belong to the Burkholderia cepacia complex and affect mostly cystic fibrosis patients. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. The first line of defense against antimicrobials in Burkholderia species is the outer membrane penetration barrier. Most Burkholderia contain a modified lipopolysaccharide that causes intrinsic polymyxin resistance. Contributing to reduced drug penetration are restrictive porin proteins. Efflux pumps of the resistance nodulation cell division family are major players in Burkholderia multidrug resistance. Third and fourth generation β-lactam antibiotics are seminal for treatment of Burkholderia infections, but therapeutic efficacy is compromised by expression of several β-lactamases and ceftazidime target mutations. Altered DNA gyrase and dihydrofolate reductase targets cause fluoroquinolone and trimethoprim resistance, respectively. Although antibiotic resistance hampers therapy of Burkholderia infections, the characterization of resistance mechanisms lags behind other non-enteric Gram-negative pathogens, especially ESKAPE bacteria such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa.

  • Renew or die: The molecular mechanisms of peptidoglycan recycling and antibiotic resistance in Gram-negative pathogens
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-07-29
    Teresa Domínguez-Gil, Rafael Molina, Martín Alcorlo, Juan A. Hermoso

    Antimicrobial resistance is one of the most serious health threats. Cell-wall remodeling processes are tightly regulated to warrant bacterial survival and in some cases are directly linked to antibiotic resistance. Remodeling produces cell-wall fragments that are recycled but can also act as messengers for bacterial communication, as effector molecules in immune response and as signaling molecules triggering antibiotic resistance. This review is intended to provide state-of-the-art information about the molecular mechanisms governing this process and gather structural information of the different macromolecular machineries involved in peptidoglycan recycling in Gram-negative bacteria. The growing body of literature on the 3D structures of the corresponding macromolecules reveals an extraordinary complexity. Considering the increasing incidence and widespread emergence of Gram-negative multidrug-resistant pathogens in clinics, structural information on the main actors of the recycling process paves the way for designing novel antibiotics disrupting cellular communication in the recycling-resistance pathway.

  • Multidrug efflux pumps of Gram-positive bacteria
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-04-30
    Bryan D. Schindler, Glenn W. Kaatz

    Gram-positive organisms are responsible for some of the most serious of human infections. Resistance to front-line antimicrobial agents can complicate otherwise curative therapy. These organisms possess multiple drug resistance mechanisms, with drug efflux being a significant contributing factor. Efflux proteins belonging to all five transporter families are involved, and frequently can transport multiple structurally unrelated compounds resulting in a multidrug resistance (MDR) phenotype. In addition to clinically relevant antimicrobial agents, MDR efflux proteins can transport environmental biocides and disinfectants which may allow persistence in the healthcare environment and subsequent acquisition by patients or staff. Intensive research on MDR efflux proteins and the regulation of expression of their genes is ongoing, providing some insight into the mechanisms of multidrug recognition and transport. Inhibitors of many of these proteins have been identified, including drugs currently being used for other indications. Structural modifications guided by structure–activity studies have resulted in the identification of potent compounds. However, lack of broad-spectrum pump inhibition combined with potential toxicity has hampered progress. Further work is required to gain a detailed understanding of the multidrug recognition process, followed by application of this knowledge in the design of safer and more highly potent inhibitors.

  • Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-05-13
    Wen Li, Han Zhang, Yehuda G. Assaraf, Kun Zhao, Xiaojun Xu, Jinbing Xie, Dong-Hua Yang, Zhe-Sheng Chen

    Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the ‘Omics’ era – genomics, epigenomics, transcriptomics, proteomics, and metabolomics – these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR.

  • Cryptic prophages as targets for drug development
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-06-06
    Xiaoxue Wang, Thomas K. Wood

    Bacterial chromosomes may contain up to 20% phage DNA that encodes diverse proteins ranging from those for photosynthesis to those for autoimmunity; hence, phages contribute greatly to the metabolic potential of pathogens. Active prophages carrying genes encoding virulence factors and antibiotic resistance can be excised from the host chromosome to form active phages and are transmissible among different bacterial hosts upon SOS responses. Cryptic prophages are artifacts of mutagenesis in which lysogenic phage are captured in the bacterial chromosome: they may excise but they do not form active phage particles or lyse their captors. Hence, cryptic prophages are relatively permanent reservoirs of genes, many of which benefit pathogens, in ways we are just beginning to discern. Here we explore the role of active prophage- and cryptic prophage-derived proteins in terms of (i) virulence, (ii) antibiotic resistance, and (iii) antibiotic tolerance; antibiotic tolerance occurs as a result of the non-heritable phenotype of dormancy which is a result of activation of toxins of toxin/antitoxin loci that are frequently encoded in cryptic prophages. Therefore, cryptic prophages are promising targets for drug development.

