DDRE-27. METABOLIC SWITCHING AS A MECHANISM OF DRUG RESISTANCE AGAINST NAMPT INHIBITION IN GLIOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi80-vi80
Author(s):  
Pratibha Sharma ◽  
Vinay Puduvalli
Keyword(s):  
Drug Resistance ◽  
Energy Metabolism ◽  
Cross Reactivity ◽  
Alternative Methods ◽  
Cross Resistance ◽  
Significant Heterogeneity ◽  
Drug Resistant ◽  
High Accumulation ◽  
Metabolic Switch ◽  
Nicotinamide Phosphoribosyltransferase

Abstract BACKGROUND Gliomas exhibit significant heterogeneity in treatment response and characteristically deploy resistance mechanisms that render conventional therapies ineffective. Recently, novel agents have been developed that target regulators of differential energy pathways specifically utilized by gliomas. We previously reported on the targeting of Nicotinamide Phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway and its essential role in glioma cell energy metabolism. Here, we determined the mechanisms by which glioma cells bypass blockade of energy metabolism and develop resistance to NAMPT inhibitors. METHODS Using isogenic parental and drug-resistant patient-derived glioma stem-like cells (GSCs), we examined adaptive changes after NAMPT inhibition in glycolysis, mitochondrial function (oxidative state, basal respiration rate, spare respiratory capacity, maximum respiration capacity and proton leak) and metabolite levels using Agilent Seahorse assay and targeted metabolomics. Cross reactivity across various NAMPT inhibitors was measured using Cell Titer Glo assay. RESULTS GSCs exposed for an extended period to sub-lethal doses of FK866, a potent NAMPT inhibitor, acquired drug resistance to the agent which were also cross-resistant to other NAMPT inhibitors. Drug-resistant GSCs showed a decrease in extracellular acidification rate and oxygen consumption rate compared to isogenic parental lines. Further, metabolomic analysis showed a high accumulation of glutamate, creatine and histidine metabolites in these cells. These results indicate a shift in metabolism of drug-resistant GSCs from carbon metabolism to nitrogen metabolism. CONCLUSIONS GSCs resistant to the NAMPT inhibitor, FK866 showed cross resistance to other NAMPT inhibitors indicating specificity of this effect. The resistance mechanism involves a shift of preferential energy generation from glycolysis to amino acid metabolism which allows the cells to use alternative methods to generate NAD. Additional results from ongoing studies to delineate the mechanisms of metabolic switch in the drug resistance lines will be presented that will help develop strategies to combat resistance to NAMPT inhibitors.

Further studies on the use of chicken embryo infections for the study of drug resistance in Eimeria tenella

Parasitology ◽  
1976 ◽  
Vol 73 (3) ◽  
pp. 275-282 ◽  
Author(s):  
H. D. Chapman
Keyword(s):  
Drug Resistance ◽  
Drug Concentration ◽  
Chicken Embryo ◽  
The Other ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Mutagenic Agent ◽  
Development Of Resistance ◽  
Drug Concentrations ◽  
Resistant Lines

Infections in the chicken embryo have been used to study the development of drug resistance in an embryo adapted strain of E. tenella. Resistance was developed to decoquinate, clopidol and robenidine by serially passaging this strain, but evidence for the development of resistance to amprolium was inconclusive. Resistance to decoquinate developed more readily than to the other drugs. Attempts to increase resistance to clopidol, robenidine and amprolium by increasing the sporozoite inoculum and by the use of a mutagenic agent were unsuccesful. No cross-resistance was found between the 4 drugs.Drug resistant lines of the Houghton strain (H) of E. tenella, made resistant to the 4 anticoccidial drugs by passage in chickens, were found to be resistant when evaluated using chicken embryo infections. Lines made resistant to decoquinate were not controlled by any concentration of this drug, suggesting that resistance, once developed, was absolute and not dependent on drug concentration. Lines made resistant to robenidine, clopidol and amprolium, however, were controlled by higher drug concentrations suggesting that in this case resistance was dependent on drug concentration.

scholarly journals Multidrug-resistant phenotype cosegregates with an amplified gene in somatic cell hybrids of drug-resistant Chinese hamster ovary cells and drug-sensitive murine cells.

