Intracellular self-disassemble polysaccharide nanoassembly for multi-factors tumor drug resistance modulation of doxorubicin

2018 ◽  
Vol 6 (9) ◽  
pp. 2527-2540 ◽  
Author(s):  
Hui Xiong ◽  
Jiang Ni ◽  
Zhijie Jiang ◽  
Fengchun Tian ◽  
Jianping Zhou ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Drug Release ◽  
Tumor Cells ◽  
Drug Carriers ◽  
Drug Efflux ◽  
Tumor Drug Resistance ◽  
Resistance Modulation

Drug efflux induced by multidrug resistance (MDR) overexpression, as well as secondary drug resistance caused by subtoxic drug microenvironments as a result of inefficient drug release of nanoscopic drug carriers in tumor cells, are major bottlenecks for chemotherapy.

Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance.

1998 ◽  
Vol 16 (11) ◽  
pp. 3674-3690 ◽  
Author(s):  
D M Bradshaw ◽  
R J Arceci
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Multidrug Resistance ◽  
Programmed Cell Death ◽  
Tumor Cells ◽  
Efflux Pump ◽  
Active Form ◽  
Cytotoxic Agents ◽  
Transport Systems ◽  
Drug Efflux

For cytotoxic agents to have an effect on tumor cells, drugs must first be transported into the cell, potentially be metabolized to an active form, and interact appropriately with target molecules. A final common pathway of cytotoxic agents is usually the initiation of programmed cell death, or apoptosis. Tumor cells overcome the effects of cytotoxic agents at one or more of these levels. The classic multidrug-resistance (MDR) phenotype, as mediated by the drug efflux pump, P-glycoprotein, is one of the most extensively studied mechanisms of drug resistance. Additional drug transporters, such as the multidrug resistance-associated proteins (MRPs), have also been identified and can convey drug-resistance phenotypes. Important questions remain as to how and whether such transport systems can be specifically measured and effectively targeted to improve therapeutic outcomes. Furthermore, alterations in drug targets, drug metabolism, repair of DNA damage caused by drugs, and the inability to initiate programmed cell death can all contribute to drug resistance and must be ultimately considered in the explanation of tumor-cell resistance to therapy. Continued exploration of the pharmacologic methods to circumvent drug resistance, as well as strategies that involve targeted therapy and immunomodulation, should increase the specificity and efficacy of treatments for patients with cancer.

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.

Gene expression profile of circulating tumor cells (CTCs) in clear cell metastatic renal cell carcinoma (mRCC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 302-302
Author(s):  
R. Iacovelli ◽  
C. Nicolazzo ◽  
A. Petracca ◽  
E. Risi ◽  
E. Cortesi
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Clear Cell ◽  
Tumor Phenotype ◽  
Clear Cell Rcc

302 Background: The presence of circulating tumor cells (CTCs) is described in 50% of patients affected by mRCC. The detection of CTC seems to be correlated with advanced tumor stage and more aggressive tumor phenotype. In some other solid tumors, such as breast, colorectal and prostate cancer, a growing body of evidence is emerging about the molecular portrait of these cells, whose nature is still largely unknown. The lack of information about CTCs characterization in RCC strongly hampers their application into the clinical practice. Aim of the study was to trace a gene expression profile of CTCs in mRCC patients. Methods: 18 metastatic clear cell mRCC patients were enrolled in the study. All patients provided informed consent. CTCs were isolated from 10cc of peripheral blood by CELLection Dynabeads coated with the monoclonal antibody towards the human Epithelial Cell Adhesion Molecule (EpCam). CELLection Epithelial Enrich is designed to optimally enrich bead-free, viable epithelial tumor cells. Tumor cells were eluted, subjected to RNA extraction and cDNA synthesis. PCR was then performed to investigate the expression of cytokeratin 8 (CK8) and vimentin as markers of clear cell RCC, multidrug resistance (MDR1), multidrug resistance related proteins 1–5–7 (MRP 1, MRP5, MRP 7) as drug resistance markers. Results: According with standard CTCs definition (CK+/CD45-), we found their presence in 9/18 samples (50%). Out of them, vimentin was found in 2/9 (22%), MDR1 in 3/9 (33%), MRP1 in 1/9 (11%), MRP5 in 6/9 (66%) and MRP7 in 9/9 (100%). Conclusions: To our knowledge this is the first attempt to describe a gene expression portrait in CTCs from clear cell mRCC. Of note is that vimentin, classically used as diagnostic marker for clear cell RCC is often lost in CTCs. This seems to further confirm the discrepancy between CTCs and primary tumor phenotype, already demonstrated in breast cancer. The expression profile of genes involved in multidrug resistance in CTCs seems to reflect the well known drug resistance observed in RCC. How these biological information obtainable from a gene expression profile performed on CTCs in clear cell mRCC may be translated into the clinic is currently under investigation. No significant financial relationships to disclose.