  • Are nanotheranostics and nanodiagnostics-guided drug delivery stepping stones towards precision medicine?
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-06-16
    Rachel Blau, Adva Krivitsky, Yana Epshtein, Ronit Satchi-Fainaro

    The progress in medical research has led to the understanding that cancer is a large group of heterogeneous diseases, with high variability between and within individuals. This variability sprouted the ambitious goal to improve therapeutic outcomes, while minimizing drug adverse effects through stratification of patients by the differences in their disease markers, in a personalized manner, as opposed to the strategy of “one therapy fits all”. Nanotheranostics, composed of nanoparticles (NPs) carrying therapeutic and/or diagnostics probes, have the potential to revolutionize personalized medicine. There are different modalities to combine these two distinct fields into one system for a synergistic outcome. The addition of a nanocarrier to a theranostic system holds great promise. Nanocarriers possess high surface area, enabling sophisticated functionalization with imaging agents, thus gaining enhanced diagnostic ability in real-time. Yet, most of the FDA-approved theranostic approaches are based on small molecules. The theranostic approaches that are reviewed herein are paving the road towards personalized medicine through all stages of patient care: starting from screening and diagnostics, proceeding to treatment and ending with treatment follow-up. Our current review provides a broad background and highlights new insights for the rational design of theranostic nanosystems for desired therapeutic niches, while summoning the hurdles on their way to become first-line diagnostics and therapeutics for cancer patients.

  • Reprogrammable microbial cell-based therapeutics against antibiotic-resistant bacteria
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-06-22
    In Young Hwang, Elvin Koh, Hye Rim Kim, Wen Shan Yew, Matthew Wook Chang

    The discovery of antimicrobial drugs and their subsequent use has offered an effective treatment option for bacterial infections, reducing morbidity and mortality over the past 60 years. However, the indiscriminate use of antimicrobials in the clinical, community and agricultural settings has resulted in selection for multidrug-resistant bacteria, which has led to the prediction of possible re-entrance to the pre-antibiotic era. The situation is further exacerbated by significantly reduced antimicrobial drug discovery efforts by large pharmaceutical companies, resulting in a steady decline in the number of new antimicrobial agents brought to the market in the past several decades. Consequently, there is a pressing need for new antimicrobial therapies that can be readily designed and implemented. Recently, it has become clear that the administration of broad-spectrum antibiotics can lead to collateral damage to the human commensal microbiota, which plays several key roles in host health. Advances in genetic engineering have opened the possibility of reprogramming commensal bacteria that are in symbiotic existence throughout the human body to implement antimicrobial drugs with high versatility and efficacy against pathogenic bacteria. In this review, we discuss recent advances and potentialities of engineered bacteria in providing a novel antimicrobial strategy against antibiotic resistance.

  • The impact of Organic Anion-Transporting Polypeptides (OATPs) on disposition and toxicity of antitumor drugs: Insights from knockout and humanized mice
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-06-25
    Selvi Durmus, Stéphanie van Hoppe, Alfred H. Schinkel

