Lysosomes as mediators of drug resistance in cancer
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 biogene...
Source: Drug Resistance Updates - November 26, 2015 Category: Drugs & Pharmacology Authors: Benny Zhitomirsky, Yehuda G. Assaraf Source Type: research
Studying platinum sensitivity and resistance in high-grade serous ovarian cancer: different models for different questions
High-grade serous ovarian cancer (HGSOC) has the highest mortality rate among all gynecological cancers. Patients are generally diagnosed in an advanced stage with the majority of cases displaying platinum resistant relapses. Recent genomic interrogation of large numbers of HGSOC patient samples indicated high complexity in terms of genetic aberrations, intra- and intertumor heterogeneity and underscored their lack of targetable oncogenic mutations. Sub-classifications of HGSOC based on expression profiles, termed ‘differentiated’, ‘immunoreactive’, ‘mesenchymal’ and ‘proliferative’, were shown to have prog...
Source: Drug Resistance Updates - November 26, 2015 Category: Drugs & Pharmacology Authors: Nicolette G. Alkema, G. Bea A. Wisman, Ate G.J. van der Zee, Marcel A.T.M. van Vugt, Steven de Jong Source Type: research
Mechanisms of cisplatin resistance and targeting of cancer stem cells: Adding glycosylation to the equation
Cisplatin-based chemotherapeutic regimens are the most frequently used (neo)adjuvant treatments for the majority of solid tumors. While platinum-based chemotherapeutic regimens have proven effective against highly proliferative malignant tumors, significant relapse and progression rates as well as decreased overall survival are still observed. Currently, it is known that sub-populations of chemoresistant cells share biological properties with cancer stem cells (CSC), which are believed to be responsible for tumor relapse, invasion and ultimately disease dissemination through acquisition of mesenchymal cell traits. (Source:...
Source: Drug Resistance Updates - November 25, 2015 Category: Drugs & Pharmacology Authors: José Alexandre Ferreira, Andreia Peixoto, Manuel Neves, Cristiana Gaiteiro, Celso A. Reis, Yehuda G. Assaraf, Lúcio Lara Santos Source Type: research
Mitotic catastrophe and cancer drug resistance: A link that must to be broken
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. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - November 12, 2015 Category: Drugs & Pharmacology Authors: Tatiana V. Denisenko, Irina V. Sorokina, Vladimir Gogvadze, Boris Zhivotovsky Source Type: research
Treatment strategies for advanced hormone receptor-positive and human epidermal growth factor 2-negative breast cancer: the role of treatment order
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 a...
Source: Drug Resistance Updates - November 10, 2015 Category: Drugs & Pharmacology Authors: Edith A. Perez Source Type: research
Treatment strategies for advanced hormone receptor–positive and human epidermal growth factor 2–negative breast cancer: the role of treatment order
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 a...
Source: Drug Resistance Updates - November 10, 2015 Category: Drugs & Pharmacology Authors: Edith A. Perez Source Type: research
Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDA) ranks fourth among cancer related deaths. The disappointing 5-year survival rate of below 5% stems from drug resistance to all known therapies, as well as from disease presentation at a late stage when PDA is already metastatic. Gemcitabine has been the cornerstone of PDA treatment in all stages of the disease for the last two decades, but gemcitabine resistance develops within weeks of chemotherapy initiation. From a mechanistic perspective, gemcitabine resistance may result from alterations in drug metabolism until the point that the cytidine analogue is incorporated into the DNA, o...
Source: Drug Resistance Updates - November 2, 2015 Category: Drugs & Pharmacology Authors: Yoav Binenbaum, Shorook Na’ara, Ziv Gil Source Type: research
Inside the biochemical pathways of thymidylate synthase perturbed by anticancer drugs: novel strategies to overcome cancer chemoresistance
Our current understanding of the mechanisms of action of antitumor agents and the precise mechanisms underlying drug resistance is that these two processes are directly linked. Moreover, it is often possible to delineate chemosresistance mechanisms based on the specific mechanism of action of a given anticancer drug. A more holistic approach to the chemoresistance problem suggests that entire metabolic pathways, rather than single enzyme targets may better explain and educate us about the complexity of the cellular responses upon cytotoxic drug administration. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - October 31, 2015 Category: Drugs & Pharmacology Authors: Laura Taddia, Domenico D’Arca, Stefania Ferrari, Chiara Marraccini, Leda Severi, Glauco Ponterini, Yahuda G. Assaraf, Gaetano Marverti, Maria Paola Costi Source Type: research
Defining the frontiers between antifungal resistance, tolerance and the concept of persistence
A restricted number of antifungal agents are available for the therapy of fungal diseases. With the introduction of epidemiological cut-off values for each agent in important fungal pathogens, the distinction between wild type and drug-resistant populations has been facilitated. Antifungal resistance has been described for all currently available antifungal agents in several pathogens and most of the associated resistance mechanisms have been deciphered at the molecular level. Clinical breakpoints for some agents have been proposed and can have predictive value for the success or failure of therapy. (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - October 30, 2015 Category: Drugs & Pharmacology Authors: Eric Delarze, Dominique Sanglard Source Type: research
Dysregulation of ubiquitin ligases in cancer
Ubiquitin ligases are critical components of the ubiquitin proteasome system (UPS), which governs fundamental processes regulating normal cellular homeostasis, metabolism, and cell cycle in response to external stress signals and DNA damage. Among multiple steps of the UPS system required to regulate protein ubiquitination and stability, UBLs define specificity, as they recognize and interact with substrates in a temporally- and spatially-regulated manner. Such interactions are required for substrate modification by ubiquitin chains, which marks proteins for recognition and degradation by the proteasome, or alters their su...
