ABCB1 in children's brain tumours

2015 ◽  
Vol 43 (5) ◽  
pp. 1018-1022 ◽  
Author(s):  
Beth Coyle ◽  
Maya Kessler ◽  
Durgagauri H. Sabnis ◽  
Ian D. Kerr
Keyword(s):  
Drug Resistance ◽  
Adjuvant Chemotherapy ◽  
Brain Tumours ◽  
Survival Rates ◽  
Local Relapse ◽  
Drug Resistant ◽  
Chemotherapy Drugs ◽  
Resistant Disease ◽  
Increased Risk ◽  
Disseminated Disease

Tumours of the central nervous system are the most common solid tumour, accounting for a quarter of the 1500 cases of childhood cancer diagnosed each year in the U.K. They are the most common cause of cancer-related death in children. Treatment consists of surgery followed by adjuvant chemotherapy and/or radiotherapy. Survival rates have generally increased, but many survivors suffer from radiotherapy-related neurocognitive and endocrine side effects as well as an increased risk of secondary cancer. Adjuvant chemotherapy is normally given in combination to circumvent chemoresistance, but several studies have demonstrated it to be ineffective in the absence of radiotherapy. The identification of children with drug-resistant disease at the outset could allow stratification of those that are potentially curable by chemotherapy alone. Ultimately, however, what is required is a means to overcome this drug resistance and restore the effectiveness of chemotherapy. Medulloblastomas and ependymomas account for over 30% of paediatric brain tumours. Advances in neurosurgery, adjuvant radiotherapy and chemotherapy have led to improvements in 5-year overall survival rates. There remain, however, significant numbers of medulloblastoma patients that have intrinsically drug-resistant tumours and/or present with disseminated disease. Local relapse in ependymoma is also common and has an extremely poor prognosis with only 25% of children surviving first relapse. Each of these is consistent with the acquisition of drug and radiotherapy resistance. Since the majority of chemotherapy drugs currently used to treat these patients are transport substrates for ATP-binding cassette sub-family B member 1 (ABCB1) we will address the hypothesis that ABCB1 expression underlies this drug resistance.

scholarly journals Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

Metabolites ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 289 ◽  
Author(s):  
Xun Chen ◽  
Shangwu Chen ◽  
Dongsheng Yu
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Metabolic Regulation ◽  
Metabolic Response ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Drug Resistant ◽  
Chemotherapy Drugs

Metabolic reprogramming is one of the hallmarks of tumors. Alterations of cellular metabolism not only contribute to tumor development, but also mediate the resistance of tumor cells to antitumor drugs. The metabolic response of tumor cells to various chemotherapy drugs can be analyzed by metabolomics. Although cancer cells have experienced metabolic reprogramming, the metabolism of drug resistant cancer cells has been further modified. Metabolic adaptations of drug resistant cells to chemotherapeutics involve redox, lipid metabolism, bioenergetics, glycolysis, polyamine synthesis and so on. The proposed metabolic mechanisms of drug resistance include the increase of glucose and glutamine demand, active pathways of glutaminolysis and glycolysis, promotion of NADPH from the pentose phosphate pathway, adaptive mitochondrial reprogramming, activation of fatty acid oxidation, and up-regulation of ornithine decarboxylase for polyamine production. Several genes are associated with metabolic reprogramming and drug resistance. Intervening regulatory points described above or targeting key genes in several important metabolic pathways may restore cell sensitivity to chemotherapy. This paper reviews the metabolic changes of tumor cells during the development of chemoresistance and discusses the potential of reversing chemoresistance by metabolic regulation.

scholarly journals Mycobacteriophages to Treat Tuberculosis: Dream or Delusion?

Respiration ◽  
2021 ◽  
pp. 1-15
Author(s):  
Andreas H. Diacon ◽  
Carlos A. Guerrero-Bustamante ◽  
Bernd Rosenkranz ◽  
Francisco J. Rubio Pomar ◽  
Naadira Vanker ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Synergistic Effects ◽  
Case Reports ◽  
Resistant Bacteria ◽  
Human Consumption ◽  
Biological Entity ◽  
Optimal Dosage ◽  
Drug Resistant ◽  
Increased Risk ◽  
Phage Treatment