    It is now widely accepted that organic anion-transporting polypeptides (OATPs), especially members of the OATP1A/1B family, can have a major impact on the disposition and elimination of a variety of endogenous molecules and drugs. Owing to their prominent expression in the sinusoidal plasma membrane of hepatocytes, OATP1B1 and OATP1B3 play key roles in the hepatic uptake and plasma clearance of a multitude of structurally diverse anti-cancer and other drugs. Here, we present a thorough assessment of the currently available OATP1A and OATP1B knockout and transgenic mouse models as key tools to study OATP functions in vivo. We discuss recent studies using these models demonstrating the importance of OATPs, primarily in the plasma and hepatic clearance of anticancer drugs such as taxanes, irinotecan/SN-38, methotrexate, doxorubicin, and platinum compounds. We further discuss recent work on OATP-mediated drug–drug interactions in these mouse models, as well as on the role of OATP1A/1B proteins in the phenomenon of hepatocyte hopping, an efficient and flexible way of liver detoxification for both endogenous and exogenous substrates. Interestingly, glucuronide conjugates of both the heme breakdown product bilirubin and the protein tyrosine kinase-targeted anticancer drug sorafenib are strongly affected by this process. The clinical relevance of variation in OATP1A/1B activity in patients has been previously revealed by the effects of polymorphic variants and drug–drug interactions on drug toxicity. The development of in vivo tools to study OATP1A/1B functions has greatly advanced our mechanistic understanding of their functional role in drug pharmacokinetics, and their implications for therapeutic efficacy and toxic side effects of anticancer and other drug treatments.

  • ABC transporters as mediators of drug resistance and contributors to cancer cell biology
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-03-17
    Jamie I. Fletcher, Rebekka T. Williams, Michelle J. Henderson, Murray D. Norris, Michelle Haber

    The extrusion of anticancer drugs by members of the ATP-binding cassette (ABC) transporter family is one of the most widely recognized mechanisms of multidrug resistance, and can be considered a hijacking of their normal roles in the transport of xenobiotics, metabolites and signaling molecules across cell membranes. While roles in cancer multidrug resistance have been clearly demonstrated for P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP) and Multidrug Resistance Protein 1 (MRP1), direct evidence for a role in multidrug resistance in vivo is lacking for other family members. A less well understood but emerging theme is the drug efflux-independent contributions of ABC transporters to cancer biology, supported by a growing body of evidence that their loss or inhibition impacts on the malignant potential of cancer cells in vitro and in vivo. As with multidrug resistance, these contributions likely represent a hijacking of normal ABC transporter functions in the efflux of endogenous metabolites and signaling molecules, however they may expand the clinical relevance of ABC transporters beyond P-gp, BCRP and MRP1. This review summarizes established and emerging roles for ABC transporters in cancer, with a focus on neuroblastoma and ovarian cancer, and considers approaches to validate and better understand these roles.

  • Repositioning of drugs for intervention in tumor progression and metastasis: Old drugs for new targets
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-03-24
    Giridhar Mudduluru, Wolfgang Walther, Dennis Kobelt, Mathias Dahlmann, Christoph Treese, Yehuda G. Assaraf, Ulrike Stein

    The increasing unraveling of the molecular basis of cancer offers manifold novel options for intervention strategies. However, the discovery and development of new drugs for potential clinical applications is a tremendously time-consuming and costly process. Translating a novel lead candidate compound into an approved clinical drug takes often more than a decade, and the success rate is very low due to versatile efforts including defining its pharmacokinetics, pharmacodynamics, side effects as well as lack of sufficient efficacy. Thus, strategies are needed to minimize time and costs, while maximizing success rates. A very attractive strategy for novel cancer therapeutic options is the repositioning of already approved drugs. These medicines, approved for the treatment of non-malignant disorders, have already passed some early costs and time, have been tested in humans and are ready for clinical trials as anti-cancer drugs. Here we discuss the repositioning of nonsteroidal anti-inflammatory drugs (NSAID), statins, anti-psychotic drugs, anti-helminthic drugs and vitamin D as anti-tumor agents. We focus on their novel actions and potential for inhibition of cancer growth and metastasis by interfering with target molecules and pathways, which drive these malignant processes. Furthermore, important pre-clinical and clinical data are reviewed herein, which elucidate their therapeutic mechanisms which enable their repositioning for cancer therapy and disruption of metastasis.

  • Long non-coding RNAs: An emerging powerhouse in the battle between life and death of tumor cells
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-04-19
    Xing-dong Xiong, Xingcong Ren, Meng-yun Cai, Jay W. Yang, Xinguang Liu, Jin-Ming Yang

