The impact of Organic Anion-Transporting Polypeptides (OATPs) on disposition and toxicity of antitumor drugs; insights from knockout and humanized mice
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. ...
Source: Drug Resistance Updates - June 24, 2016 Category: Drugs & Pharmacology Authors: Selvi Durmus, Stéphanie van Hoppe, Alfred H. Schinkel Source Type: research
The bad seed: Cancer stem cells in tumor development and resistance
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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - June 23, 2016 Category: Drugs & Pharmacology Authors: Elle Koren, Yaron Fuchs Source Type: research
The Bad Seed: Cancer Stem Cells in Tumor Development and Resistance
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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - June 23, 2016 Category: Drugs & Pharmacology Authors: Elle Koren, Yaron Fuchs Source Type: research
Reprogrammable microbial cell-based therapeutics against antibiotic-resistant bacteria
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 antimicrobia...
Source: Drug Resistance Updates - June 21, 2016 Category: Drugs & Pharmacology Authors: In Young Hwang, Elvin Koh, Hye Rim Kim, Wen Shan Yew, Matthew Wook Chang Source Type: research
Are nanotheranostics and nanodiagnostics-guided drug delivery stepping stones towards precision medicine?
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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - June 15, 2016 Category: Drugs & Pharmacology Authors: Rachel Blau, Adva Krivitsky, Yana Epshtein, Ronit Satchi-Fainaro Source Type: research
Cryptic Prophages as Targets For Drug Development
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 thei...
Source: Drug Resistance Updates - June 5, 2016 Category: Drugs & Pharmacology Authors: Xiaoxue Wang, Thomas K. Wood Source Type: research
Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies
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 elemen...
Source: Drug Resistance Updates - May 11, 2016 Category: Drugs & Pharmacology Authors: Wen Li, Han Zhang, Yehuda G. Assaraf, Kun Zhao, Xiaojun Xu, Jinbing Xie, Dong-Hua Yang, Zhe-Sheng Chen Source Type: research
Multidrug Efflux Pumps of Gram-Positive Bacteria
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 whi...
Source: Drug Resistance Updates - April 28, 2016 Category: Drugs & Pharmacology Authors: Bryan D. Schindler, Glenn W. Kaatz Source Type: research
Mechanisms and Consequences of Bacterial Resistance to Antimicrobial Peptides
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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - April 18, 2016 Category: Drugs & Pharmacology Authors: D.I. Andersson, D. Hughes, J.Z. Kubicek-Sutherland Source Type: research
Long Non-coding RNAs: an Emerging Powerhouse in the Battle between Life and Death of Tumor Cells
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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - April 17, 2016 Category: Drugs & Pharmacology Authors: Xing-dong Xiong, Xingcong Ren, Meng-yun Cai, Jay W Yang, Xinguang Liu, Jin-Ming Yang Source Type: research
Repositioning of drugs for intervention in tumor progression and metastasis: Old drugs for new targets
The increasing unravelling 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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - March 22, 2016 Category: Drugs & Pharmacology Authors: Giridhar Mudduluru, Wolfgang Walther, Dennis Kobelt, Mathias Dahlmann, Christoph Treese, Yehuda G. Assaraf, Ulrike Stein Source Type: research
ABC transporters as mediators of drug resistance and contributors to cancer cell biology
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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - March 17, 2016 Category: Drugs & Pharmacology Authors: Jamie I. Fletcher, Rebekka T. Williams, Michelle J. Henderson, Murray D. Norris, Michelle Haber Source Type: research
Role of the tumor stroma in resistance to anti-angiogenic therapy
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)fibrobl...
Source: Drug Resistance Updates - February 24, 2016 Category: Drugs & Pharmacology Authors: Elisabeth J.M. Huijbers, Judy R. van Beijnum, Victor L. Thijssen, Siamack Sabrkhany, Patrycja Nowak-Sliwinska, Arjan W. Griffioen Source Type: research
Could drugs inhibiting the mevalonate pathway also target cancer stem cells?
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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - February 20, 2016 Category: Drugs & Pharmacology Authors: 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 Source Type: research
The ERK cascade inhibitors: Towards overcoming resistance
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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - January 2, 2016 Category: Drugs & Pharmacology Authors: Galia Maik-Rachline, Rony Seger Source Type: research