Source: Drug Resistance Updates - September 27, 2015 Category: Drugs & Pharmacology Authors: Jianfei Qi, Ze’ev A. Ronai Source Type: research
Microenvironment acidity as a major determinant of tumor chemoresistance: Proton Pump Inhibitors (PPIs) as a novel therapeutic approach
Despite the major progresses in biomedical research and the development of novel therapeutics and treatment strategies, cancer is still among the dominant causes of death worldwide. One of the crucial challenges in the clinical management of cancer is primary (intrinsic) and secondary (acquired) resistance to both conventional and targeted chemotherapeutics. Multiple mechanisms have been identifiedthat underlie intrinsic and acquired chemoresistance: these include impaired drug uptake, increased drug efflux, deletion of receptors, altered drug metabolism, quantitative and qualitative alterations in drug targets, increased ...
Source: Drug Resistance Updates - August 22, 2015 Category: Drugs & Pharmacology Authors: Sophie Taylor, Enrico Pierluigi Spugnini, Yehuda G. Assaraf, Tommaso Azzarito, Cyril Rauch, Stefano Fais Source Type: research
Minimal residual disease in cancer therapy – Small things make all the difference
Minimal residual disease (MRD) is a major hurdle in the eradication of malignant tumors. Despite the high sensitivity of various cancers to treatment, some residual cancer cells persist and lead to tumor recurrence and treatment failure. Obvious reasons for residual disease include mechanisms of secondary therapy resistance, such as the presence of mutant cells that are insensitive to the drugs, or the presence of cells that become drug resistant due to activation of survival pathways. In addition to such unambiguous resistance modalities, several patients with relapsing tumors do not show refractory disease and respond ag...
Source: Drug Resistance Updates - August 13, 2015 Category: Drugs & Pharmacology Authors: Sohvi Blatter, Sven Rottenberg Source Type: research
Minimal residual disease in cancer therapy - Small things make all the difference
Minimal residual disease (MRD) is a major hurdle in the eradication of malignant tumors. Despite the high sensitivity of various cancers to treatment, some residual cancer cells persist and lead to tumor recurrence and treatment failure. Obvious reasons for residual disease include mechanisms of secondary therapy resistance, such as the presence of mutant cells that are insensitive to the drugs, or the presence of cells that become drug resistant due to activation of survival pathways. In addition to such unambiguous resistance modalities, several patients with relapsing tumors do not show refractory disease and respond ag...
Source: Drug Resistance Updates - August 13, 2015 Category: Drugs & Pharmacology Authors: Sohvi Blatter, Sven Rottenberg Source Type: research
The increasing threat of high-risk clones
The increasing prevalence of chronic and hospital-acquired infections produced by multidrug-resistant (MDR) or extensively drug-resistant (XDR) Pseudomonas aeruginosa strains is associated with significant morbidity and mortality. This growing threat results from the extraordinary capacity of this pathogen for developing resistance through chromosomal mutations and from the increasing prevalence of transferable resistance determinants, particularly those encoding carbapenemasesor extended-spectrum β-lactamases (ESBLs). (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - August 10, 2015 Category: Drugs & Pharmacology Authors: Antonio Oliver, Xavier Mulet, Carla López-Causapé, Carlos Juan Source Type: research
International expert opinion on the management of infection caused by azole-resistant
An international expert panel was convened to deliberate the management of azole-resistant aspergillosis. In culture-positive cases, in vitro susceptibility testing should always be performed if antifungal therapy is intended. Different patterns of resistance are seen, with multi-azole and pan-azole resistance more common than resistance to a single triazole. In confirmed invasive pulmonary aspergillosis due to an azole-resistant Aspergillus, the experts recommended a switch from voriconazole to liposomal amphotericin B (L-AmB; Ambisome®). (Source: Drug Resistance Updates)
Source: Drug Resistance Updates - August 7, 2015 Category: Drugs & Pharmacology Authors: Paul E. Verweij, Michelle Ananda-Rajah, David Andes, Maiken C. Arendrup, Roger J. Brüggemann, Anuradha Chowdhary, Oliver A. Cornely, David W. Denning, Andreas H. Groll, Koichi Izumikawa, Bart Jan Kullberg, Katrien Lagrou, Johan Maertens, Jacques F. Meis, Source Type: research