    Long non-coding RNAs (lncRNAs) represent a class of non-protein coding transcripts longer than 200 nucleotides that have aptitude for regulating gene expression at the transcriptional, post-transcriptional or epigenetic levels. In recent years, lncRNAs, which are believed to be the largest transcript class in the transcriptomes, have emerged as important players in a variety of biological processes. Notably, the identification and characterization of numerous lncRNAs in the past decade has revealed a role for these molecules in the regulation of cancer cell survival and death. It is likely that this class of non-coding RNA constitutes a critical contributor to the assorted known or/and unknown mechanisms of intrinsic or acquired drug resistance. Moreover, the expression of lncRNAs is altered in various patho-physiological conditions, including cancer. Therefore, lncRNAs represent potentially important targets in predicting or altering the sensitivity or resistance of cancer cells to various therapies. Here, we provide an overview on the molecular functions of lncRNAs, and discuss their impact and importance in cancer development, progression, and therapeutic outcome. We also provide a perspective on how lncRNAs may alter the efficacy of cancer therapy and the promise of lncRNAs as novel therapeutic targets for overcoming chemoresistance. A better understanding of the functional roles of lncRNA in cancer can ultimately translate to the development of novel, lncRNA-based intervention strategies for the treatment or prevention of drug-resistant cancer.

  • Mechanisms and consequences of bacterial resistance to antimicrobial peptides
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-04-20
    D.I. Andersson, D. Hughes, J.Z. Kubicek-Sutherland

    Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an alternative antibacterial therapy. Several cationic peptides that are derivatives of AMPs from the human innate immune system are currently in clinical development. There are also ongoing clinical studies aimed at modulating the expression of AMPs to boost the human innate immune response. In this review we discuss the potential problems associated with these therapeutic approaches. There is considerable experimental data describing mechanisms by which bacteria can develop resistance to AMPs. As for any type of drug resistance, the rate by which AMP resistance would emerge and spread in a population of bacteria in a natural setting will be determined by a complex interplay of several different factors, including the mutation supply rate, the fitness of the resistant mutant at different AMP concentrations, and the strength of the selective pressure. Several studies have already shown that AMP-resistant bacterial mutants display broad cross-resistance to a variety of AMPs with different structures and modes of action. Therefore, routine clinical administration of AMPs to treat bacterial infections may select for resistant bacterial pathogens capable of better evading the innate immune system. The ramifications of therapeutic levels of exposure on the development of AMP resistance and bacterial pathogenesis are not yet understood. This is something that needs to be carefully studied and monitored if AMPs are used in clinical settings.

  • The ERK cascade inhibitors: Towards overcoming resistance
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-01-02
    Galia Maik-Rachline, Rony Seger

    The RAS–ERK pathway plays a major regulatory role in various cellular processes. This pathway is hyperactivated and takes an active part in the malignant transformation of more than 85% of cancers. The hyperactivation is mainly due to oncogenic activating mutations in the pathway's components RAS, RAF and MEK, but also due to indirect mechanisms in cells transformed by other oncogenes. Various inhibitors targeting the different tiers of the cascade have been successfully developed and clinically approved, while some are still undergoing preclinical and clinical evaluation. Treatments with the clinically approved RAF and MEK inhibitors have substantially improved the clinical outcome of metastatic mutated-BRAF melanoma. However, the rapid emergence of drug resistance of initially responsive cancers and limited efficacy towards other cancers has led to only marginal patient benefit. Deciphering the molecular mechanisms underlying intrinsic or acquired resistance is a necessity in order to enhance the treatment efficacy of ERK-addicted cancers. Therefore, many studies in the past 5 years embarked on this campaign, revealing several resistance mechanisms. These include, expression of drug-resistant RAF isoforms, molecular or genetic alterations of active downstream components, overexpression of upstream components of the cascade that can reactivate ERK and other survival-related pathways. The understanding of these molecular resistance mechanisms led to further development of drugs that can overcome drug resistance, including our own effort aiming to prevent the nuclear translocation of ERK without affecting its activation. In this review we will focus on the mechanisms underlying drug resistance and efforts to develop activity-independent, more efficacious, antitumor drugs.

  • Could drugs inhibiting the mevalonate pathway also target cancer stem cells?
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-02-20
    Wirginia Likus, Krzysztof Siemianowicz, Konrad Bieńk, Małgorzata Pakuła, Himani Pathak, Chhanda Dutta, Qiong Wang, Shahla Shojaei, Yehuda G. Assaraf, Saeid Ghavami, Artur Cieślar-Pobuda, Marek J. Łos

    Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.