1986 ◽  
Vol 6 (12) ◽  
pp. 4268-4273 ◽  
Author(s):  
L D Teeter ◽  
J A Sanford ◽  
S Sen ◽  
R L Stallings ◽  
M J Siciliano ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Somatic Cell ◽  
Chinese Hamster Ovary ◽  
Cho Cells ◽  
Chinese Hamster ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Somatic Cell Hybrids ◽  
Cell Hybrids ◽  
Primary Drug Resistance

Gene amplification has been associated with multidrug resistance (MDR) in several drug-resistant Chinese hamster ovary (CHO) cell lines which exhibit cross-resistance to other unrelated, cytotoxic drugs. In situ hybridization studies (Teeter et al., J. Cell Biol., in press) suggested the presence of an amplified gene associated with the MDR phenotype on the long arm of either of the largest CHO chromosomes (1 or Z1) in vincristine-resistant cells. In this study, somatic cell hybrids were constructed between these vincristine-resistant CHO cells and drug-sensitive murine cells to determine the functional relationship between the chromosome bearing the amplified sequences and the MDR phenotype. Hybrids exhibited primary drug resistance and MDR in an incomplete dominant fashion. Hybrid clones and subclones segregated CHO chromosomes. Concordant segregation between vincristine resistance, the MDR phenotype, the presence of the MDR-associated amplified sequences, overexpression of the gene located in those sequences, and CHO chromosome Z1 was consistent with the hypothesis that there is an amplified gene on chromosome Z1 of the vincristine-resistant CHO cells which is responsible for the MDR in these cells. A low level of discordance between CHO chromosomes Z8 and 2 and the drug resistance phenotype suggests that these chromosomes may contain genes involved with the MDR phenotype.

scholarly journals Efficacy and tolerability of rufinamide in the treatment of epilepsy (experience of the Svt. Luka’s Institute of Child Neurology and Epilepsy)

2018 ◽  
Vol 13 (2) ◽  
pp. 7-19
Author(s):  
K. Yu. Mukhin ◽  
O. A. Pylaeva ◽  
M. Yu. Bobylova ◽  
N. V. Freydkova ◽  
L. Yu. Glukhova ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Side Effects ◽  
Antiepileptic Drugs ◽  
Seizure Frequency ◽  
Focal Epilepsy ◽  
Alternative Methods ◽  
Chromosomal Microarray ◽  
Study Cohort ◽  
Chromosomal Microarray Analysis ◽  
Drug Resistant

Background. Despite significant advances in epileptology, approximately one-third of epilepsy patients suffer from drug-resistant seizures. Numerous approaches are currently available to treat epilepsy; however, there are still many patients with treatment-resistant epilepsy, in whom surgical treatment is impossible and alternative methods (vagus nerve stimulation and ketogenic diet) are ineffective. Therefore, searching for novel effective antiepileptic drugs (AEDs) is crucial for these patients.Objective: analysis of own data on the efficacy and tolerability of rufinamide in patients with severe forms of epilepsy and seizures typical of Lennox–Gastaut syndrome (LGS).Materials and methods. The study included 31 patients aged between 4 and 26 years (mean age 7.5 years) that received rufinamide (inovelon). The study cohort comprised 21 males and 10 females. Fifteen patients were diagnosed with LGS, whereas 16 patients were diagnosed with structural focal epilepsy with a phenocopy of LGS. Five patients had an evolution of West syndrome to LGS. The majority of patients (n = 22) experienced predominantly axial tonic seizures and epileptic spasms that were considered as indications for introduction of rufinamide. All patients underwent electroencephalography, video-electroencephalography monitoring during wakefulness and sleep, magnetic resonance imaging (MRI) (including high-resolution MRI with special epilepsy protocols when indicated), genetic examination (tandem mass spectrometry, hereditary epilepsy gene panel test and chromosomal microarray analysis) when indicated, and laboratory tests to assess tolerability of antiepileptic drugs.Results. Good therapeutic effect (more than 50 % reduction in seizure frequency) was achieved in 14 (45.2 %) patients. A less than 50 % reduction in seizure frequency occurred in 5 (16.1 %) patients; in 2 of them seizures became shorter and milder without a significant reduction in their frequency. Rufinamide was ineffective in 9 (29 %) patients. Three (9.7 %) patients experienced aggravation (increased seizure frequency) after the introduction of rufinamide. Thus, treatment with rufinamide was effective in 19 (61.3 %) patients. Rufinamide was well tolerated by most of the patients. Side effects were observed in 6 (19 %) participants. Side effects (forced normalization) caused withdrawal of rufinamide in 1 (3.2 %) patient. Currently, 10 (32 %) patients continue to take rufinamide. Sixteen patients received rufinamide for <6 months, 17 patients – for >6 months, 5 patients – for >12 months, and 1 patient – for >2 years.Conclusion. Our findings are consistent with the results obtained by foreign authors in routine clinical practice. In our study, rufinamide was used only in patients with drug-resistant epilepsy that earlier received many of currently available AEDs (both in monotherapy and in combination with other drugs). All study participants were earlier treated with at least three different AEDs that were ineffective. Seven patients received more than 8 AEDs in various combinations. This initial drug resistance should be taken into account when analyzing the data, which can not be extrapolated to patients with unknown drug resistance. We assume that the early introduction of rufinamide (prior to the detection of drug resistance) might have yielded better results.