Rates of antimicrobial resistance are increasing globally while the pipeline of new antibiotics is drying up, putting patients with disease caused by drug-resistant bacteria at increased risk of complications and death. The growing costs for diagnosis and management of drug resistance threaten tuberculosis control where the disease is endemic and resources limited. Bacteriophages are viruses that attack bacteria. Phage preparations served as anti-infective agents long before antibiotics were discovered. Though small in size, phages are the most abundant and diverse biological entity on earth. Phages have co-evolved with their hosts and possess all the tools needed to infect and kill bacteria, independent of drug resistance. Modern biotechnology has improved our understanding of the biology of phages and their possible uses. Phage preparations are available to treat meat, fruit, vegetables, and dairy products against parasites or to prevent contamination with human pathogens, such as <i>Listeria monocytogenes, Escherichia coli</i>, or <i>Staphylococcus aureus</i>. Such phage-treated products are considered fit for human consumption. A number of recent case reports describe in great detail the successful treatment of highly drug-resistant infections with individualized phage preparations. Formal clinical trials with standardized products are slowly emerging. With its highly conserved genome and relative paucity of natural phage defence mechanisms <i>Mycobacterium tuberculosis</i> appears to be a suitable target for phage treatment. A phage cocktail with diverse and strictly lytic phages that kill all lineages of <i>M. tuberculosis,</i> and can be propagated on <i>Mycobacterium smegmatis</i>, has been assembled and is available for the evaluation of optimal dosage and suitable routes of administration for tuberculosis in humans. Phage treatment can be expected to be safe and active on extracellular organisms, but phage penetration to intracellular and granulomatous environments as well as synergistic effects with antibiotics are important questions to address during further evaluation.

scholarly journals Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation

2019 ◽  
Vol 60 (6) ◽  
pp. 1078-1086 ◽  
Author(s):  
Su-Fern Tan ◽  
Wendy Dunton ◽  
Xin Liu ◽  
Todd E. Fox ◽  
Samy A. F. Morad ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Resistant ◽  
Chemotherapeutic Drugs ◽  
Acid Ceramidase ◽  
Resistant Disease ◽  
P Glycoprotein ◽  
Nf Kappab ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of older AML patients fail to respond to cytotoxic chemotherapy, and most responders relapse with drug-resistant disease. Failure to achieve complete remission can be partly attributed to the drug resistance advantage of AML blasts that frequently express P-glycoprotein (P-gp), an ATP-binding cassette transporter. Our previous work showed that elevated acid ceramidase (AC) levels in AML contribute to blast survival. Here, we investigated P-gp expression levels in AML relative to AC. Using parental HL-60 cells and drug-resistant derivatives as our model, we found that P-gp expression and efflux activity were highly upregulated in resistant derivatives. AC overexpression in HL-60 conferred resistance to the AML chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and was linked to P-gp upregulation. Furthermore, targeting AC through pharmacologic or genetic approaches decreased P-gp levels and increased sensitivity to chemotherapeutic drugs. Mechanistically, AC overexpression increased NF-κB activation whereas NF-kB inhibitors reduced P-gp levels, indicating that the NF-kappaB pathway contributes to AC-mediated modulation of P-gp expression. Hence, our data support an important role for AC in drug resistance as well as survival and suggest that sphingolipid targeting approaches may also impact drug resistance in AML.

scholarly journals Risk Factors and Treatment Outcome Analysis Associated with Second-Line Drug-Resistant Tuberculosis

2021 ◽  
Vol 2 (1) ◽  
pp. 1-12
Author(s):  
Muralidhar Aaina ◽  
Kaliyaperumal Venkatesh ◽  
Brammacharry Usharani ◽  
Muthukumar Anbazhagi ◽  
Gerard Rakesh ◽  
...  
Keyword(s):  
Risk Factors ◽  
Drug Resistance ◽  
Drug Resistant ◽  
First Line ◽  
Drug Resistant Tuberculosis ◽  
Factors Associated ◽  
Resistant Tuberculosis ◽  
Increased Risk ◽  
Mdr Tb ◽  
Line Drug

The present study aimed at analyzing the treatment outcomes and risk factors associated with fluoroquinolone drug resistance having mutations in the gyrA and gyrB genes. A total of 258 pulmonary tuberculosis samples with first-line drug-resistant (H, R, or HR) were subjected to GenoType MTBDRsl assay for the molecular detection of mutations. Among the 258 samples, 251 were drug-resistant tuberculosis and seven were sensitive to all first-line TB drugs. Out of 251 DR-TB cases, 42 cases were MDR TB, 200 were INH mono-resistant and nine cases were RIF mono-resistant tuberculosis. Out of 251 DR-TB cases performed with a MTBDRsl assay, 14 had Pre-XDR-FQ, one patient had pre-XDR-SLID, one had extensively drug-resistant tuberculosis (XDR-TB) and 235 cases were sensitive to both FQ and SLID drugs. The study group had a mean average of 42.7 ± 16.4 years. The overall successful treatment outcomes among the MDR, INH mono-resistant, and pre-XRD patients were 70.6%, 82.0%, and 51%, respectively. The percentage of risk for the unfavorable outcomes in the pre-XDR, INH -mono-resistant, and XDR cases were 113.84% increased risk with RR 2.14; 95% CI 0.7821–5.8468. The independent risk factor associated with the unfavorable outcomes to failure was 77.78% increased risk with RR 1.78; 95% CI 0.3375–9.3655. Logistic regression analysis revealed that the percentage relative risk among MDR-TB patients for gender, male (RR: 1.85), age ≥ 61 years (RR: 1.96), and diabetics (RR: 1.05) were 84.62%, 95.83%, and 4.76%, respectively. The independent risk factors associated with INH mono-resistant cases of age 16–60 (RR: 1.86), ≥61 year (RR: 1.18), and treated cases (RR: 5.06). This study presaged the significant risk of INH mono-resistant, pre-XDR, and MDR among males, young adults, diabetics, and patients with previous treatment failure. Timely identification of high-risk patients will give pronounced advantages to control drug resistance tuberculosis diseases.