scholarly journals Research and application of single-cell sequencing in tumor heterogeneity and drug resistance of circulating tumor cells

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Zhe Dai ◽  
Xu-yu Gu ◽  
Shou-yan Xiang ◽  
Dan-dan Gong ◽  
Chang-feng Man ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Single Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Tumor Heterogeneity ◽  
Malignant Tumors ◽  
Single Cell Sequencing ◽  
Tumor Drug Resistance ◽  
New Perspective ◽  
Tumor Drugs

Abstract Malignant tumor is a largely harmful disease worldwide. The cure rate of malignant tumors increases with the continuous discovery of anti-tumor drugs and the optimisation of chemotherapy options. However, drug resistance of tumor cells remains a massive obstacle in the treatment of anti-tumor drugs. The heterogeneity of malignant tumors makes studying it further difficult for us. In recent years, using single-cell sequencing technology to study and analyse circulating tumor cells can avoid the interference of tumor heterogeneity and provide a new perspective for us to understand tumor drug resistance.

scholarly journals Expressional Study of Permeability glycoprotein (P-gp) and Multidrug Resistance Protein 1 (MRP-1) in Drug-Resistant Mesial Temporal Lobe Epilepsy

2021 ◽  
pp. 1-31
Author(s):  
Mandeep Kaur ◽  
◽  
Tulika Gupta ◽  
Mili Gupta ◽  
Parampreet S. Kharbanda ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Mesial Temporal Lobe Epilepsy ◽  
Efflux Transporters ◽  
P Value ◽  
Drug Efflux ◽  
Drug Resistant ◽  
Glycoprotein P ◽  
Mesial Temporal Lobe ◽  
Drug Efflux Transporters

About 30% of epileptic patients do not react to anti-epileptic drugs leading to refractory seizures. The pathogenesis of drug-resistance in Mesial Temporal Lobe Epilepsy (MTLE) is not completely understood. Increased activity of drug-efflux transporters might be involved, resulting in subclinical concentrations of the drug at the target site. The major drug-efflux transporters are permeability glycoprotein (P-gp) and multidrug-resistance associated protein-1 (MRP-1). The major drawback so far is the expressional analysis of transporters in equal numbers of drug-resistant epileptic tissue and age-matched non-epileptic tissue. We have studied these two transporters in the sclerotic hippocampal tissues resected from the epilepsy surgery (n=15) and compared their expression profile with the tissues resected from non-epileptic autopsy cases (n=15). Statistically significant over expression of both P-gp (p-value <0.0001) and MRP-1 (p-value 0.01) at gene and protein levels was found in the MTLE cases. The fold change of P-gp was more pronounced than MRP-1. Immunohistochemistry of patient group showed increased immunoreactivity of P-gp at blood brain barrier and increased reactivity of MRP-1 in parenchyma. The results were confirmed by confocal immunofluorescence microscopy. The study demonstrated that P-gp in association with MRP-1 might be responsible for the multi-drug resistance in epilepsy

Application of Nanoemulsions in Breast Cancer Treatment

2022 ◽  
pp. 277-306
Author(s):  
M Joyce Nirmala ◽  
Shiny P. J. ◽  
Sindhu Priya Dhas ◽  
Uma Kizhuveetil ◽  
Uppada Sumanth Raj ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Contrast Agents ◽  
Tumor Cells ◽  
Cancer Therapeutics ◽  
Drug Carriers ◽  
Healthcare Services ◽  
Breast Cancer Treatment ◽  
Multi Drug Resistance ◽  
Clinical Approach

A new, efficient, and secure clinical approach is increasingly being sought for the treatment of cancer. Nanoemulsions (NE) are projected to have a profound effect on delivering improved healthcare services with significant implications on forthcoming healthcare policies. In contrast to other drug carriers, the key value of NEs is that they can be engineered to target tumor cells and overcome the major challenge of multi-drug resistance. Multifunctional NEs are being investigated by researchers in various fields of study, primarily in the treatment of different forms of cancer. The congruent presence of NEs with contrast agents or certain dyes increases the accuracy of cancer status identification by enhancing the responsiveness of the agents; thus, they are finding application as nanotheranostics. A summary of different NEs and their documented applications in cancer therapeutics, with emphasis on breast cancer, is presented in this chapter.

scholarly journals Regulatory Role of Human AP-Endonuclease (APE1/Ref-1) in YB-1-Mediated Activation of the Multidrug Resistance Gene MDR1