scholarly journals MycoResistance: a curated resource of drug resistance molecules in Mycobacteria

Database ◽  
2019 ◽  
Vol 2019 ◽  
Author(s):  
Enyu Dai ◽  
Hao Zhang ◽  
Xu Zhou ◽  
Qian Song ◽  
Di Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Genetic Determinants ◽  
Related Information ◽  
Precise Diagnosis ◽  
Global Concern ◽  
User Friendly ◽  
Extensively Drug Resistance

Abstract The emergence and spread of drug-resistant Mycobacterium tuberculosis is of global concern. To improve the understanding of drug resistance in Mycobacteria, numerous studies have been performed to discover diagnostic markers and genetic determinants associated with resistance to anti-tuberculosis drug. However, the related information is scattered in a massive body of literature, which is inconvenient for researchers to investigate the molecular mechanism of drug resistance. Therefore, we manually collected 1707 curated associations between 73 compounds and 132 molecules (including coding genes and non-coding RNAs) in 6 mycobacterial species from 465 studies. The experimental details of molecular epidemiology and mechanism exploration research were also summarized and recorded in our work. In addition, multidrug resistance and extensively drug resistance molecules were also extracted to interpret the molecular mechanisms that are responsible for cross resistance among anti-tuberculosis drugs. Finally, we constructed an omnibus repository named MycoResistance, a user friendly interface to conveniently browse, search and download all related entries. We hope that this elaborate database will serve as a beneficial resource for mechanism explanations, precise diagnosis and effective treatment of drug-resistant mycobacterial strains.

scholarly journals Deciphering the Effects of Injectable Pre-exposure Prophylaxis for Combination Human Immunodeficiency Virus Prevention

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Robert L. Glaubius ◽  
Urvi M. Parikh ◽  
Greg Hood ◽  
Kerri J. Penrose ◽  
Eran Bendavid ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Scale Up ◽  
Cross Resistance ◽  
Human Immunodeficiency Virus Prevention ◽  
Reference Scenario ◽  
Drug Resistant ◽  
Kwazulu Natal ◽  
Immunodeficiency Virus ◽  
Exposure Prophylaxis