scholarly journals Neurocognitive Implications in Children Undergoing Chemotherapy and Radiotherapy

2021 ◽  
Author(s):  
Natália Barros Salgado Vieira ◽  
Sarah Joanny da Silva Pereira ◽  
Ana Flávia Silva Castro
Keyword(s):  
Radiation Therapy ◽  
Early Recognition ◽  
Survival Rates ◽  
Life Quality ◽  
Complete Analysis ◽  
Chemotherapy Drugs ◽  
Verbal Skills ◽  
Increased Risk ◽  
Pediatric Cancer Patients ◽  
Higher Doses

Background: Radiotherapy and chemotherapy drugs were essential for increasing the survival rates of pediatric cancer patients, but dysfunctions associated with treatment, mainly neurological and cognitive, are recorded and should be considered in deciding the therapeutic plan. Objectives: Analyze the current literature on the neurocognitive effects in children undergoing chemotherapy and radiation therapy. Methods: A bibliographic review was carried out in the MEDLINE / Pubmed and LILACS databases, using the terms “cognitive effects”, “chemotherapy”, “radiotherapy” and “child”, in Portuguese and in English. 79 articles were found and 6 followed for complete analysis. Articles published more than 5 years ago and that did not address the proposed subject were not used. Results: Radiotherapy, especially cranial (CRT), is associated with serious effects, such as induction of vasculopathy, stroke, cerebrovascular malformations, in addition to an increased risk for subsequent malignant CNS tumors. Despite being a standard treatment for several neoplasms, radiotherapy has been replaced, when possible, by higher doses of chemotherapy, which has a considerable level of neurotoxicity, capable of causing coagulopathy, encephalopathy, seizures and neuropathies, both sensory and motor. However, deficits in children’s attentional capacity in both treatment categories stood out, sometimes implying educational difficulties and decline in non-verbal skills. Conclusions: Although chemotherapy and radiation therapy represent impressive advances, their consequences remain a concern. Future studies should seek strategies for prevention, early recognition and management of neurotoxicity, in order to promote better life quality for patients.

Candida auris and Nosocomial Infection

2020 ◽  
Vol 21 (4) ◽  
pp. 365-373 ◽  
Author(s):  
Sweety Dahiya ◽  
Anil K. Chhillar ◽  
Namita Sharma ◽  
Pooja Choudhary ◽  
Aruna Punia ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Pathogenic Fungus ◽  
Control Measures ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Drug Resistant ◽  
Candida Auris ◽  
Preventive Control ◽  
Identification Techniques ◽  
Sensitivity Profile

The existence of the multi-drug resistant (MDR) pathogenic fungus, Candida auris came to light in 2009. This particular organism is capable of causing nosocomial infections in immunecompromised persons. This pathogen is associated with consistent candidemia with high mortality rate and presents a serious global health threat. Whole genome sequence (WGS) investigation detected powerful phylogeographic Candida auris genotypes which are specialized to particular geological areas indicating dissemination of particular genotype among provinces. Furthermore, this organism frequently exhibits multidrug-resistance and displays an unusual sensitivity profile. Identification techniques that are commercialized to test Candida auris often show inconsistent results and this misidentification leads to treatment failure which complicates the management of candidiasis. Till date, Candida auris has been progressively recorded from several countries and therefore its preventive control measures are paramount to interrupt its transmission. In this review, we discussed prevalence, biology, drug-resistance phenomena, virulence factors and management of Candida auris infections.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery

2017 ◽  
Vol 17 (19) ◽  
pp. 2129-2142 ◽  
Author(s):  
Renata Płocinska ◽  
Malgorzata Korycka-Machala ◽  
Przemyslaw Plocinski ◽  
Jaroslaw Dziadek
Keyword(s):  
Drug Resistance ◽  
Dna Replication ◽  
Drug Targets ◽  
Rapid Development ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drug ◽  
Nucleotide Synthesis ◽  
Antituberculosis Therapy ◽  
Optimal Drug

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

Silencing PEX26 as an Unconventional Mode to Kill Drug-Resistant Cancer Cells and Forestall Drug Resistance

Autophagy ◽  
2021 ◽  
Author(s):  
Michael S. Dahabieh ◽  
Fan Huang ◽  
Christophe Goncalves ◽  
Raúl Ernesto Flores González ◽  
Sathyen Prabhu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Drug Resistant
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