scholarly journals Mechanistic Modeling Identifies Drug-Uptake History as Predictor of Tumor Drug Resistance and Nano-Carrier-Mediated Response

ACS Nano ◽  
2013 ◽  
Vol 7 (12) ◽  
pp. 11174-11182 ◽  
Author(s):  
Jennifer Pascal ◽  
Carlee E. Ashley ◽  
Zhihui Wang ◽  
Terisse A. Brocato ◽  
Joseph D. Butner ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mechanistic Modeling ◽  
Drug Uptake ◽  
Tumor Drug Resistance

scholarly journals A histone methyltransferase inhibitor can reverse epigenetically acquired drug resistance in the malaria parasite Plasmodium falciparum

2019 ◽  
Author(s):  
Amanda Chan ◽  
Alexis Dziedziech ◽  
Laura A Kirkman ◽  
Kirk W Deitsch ◽  
Johan Ankarklev
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acquired Resistance ◽  
Anion Channel ◽  
Histone Methyltransferase ◽  
Drug Uptake ◽  
Natural Setting ◽  
Membrane Expression ◽  
Acquired Drug Resistance ◽  
Histone Modifiers

AbstractMalaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.ImportanceDrug resistance is a major concern for the treatment of infectious diseases throughout the world. For malaria, a novel mechanism of resistance was recently described in which epigenetic modifications led to a resistance phenotype that is rapidly reversible, thus reducing the fitness cost that is often associated with genetic mutations that lead to resistance. The possibility of this type of resistance arising in a natural setting is particularly troubling since parasites could rapidly switch to and from a resistant phenotype, thus making it especially difficult to combat. Here we show that application of a histone methyltransferase inhibitor can rapidly reverse the epigenetic changes that lead to drug resistance, thereby causing parasites to revert to a drug sensitive phenotype. This is a novel application of drugs that target epigenetic modifiers and lends additional support for ongoing efforts to develop drugs against malaria that target the histone modifiers of the parasite.

scholarly journals Inverse mechanistic modeling of transdermal drug delivery for fast identification of optimal model parameters

2020 ◽  
Author(s):  
Thijs Defraeye ◽  
Flora Bahrami ◽  
Rene M Rossi
Keyword(s):  
Drug Delivery ◽  
Inverse Modeling ◽  
Transdermal Drug Delivery ◽  
Drug Transport ◽  
Mechanistic Model ◽  
Mechanistic Modeling ◽  
Drug Uptake ◽  
Added Value ◽  
Model Parameters ◽  
Transdermal Drug Delivery Systems

Transdermal drug delivery systems are a key technology to administer drugs with a high first-pass effect in a non-invasive and controlled way. Physics-based modeling and simulation are on their way to become a cornerstone in the engineering of these healthcare devices since it provides a unique complementarity to experimental data and insights. Simulations enable to virtually probe the drug transport inside the skin at each point in time and space. However, the tedious experimental or numerical determination of material properties currently forms a bottleneck in the modeling workflow. We show that multiparameter inverse modeling to determine the drug diffusion and partition coefficients is a fast and reliable alternative. We demonstrate this strategy for transdermal delivery of fentanyl. We found that inverse modeling reduced the normalized root mean square deviation of the measured drug uptake flux from 26 to 9%, when compared to the experimental measurement of all skin properties. We found that this improved agreement with experiments was only possible if the diffusion in the reservoir holding the drug was smaller than the experimentally-measured diffusion coefficients suggested. For indirect inverse modeling, which systematically explores the entire parametric space, 30 000 simulations were required. By relying on direct inverse modeling, we reduced the number of simulations to be performed to only 300, so a factor 100 difference. The modeling approach's added value is that it can be calibrated once in-silico for all model parameters simultaneously by solely relying on a single measurement of the drug uptake flux evolution over time. We showed that this calibrated model could accurately be used to simulate transdermal patches with other drug doses. We showed that inverse modeling is a fast way to build up an accurate mechanistic model for drug delivery. This strategy opens the door to clinically-ready therapy that is tailored to patients.

scholarly journals Artificial microenvironment of in vitro glioblastoma cell cultures changes profile of miRNAs related to tumor drug resistance

2019 ◽  
Vol Volume 12 ◽  
pp. 3905-3918
Author(s):  
Monika Witusik-Perkowska ◽  
Magdalena Zakrzewska ◽  
Dariusz Jaskolski ◽  
Paweł P Liberski ◽  
Janusz Szemraj
Keyword(s):  
Drug Resistance ◽  
Cell Cultures ◽  
Glioblastoma Cell ◽  
Tumor Drug Resistance

Biotinylated carboxymethyl chitosan/CaCO3 hybrid nanoparticles for targeted drug delivery to overcome tumor drug resistance

RSC Advances ◽  
2016 ◽  
Vol 6 (73) ◽  
pp. 69083-69093 ◽  
Author(s):  
Jin-Long Wu ◽  
Xiao-Yan He ◽  
Pei-Yuan Jiang ◽  
Meng-Qing Gong ◽  
Ren-Xi Zhuo ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Tumor Cells ◽  
Targeted Drug Delivery ◽  
Carboxymethyl Chitosan ◽  
Hybrid Nanoparticles ◽  
Cancer Drug ◽  
Tumor Drug Resistance ◽  
Anti Cancer ◽  
Targeted Drug

A tumor targeted nano-sized self-assembled drug delivery system could efficiently co-deliver an anti-cancer drug and a drug resistance inhibitor to tumor cells and achieve an improved therapeutic efficiency through inhibition of P-gp function.

Mechanisms of acquired tumor drug resistance

2019 ◽  
Vol 1872 (2) ◽  
pp. 188310 ◽  
Author(s):  
Svetlana N. Aleksakhina ◽  
Aniruddh Kashyap ◽  
Evgeny N. Imyanitov
Keyword(s):  
Drug Resistance ◽  
Tumor Drug Resistance

Overcoming Tumor Drug Resistance with High-Affinity Taxanes: A SAR Study of C2-Modified 7-Acyl-10-Deacetyl Cephalomannines

ChemMedChem ◽  
2007 ◽  
Vol 2 (5) ◽  
pp. 691-701 ◽  
Author(s):  
Chun-Gang Yang ◽  
Isabel Barasoain ◽  
Xuan Li ◽  
Ruth Matesanz ◽  
Ronghua Liu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
High Affinity ◽  
Tumor Drug Resistance ◽  
Sar Study
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