2008 ◽  
Vol 28 (23) ◽  
pp. 7066-7080 ◽  
Author(s):  
Ranajoy Chattopadhyay ◽  
Soumita Das ◽  
Amit K. Maiti ◽  
Istvan Boldogh ◽  
Jingwu Xie ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Resistance Gene ◽  
Tumor Cells ◽  
Regulatory Function ◽  
Cancer Tissue ◽  
Multidrug Resistance Gene ◽  
Ap Endonuclease ◽  
Transcriptional Regulatory

ABSTRACT Human AP-endonuclease (APE1/Ref-1), a central enzyme involved in the repair of oxidative base damage and DNA strand breaks, has a second activity as a transcriptional regulator that binds to several trans-acting factors. APE1 overexpression is often observed in tumor cells and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to such agents. Because the involvement of APE1 in repairing the DNA damage induced by many of these drugs is unlikely, drug resistance may be linked to APE1's transcriptional regulatory function. Here, we show that APE1, preferably in the acetylated form, stably interacts with Y-box-binding protein 1 (YB-1) and enhances its binding to the Y-box element, leading to the activation of the multidrug resistance gene MDR1. The enhanced MDR1 level due to the ectopic expression of wild-type APE1 but not of its nonacetylable mutant underscores the importance of APE1's acetylation in its coactivator function. APE1 downregulation sensitizes MDR1-overexpressing tumor cells to cisplatin or doxorubicin, showing APE1's critical role in YB-1-mediated gene expression and, thus, drug resistance in tumor cells. A systematic increase in both APE1 and MDR1 expression was observed in non-small-cell lung cancer tissue samples. Thus, our study has established the novel role of the acetylation-mediated transcriptional regulatory function of APE1, making it a potential target for the drug sensitization of tumor cells.

scholarly journals Schiff-Linked PEGylated Doxorubicin Prodrug Forming pH-Responsive Nanoparticles With High Drug Loading and Effective Anticancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Jian Song ◽  
Bingbing Xu ◽  
Hui Yao ◽  
Xiaofang Lu ◽  
Yang Tan ◽  
...  
Keyword(s):  
Drug Release ◽  
Tumor Cells ◽  
Drug Loading ◽  
Drug Carriers ◽  
Anticancer Therapy ◽  
Therapeutic Effects ◽  
Ph Responsive ◽  
High Drug ◽  
High Drug Loading ◽  
Mcf 7

Developing efficacious drug delivery systems for targeted cancer chemotherapy remains a major challenge. Here we demonstrated a kind of pH-responsive PEGylated doxorubicin (DOX) prodrug via the effective esterification and Schiff base reactions, which could self-assemble into the biodegradable micelles in aqueous solutions. Owing to low pH values inside the tumor cells, these PEG-Schiff-DOX nanoparticles exhibited high drug loading ability and pH-responsive drug release behavior within the tumor cells or tissues upon changes in physical and chemical environments, but they displayed good stability at physiological conditions for a long period. CCK-8 assay showed that these PEGylated DOX prodrugs had a similar cytotoxicity to the MCF-7 tumor cells as the free DOX drug. Moreover, this kind of nanoparticle could also encapsulate small DOX drugs with high drug loading, sufficient drug release and enhanced therapeutic effects toward MCF-7 cells, which will be benefited for developing more drug carriers with desirable functions for clinical anticancer therapy.

scholarly journals Analysis of Multidrug Transporter in Living Cells. Inhibition of P-glycoprotein-mediated Efflux of Anthracyclines by Ionophores

1994 ◽  
Vol 1 (2-3) ◽  
pp. 175-182 ◽  
Author(s):  
Marie-Nicole Borrel ◽  
Elene Pereira ◽  
Marina Fiallo ◽  
Arlette Garnier-Suillerot
Keyword(s):  
Multidrug Resistance ◽  
Membrane Protein ◽  
Tumor Cells ◽  
Chelating Agent ◽  
Living Cells ◽  
Drug Accumulation ◽  
Multidrug Transporter ◽  
Drug Efflux ◽  
Cellular Resistance ◽  
P Glycoprotein

One of the major obstacles of chemotherapy is that, after repeated treatments, cellular resistance to the drug appears. The problem is that the tumor cells become resistant not only to the drugs which have been used during the treatment but also to other drugs which are structurally and functionally unrelated. This is termed ‘multidrug resistance’ (MDR). MDR is frequently associated with decreased drug accumulation resulting from enhanced drug efflux. This is correlated with the presence of a membrane protein, P-glycoprotein, which pumps a wide variety of drugs out of cells thus reducing their toxicity. The search for molecules able to reverse MDR is very important. We here report that mobile ionophores such as valinomycin, nonactin, nigericin, monensin, calcimycin, lasalocid inhibit the efflux of anthracycline by P-glycoprotein whereas, channel-forming ionophores such as gramicidin do not. Cyclosporin which is also a strong Ca2+ chelating agent also inhibits the P-glycoprotein-mediated efflux of anthracycline.

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