  • Role of the tumor stroma in resistance to anti-angiogenic therapy
    Drug Resist. Updat. (IF 10.906) Pub Date : 2016-02-24
    Elisabeth J.M. Huijbers, Judy R. van Beijnum, Victor L. Thijssen, Siamack Sabrkhany, Patrycja Nowak-Sliwinska, Arjan W. Griffioen

    Several angiogenesis inhibitors are currently used in the clinic for treatment of cancer. While anti-angiogenesis treatment can improve treatment outcome, the overall benefit on patient survival is still rather limited. This is partially explained by intrinsic or acquired resistance of tumor cells to angiostatic drugs. In addition, it has become evident that extrinsic mechanisms are also involved in resistance to angiostatic therapy. Most of these extrinsic mechanisms reside in the tumor stroma, which is composed of different cell types, including endothelial (progenitor) cells, smooth muscle cells, pericytes, (myo)fibroblasts, immune cells and platelets. In the current review, we describe the role of these stromal cells in the resistance to anti-angiogenic drugs and discuss possible strategies to overcome resistance and enhance the efficacy of angiostatic therapy.

  • Mitotic catastrophe and cancer drug resistance: A link that must to be broken
    Drug Resist. Updat. (IF 10.906) Pub Date : 2015-11-12
    Tatiana V. Denisenko, Irina V. Sorokina, Vladimir Gogvadze, Boris Zhivotovsky

    An increased tendency of genomic alterations during the life cycle of cells leads to genomic instability, which is a major driving force for tumorigenesis. A considerable fraction of tumor cells are tetraploid or aneuploid, which renders them intrinsically susceptible to mitotic aberrations, and hence, are particularly sensitive to the induction of mitotic catastrophe. Resistance to cell death is also closely linked to genomic instability, as it enables malignant cells to expand even in a stressful environment. Currently it is known that cells can die via multiple mechanisms. Mitotic catastrophe represents a step preceding apoptosis or necrosis, depending on the expression and/or proper function of several proteins. Mitotic catastrophe was proposed to be an onco-suppressive mechanism and the evasion of mitotic catastrophe constitutes one of the gateways to cancer development. Thus, stimulation of mitotic catastrophe appears to be a promising strategy in cancer treatment. Indeed, several chemotherapeutic drugs are currently used at concentrations that induce apoptosis irrespective of the cell cycle phase, yet are very efficient at triggering mitotic catastrophe at lower doses, significantly limiting side effects. In the present review we summarize current data concerning the role of mitotic catastrophe in cancer drug resistance and discuss novel strategies to break this link.

  • Treatment strategies for advanced hormone receptor-positive and human epidermal growth factor 2-negative breast cancer: the role of treatment order
    Drug Resist. Updat. (IF 10.906) Pub Date : 2015-11-10
    Edith A. Perez

    Although survival rates among patients with breast cancer have improved in recent years, those diagnosed with advanced disease with distant metastasis face a 5-year survival rate of less than 25%, making the management of these patients an area still in significant need of continued research. Selecting the optimal treatment order from among the variety of currently available therapy options presents a relevant challenge for medical oncologists. With the understanding that the majority of patients with breast cancer and those who succumb to this disease have HR-positive disease, this review will focus on treatment options and treatment order in patients with HR-positive advanced breast cancer. While endocrine therapy is considered the preferred treatment for first-line therapy in HR-positive/HER2-negative breast cancer, selection of the specific agent depends on the menopausal status of the patient. Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is also recommended as first-line treatment in patients with ER-positive/HER2-negative disease. In patients with endocrine therapy–resistant disease, specific strategies include sequencing of other antiestrogen receptor agents, or agents that target other molecular pathways. Future treatment strategies for patients with primary or secondary resistance to endocrine therapy for advanced disease are discussed. These strategies include first-line therapy with high-dose fulvestrant or everolimus (in combination with exemestane or letrozole or with other endocrine therapies), use of the PI3K inhibitors (e.g., buparlisib, alpelisib, pictilisib, taselisib), entinostat, CDK 4/6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib), and novel selective estrogen receptor degradation agents that may enhance the targeting of acquired mutations in the ESR1 gene.

  • Lysosomes as mediators of drug resistance in cancer
    Drug Resist. Updat. (IF 10.906) Pub Date : 2015-11-26
    Benny Zhitomirsky, Yehuda G. Assaraf

    Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug resistance as well as novel modalities to overcome this chemoresistance.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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