Abstract Background.  A long-acting injectable formulation of rilpivirine (RPV), under investigation as antiretroviral pre-exposure prophylaxis (PrEP), may facilitate PrEP adherence. In contrast, cross-resistance between RPV and nonnucleoside reverse-transcriptase inhibitors comprising first-line antiretroviral therapy (ART) could promote human immunodeficiency virus (HIV) drug resistance and reduce PrEP's effectiveness. Methods.  We use novel mathematical modeling of different RPV PrEP scale-up strategies in KwaZulu-Natal, South Africa, to investigate their effects on HIV prevention and drug resistance, compared with a reference scenario without PrEP. Results.  Pre-exposure prophylaxis scale-up modestly increases the proportion of prevalent drug-resistant infections, from 33% to ≤37%. The change in the number of prevalent drug-resistant infections depends on the interplay between PrEP factors (coverage, efficacy, delivery reliability, and scale-up strategy) and the level of cross-resistance between PrEP and ART. An optimistic scenario of 70% effective RPV PrEP (90% efficacious and 80% reliable delivery), among women aged 20–29 years, prevents 17% of cumulative infections over 10 years while decreasing prevalent resistance; however, prevention decreases and resistance increases with more conservative assumptions. Uncertainty analysis assuming 40%–70% cross-resistance prevalence predicts an increase in prevalent resistance unless PrEP's effectiveness exceeds 90%. Conclusions.  Prioritized scale-up of injectable PrEP among women in KwaZulu-Natal could reduce HIV infections, but suboptimal effectiveness could promote the spread of drug resistance.

scholarly journals Prevalence of minority Human Immunodeficiency virus multi-drug resistant mutations among patients failing a Nucleoside Reverse Transcriptase Inhibitor based regimen in Uganda

2021 ◽  
Author(s):  
Immaculate Lillian Nankya ◽  
Eva Nabulime ◽  
Fred Kyeyune ◽  
Cissy Mutuluza Kityo ◽  
Miguel Mateu Quinones
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Susceptible Genotype ◽  
Subtype C ◽  
Subtype A ◽  
Reverse Transcriptase Inhibitor

Abstract Objective To determine the prevalence of multi-drug resistant variants among patients failing on a nucleoside reverse transcriptase inhibitor (NRTI) based regimen with a detectable viral load ≥ 1000 copies/ml among patients harboring HIV subtype A, C and D. Methods Samples were obtained from patients who were failing on an NRTI based regimen. Sanger based sequencing was performed as part of the standard of care. Mutation analysis was performed using the Stanford HIV drug Resistance database. A subset of these patient samples was further analyzed using the Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cut off Results Analysis of the Non-nucleoside reverse transcriptase inhibitor (NNRTI) coding region revealed that the K101 and the Y181 mutations were more predominant among subtype C than subtype A and D. Although Thymidine analog mutations (TAMs) were prevalent in all subtypes, our analyses showed that these mutations occurred in significantly less proportions among subtype C infections when compared with the subtype A and D counterparts. Furthermore, the Q151M mutation complex which involves mutations in multiple domains was significantly more prominent among patients harboring subtype C variants. Analysis using NGS revealed that minority drug resistant mutations that confer multi-drug resistance (MDR) were present even in patients who exhibited a susceptible genotype based on the Sanger sequencing technique. Conclusion Although HIV-1 MDR variants occur in all subtypes, their predominance is subtype specific with TAMs being significantly more predominant among subtype A and D while the Q151M complex being significantly more predominant among patients harboring subtype C viruses. Even in patients with a susceptible genotype based on Sanger technology, minority variants are present and their evolution to full blown MDR occurs over time such that by the time they are detectable, cross resistance to other drugs has occurred in some cases.

Multidrug-resistant phenotype cosegregates with an amplified gene in somatic cell hybrids of drug-resistant Chinese hamster ovary cells and drug-sensitive murine cells

1986 ◽  
Vol 6 (12) ◽  
pp. 4268-4273
Author(s):  
L D Teeter ◽  
J A Sanford ◽  
S Sen ◽  
R L Stallings ◽  
M J Siciliano ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Somatic Cell ◽  
Chinese Hamster Ovary ◽  
Cho Cells ◽  
Chinese Hamster ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Somatic Cell Hybrids ◽  
Cell Hybrids ◽  
Primary Drug Resistance

Gene amplification has been associated with multidrug resistance (MDR) in several drug-resistant Chinese hamster ovary (CHO) cell lines which exhibit cross-resistance to other unrelated, cytotoxic drugs. In situ hybridization studies (Teeter et al., J. