In Vitro Models and Multidrug Resistance Mechanisms of the Placental Barrier

2007 ◽  
pp. 368-396 ◽  
Author(s):  
Pallabi Mitra ◽  
Kenneth L. Audus
Keyword(s):  
Multidrug Resistance ◽  
Resistance Mechanisms ◽  
In Vitro Models ◽  
Placental Barrier

3D Culture Modelling: An Emerging Approach for Translational Cancer Research in Sarcomas

2020 ◽  
Vol 27 (29) ◽  
pp. 4778-4788 ◽  
Author(s):  
Victoria Heredia-Soto ◽  
Andrés Redondo ◽  
José Juan Pozo Kreilinger ◽  
Virginia Martínez-Marín ◽  
Alberto Berjón ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Cancer Biology ◽  
Soft Tissues ◽  
Three Dimensional ◽  
3D Culture ◽  
Resistance Mechanisms ◽  
In Vitro Models ◽  
Tumour Spheroids ◽  
Current Therapies

Sarcomas are tumours of mesenchymal origin, which can arise in bone or soft tissues. They are rare but frequently quite aggressive and with a poor outcome. New approaches are needed to characterise these tumours and their resistance mechanisms to current therapies, responsible for tumour recurrence and treatment failure. This review is focused on the potential of three-dimensional (3D) in vitro models, including multicellular tumour spheroids (MCTS) and organoids, and the latest data about their utility for the study on important properties for tumour development. The use of spheroids as a particularly valuable alternative for compound high throughput screening (HTS) in different areas of cancer biology is also discussed, which enables the identification of new therapeutic opportunities in commonly resistant tumours.

scholarly journals Development of Resistance in Wild-Type and Hypermutable Pseudomonas aeruginosa Strains Exposed to Clinical Pharmacokinetic Profiles of Meropenem and Ceftazidime Simulated In Vitro

2007 ◽  
Vol 51 (10) ◽  
pp. 3642-3649 ◽  
Author(s):  
Beate Henrichfreise ◽  
Irith Wiegand ◽  
Ingeborg Luhmer-Becker ◽  
Bernd Wiedemann
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Parent Strain ◽  
Resistance Mechanisms ◽  
In Vitro Models ◽  
Wild Type ◽  
Resistance Development ◽  
Development Of Resistance ◽  
Pharmacokinetic Profiles ◽  
Mutant Prevention Concentration

ABSTRACT In this study we investigated the interplay of antibiotic pharmacokinetic profiles and the development of mutation-mediated resistance in wild-type and hypermutable Pseudomonas aeruginosa strains. We used in vitro models simulating profiles of the commonly used therapeutic drugs meropenem and ceftazidime, two agents with high levels of antipseudomonal activity said to have different potentials for stimulating resistance development. During ceftazidime treatment of the wild-type strain (PAO1), fully resistant mutants overproducing AmpC were selected rapidly and they completely replaced wild-type cells in the population. During treatment with meropenem, mutants of PAO1 were not selected as rapidly and showed only intermediate resistance due to the loss of OprD. These mutants also replaced the parent strain in the population. During the treatment of the mutator P. aeruginosa strain with meropenem, the slowly selected mutants did not accumulate several resistance mechanisms but only lost OprD and did not completely replace the parent strain in the population. Our results indicate that the commonly used dosing regimens for meropenem and ceftazidime cannot avoid the selection of mutants of wild-type and hypermutable P. aeruginosa strains. For the treatment outcome, including the prevention of resistance development, it would be beneficial for the antibiotic concentration to remain above the mutant prevention concentration for a longer period of time than it does in present regimens.

scholarly journals Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins

2019 ◽  
Vol 20 (18) ◽  
pp. 4647 ◽  
Author(s):  
Bart Kramer ◽  
Luuk de Haan ◽  
Marjolein Vermeer ◽  
Thomas Olivier ◽  
Thomas Hankemeier ◽  
...  
Keyword(s):  
Cell Culture ◽  
Multidrug Resistance ◽  
Pancreatic Ductal Adenocarcinoma ◽  
3D Cell Culture ◽  
In Vitro Models ◽  
Ductal Adenocarcinoma ◽  
Interstitial Flow ◽  
Multidrug Resistance Proteins ◽  
And Function

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal cancers due to a high chemoresistance and poor vascularization, which results in an ineffective systemic therapy. PDAC is characterized by a high intratumoral pressure, which is not captured by current 2D and 3D in vitro models. Here, we demonstrated a 3D microfluidic interstitial flow model to mimic the intratumoral pressure in PDAC. We found that subjecting the S2-028 PDAC cell line to interstitial flow inhibits the proliferation, while maintaining a high viability. We observed increased gemcitabine chemoresistance, with an almost nine-fold higher EC50 as compared to a monolayer culture (31 nM versus 277 nM), and an alleviated expression and function of the multidrug resistance protein (MRP) family. In conclusion, we developed a 3D cell culture modality for studying intratissue pressure and flow that exhibits more predictive capabilities than conventional 2D cell culture and is less time-consuming, and more scalable and accessible than animal models. This increase in microphysiological relevance might support improved efficiency in the drug development pipeline.

scholarly journals Mapping the malaria parasite drug-able genome using in vitro evolution and chemogenomics

2017 ◽  
Author(s):  
Annie N. Cowell ◽  
Eva S. Istvan ◽  
Amanda K. Lukens ◽  
Maria G. Gomez-Lorenzo ◽  
Manu Vanaerschot ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Resistance Genes ◽  
Genome Analysis ◽  
Drug Targets ◽  
Malaria Parasite ◽  
Resistance Mechanisms ◽  
Whole Genome

AbstractChemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.One Sentence SummaryWhole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets.

Establishment of novel advanced in vitro models of the human placental barrier for nanoparticle translocation and effect studies

2016 ◽  
Vol 64 ◽  
pp. 25
Author(s):  
Tina Buerki-Thurnherr ◽  
Carina Muoth ◽  
Leonie Aengenheister ◽  
Melanie Kucki ◽  
Pius Manser ◽  
...  
Keyword(s):  
In Vitro Models ◽  
Placental Barrier

scholarly journals Nanoparticles for Cancer Therapy: Current Progress and Challenges

2021 ◽  
Author(s):  
Shreelaxmi Gavas ◽  
Sameer Quazi ◽  
Tomasz Karpiński
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Resistance Mechanisms ◽  
Multi Drug Resistance ◽  
Cancer Therapies ◽  
Therapeutic Implications ◽  
Current Perspective ◽  
Reduced Toxicity

Cancer is one of the leading causes of death and morbidity with a complex pathophysiology. Traditional cancer therapies include chemotherapy, radiation therapy, targeted therapy, and immunotherapy. However, limitations such as lack of specificity, cytotoxicity, and multi-drug resistance pose a substantial challenge for favorable cancer treatment. The advent of nanotechnology has revolutionized the arena of cancer diagnosis and treatment. Nanoparticles (1-100nm) can be used in the treatment of cancer owing to their specific advantages such as biocompatibility, reduced toxicity, more excellent stability, enhanced permeability and retention effect, and precise targeting. Nanoparticles are classified into several main categories. The nanoparticle drug delivery system is particular and utilizes tumor and tumor environment characteristics. Nanoparticles not only solve the limitations of conventional cancer treatment but also overcome multidrug resistance. Additionally, as new multidrug resistance mechanisms are unraveled and studied, nanoparticles are being investigated more vigorously. Various therapeutic implications of nano-formulations have created brand new perspectives for cancer treatment. However, a majority of the research is limited to in vivo and in vitro studies, and the number of nano-drugs that are approved has not much amplified over the years. In this review, we discuss numerous types of nanoparticles, targeting mechanisms along with approved nanotherapeutics for oncological implications in cancer treatment. Further, we also summarize the current perspective, advantages, and challenges in clinical translation.

scholarly journals Nanoparticles for Cancer Therapy: Current Progress and Challenges

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shreelaxmi Gavas ◽  
Sameer Quazi ◽  
Tomasz M. Karpiński
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Resistance Mechanisms ◽  
Multi Drug Resistance ◽  
Cancer Therapies ◽  
Therapeutic Implications ◽  
Current Perspective ◽  
Reduced Toxicity

AbstractCancer is one of the leading causes of death and morbidity with a complex pathophysiology. Traditional cancer therapies include chemotherapy, radiation therapy, targeted therapy, and immunotherapy. However, limitations such as lack of specificity, cytotoxicity, and multi-drug resistance pose a substantial challenge for favorable cancer treatment. The advent of nanotechnology has revolutionized the arena of cancer diagnosis and treatment. Nanoparticles (1–100 nm) can be used to treat cancer due to their specific advantages such as biocompatibility, reduced toxicity, more excellent stability, enhanced permeability and retention effect, and precise targeting. Nanoparticles are classified into several main categories. The nanoparticle drug delivery system is particular and utilizes tumor and tumor environment characteristics. Nanoparticles not only solve the limitations of conventional cancer treatment but also overcome multidrug resistance. Additionally, as new multidrug resistance mechanisms are unraveled and studied, nanoparticles are being investigated more vigorously. Various therapeutic implications of nanoformulations have created brand new perspectives for cancer treatment. However, most of the research is limited to in vivo and in vitro studies, and the number of approved nanodrugs has not much amplified over the years. This review discusses numerous types of nanoparticles, targeting mechanisms, and approved nanotherapeutics for oncological implications in cancer treatment. Further, we also summarize the current perspective, advantages, and challenges in clinical translation.

Syncytialization alters the extracellular matrix and barrier function of placental trophoblasts

2021 ◽  
Author(s):  
Kyle H. Moore ◽  
Hayley A. Murphy ◽  
Heather Chapman ◽  
Eric M. George
Keyword(s):  
Extracellular Matrix ◽  
Barrier Function ◽  
Marked Change ◽  
Maternal Blood ◽  
In Vitro Models ◽  
Placental Barrier ◽  
Barrier Dysfunction ◽  
Choriocarcinoma Cells

The human placenta is of vital importance for proper nutrient and waste exchange, immune regulation, and overall fetal health and growth. Specifically, the extracellular matrix (ECM) of placental syncytiotrophoblasts, which extends outward from the placental chorionic villi into maternal blood, acts on a molecular level to regulate and maintain this barrier. Importantly, placental barrier dysfunction has been linked to diseases of pregnancy such as preeclampsia and intrauterine growth restriction. To help facilitate our understanding of the interface, and develop therapeutics to repair or prevent dysfunction of the placental barrier, in vitro models of the placental ECM would be of great value. In this study we aimed to characterize the ECM of an in vitro model of the placental barrier using syncytialized BeWo choriocarcinoma cells. Syncytialization caused a marked change in syndecans, integral proteoglycans of the ECM, which matched observations of in vivo placental ECM. Syndecan-1 expression increased greatly and predominated the other variants. Barrier function of the ECM, as measured by electrical impedance, increased significantly during and after syncytialization, while the ability of THP-1 monocytes to adhere to syncytialized BeWos was greatly reduced compared to non-syncytialized controls. Furthermore, ECIS measurements indicated that ECM degradation with MMP-9, but not heparanase, decreased barrier function. This decrease in ECIS-measured barrier function was not associated with any changes in THP-1 adherence to syncytialized BeWos treated with heparanase or MMP9. Thus, syncytialization of BeWos provides a physiologically accurate placental ECM with a barrier function matching that seen in vivo.

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