scholarly journals The Role of Chloride Channels in the Multidrug Resistance

Membranes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 38
Author(s):  
Bartosz Wilczyński ◽  
Alicja Dąbrowska ◽  
Jolanta Saczko ◽  
Julita Kulbacka
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Ion Channels ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Cell Metabolism ◽  
A Subunit ◽  
Cancerous Cells ◽  
Volume Decrease

Nowadays, one of medicine’s main and most challenging aims is finding effective ways to treat cancer. Unfortunately, although there are numerous anti-cancerous drugs, such as cisplatin, more and more cancerous cells create drug resistance. Thus, it is equally important to find new medicines and research the drug resistance phenomenon and possibilities to avoid this mechanism. Ion channels, including chloride channels, play an important role in the drug resistance phenomenon. Our article focuses on the chloride channels, especially the volume-regulated channels (VRAC) and CLC chloride channels family. VRAC induces multidrug resistance (MDR) by causing apoptosis connected with apoptotic volume decrease (AVD) and VRAC are responsible for the transport of anti-cancerous drugs such as cisplatin. VRACs are a group of heterogenic complexes made from leucine-rich repetition with 8A (LRRC8A) and a subunit LRRC8B-E responsible for the properties. There are probably other subunits, which can create those channels, for example, TTYH1 and TTYH2. It is also known that the ClC family is involved in creating MDR in mainly two mechanisms—by changing the cell metabolism or acidification of the cell. The most researched chloride channel from this family is the CLC-3 channel. However, other channels are playing an important role in inducing MDR as well. In this paper, we review the role of chloride channels in MDR and establish the role of the channels in the MDR phenomenon.

scholarly journals The Role of Serum Chloride in Acute and Chronic Heart Failure: A Narrative Review

2021 ◽  
Vol 11 (2) ◽  
pp. 87-98
Author(s):  
Frederick Berro Rivera ◽  
Pia Alfonso ◽  
Jem Marie Golbin ◽  
Kevin Lo ◽  
Edgar Lerma ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Prognostic Value ◽  
Diuretic Therapy ◽  
Juxtaglomerular Apparatus ◽  
Sodium Chloride Cotransporter ◽  
Serum Chloride ◽  
And Function

Clinical guidelines include diuretics for the treatment of heart failure (HF), not to decrease mortality but to decrease symptoms and hospitalizations. More attention has been paid to the worse outcomes, including mortality, associated with continual diuretic therapy due to hypochloremia. Studies have revealed a pivotal role for serum chloride in the pathophysiology of HF and is now a target of treatment to decrease mortality. The prognostic value of serum chloride in HF has been the subject of much attention. Mechanistically, the macula densa, a region in the renal juxtaglomerular apparatus, relies on chloride levels to sense salt and volume status. The recent discovery of with-no-lysine (K) (WNK) protein kinase as an intracellular chloride sensor sheds light on the possible reason of diuretic resistance in HF. The action of chloride on WNKs results in the upregulation of the sodium-potassium-chloride cotransporter and sodium-chloride cotransporter receptors, which could lead to increased electrolyte and fluid reabsorption. Genetic studies have revealed that a variant of a voltage-sensitive chloride channel (CLCNKA) gene leads to almost a 50% decrease in current amplitude and function of the renal chloride channel. This variant increases the risk of HF. Several trials exploring the prognostic value of chloride in both acute and chronic HF have shown mostly positive results, some even suggesting a stronger role than sodium. However, so far, interventional trials exploring serum chloride as a therapeutic target have been largely inconclusive. This study is a review of the pathophysiologic effects of hypochloremia in HF, the genetics of chloride channels, and clinical trials that are underway to investigate novel approaches to HF management.

scholarly journals The Emerging Role of Extracellular Vesicle-Mediated Drug Resistance in Cancers: Implications in Advanced Prostate Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Carolina Soekmadji ◽  
Colleen C. Nelson
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Advanced Prostate Cancer ◽  
Control Cell ◽  
Extracellular Vesicle ◽  
Multidrug Resistance Proteins ◽  
Acquired Drug Resistance ◽  
Resistance Proteins

Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.

The role of microvesicles in cancer progression and drug resistance

2013 ◽  
Vol 41 (1) ◽  
pp. 293-298 ◽  
Author(s):  
Samireh Jorfi ◽  
Jameel M. Inal
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cancer Progression ◽  
Chemotherapeutic Agents ◽  
Malignant Cells ◽  
Intercellular Transport ◽  
Wide Range ◽  
Anti Cancer ◽  
Mdr Multidrug Resistance

Microvesicles are shed constitutively, or upon activation, from both normal and malignant cells. The process is dependent on an increase in cytosolic Ca2+, which activates different enzymes, resulting in depolymerization of the actin cytoskeleton and release of the vesicles. Drug resistance can be defined as the ability of cancer cells to survive exposure to a wide range of anti-cancer drugs, and anti-tumour chemotherapeutic treatments are often impaired by innate or acquired MDR (multidrug resistance). Microvesicles released upon chemotherapeutic agents prevent the drugs from reaching their targets and also mediate intercellular transport of MDR proteins.

scholarly journals Molecular surveillance of the Plasmodium vivax multidrug resistance 1 gene in Peru between 2006 and 2015

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Fredy E. Villena ◽  
Jorge L. Maguiña ◽  
Meddly L. Santolalla ◽  
Edwar Pozo ◽  
Carola J. Salas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Plasmodium Vivax ◽  
Amazon Basin ◽  
North Coast ◽  
Molecular Surveillance ◽  
Synonymous Mutations ◽  
The North ◽  
Multidrug Resistance 1 Gene

Abstract Background The high incidence of Plasmodium vivax infections associated with clinical severity and the emergence of chloroquine (CQ) resistance has posed a challenge to control efforts aimed at eliminating this disease. Despite conflicting evidence regarding the role of mutations of P. vivax multidrug resistance 1 gene (pvmdr1) in drug resistance, this gene can be a tool for molecular surveillance due to its variability and spatial patterns. Methods Blood samples were collected from studies conducted between 2006 and 2015 in the Northern and Southern Amazon Basin and the North Coast of Peru. Thick and thin blood smears were prepared for malaria diagnosis by microscopy and PCR was performed for detection of P. vivax monoinfections. The pvmdr1 gene was subsequently sequenced and the genetic data was used for haplotype and diversity analysis. Results A total of 550 positive P. vivax samples were sequenced; 445 from the Northern Amazon Basin, 48 from the Southern Amazon Basin and 57 from the North Coast. Eight non-synonymous mutations and three synonymous mutations were analysed in 4,395 bp of pvmdr1. Amino acid changes at positions 976F and 1076L were detected in the Northern Amazon Basin (12.8%) and the Southern Amazon Basin (4.2%) with fluctuations in the prevalence of both mutations in the Northern Amazon Basin during the course of the study that seemed to correspond with a malaria control programme implemented in the region. A total of 13 pvmdr1 haplotypes with non-synonymous mutations were estimated in Peru and an overall nucleotide diversity of π = 0.00054. The Northern Amazon Basin was the most diverse region (π = 0.00055) followed by the Southern Amazon and the North Coast (π = 0.00035 and π = 0.00014, respectively). Conclusion This study showed a high variability in the frequencies of the 976F and 1076L polymorphisms in the Northern Amazon Basin between 2006 and 2015. The low and heterogeneous diversity of pvmdr1 found in this study underscores the need for additional research that can elucidate the role of this gene on P. vivax drug resistance as well as in vitro and clinical data that can clarify the extend of CQ resistance in Peru.

Cancer Cell Metabolism Featuring Nrf2

2020 ◽  
Vol 17 (3) ◽  
pp. 263-271 ◽  
Author(s):  
Payal Chatterjee ◽  
Mukesh Yadav ◽  
Namrata Chauhan ◽  
Ying Huang ◽  
Yun Luo
Keyword(s):  
Cancer Cells ◽  
Cell Metabolism ◽  
Cellular Metabolism ◽  
Energy Requirements ◽  
Genetic Mutations ◽  
Cellular Protection ◽  
Key Factor ◽  
Cancer Cell Metabolism ◽  
Cancerous Cells

Although the major role of Nrf2 has long been established as a transcription factor for providing cellular protection against oxidative stress, multiple pieces of research and reviews now claim exactly the opposite. The dilemma - “to activate or inhibit” the protein requires an immediate answer, which evidently links cellular metabolism to the causes and purpose of cancer. Profusely growing cancerous cells have prolific energy requirements, which can only be fulfilled by modulating cellular metabolism. This review highlights the cause and effect of Nrf2 modulation in cancer that in turn channelize cellular metabolism, thereby fulfilling the energy requirements of cancer cells. The present work also highlights the purpose of genetic mutations in Nrf2, in relation to cellular metabolism in cancer cells, thus pointing out a newer approach where parallel mutations may be the key factor to decide whether to activate or inhibit Nrf2.

scholarly journals New Insights into the Mechanism of NO3- Selectivity in the Human Kidney Chloride Channel ClC-Ka and the CLC Protein Family

2019 ◽  
Vol 30 (2) ◽  
pp. 293-302
Author(s):  
Laura Lagostena ◽  
Giovanni Zifarelli ◽  
Alessandra Picollo
Keyword(s):  
Chloride Channel ◽  
Chloride Channels ◽  
Human Kidney ◽  
Protein Family ◽  
Side Chain ◽  
Anion Selectivity ◽  
And Function ◽  
The Relationship ◽  
Insight Into

BackgroundThe mechanism of anion selectivity in the human kidney chloride channels ClC-Ka and ClC-Kb is unknown. However, it has been thought to be very similar to that of other channels and antiporters of the CLC protein family, and to rely on anions interacting with a conserved Ser residue (Sercen) at the center of three anion binding sites in the permeation pathway Scen. In both CLC channels and antiporters, mutations of Sercen alter the anion selectivity. Structurally, the side chain of Sercen of CLC channels and antiporters typically projects into the pore and coordinates the anion bound at Scen.MethodsTo investigate the role of several residues in anion selectivity of ClC-Ka, we created mutations that resulted in amino acid substitutions in these residues. We also used electrophysiologic techniques to assess the properties of the mutants.ResultsMutations in ClC-Ka that change Sercen to Gly, Pro, or Thr have only minor effects on anion selectivity, whereas the mutations in residues Y425A, F519A, and Y520A increase the NO3−/Cl− permeability ratio, with Y425A having a particularly strong effect.Conclusions ClC-Ka’s mechanism of anion selectivity is largely independent of Sercen, and it is therefore unique in the CLC protein family. We identified the residue Y425 in ClC-Ka—and the corresponding residue (A417) in the chloride channel ClC-0—as residues that contribute to NO3− discrimination in these channels. This work provides important and timely insight into the relationship between structure and function for the kidney chloride channels ClC-Ka and ClC-Kb, and for CLC proteins in general.

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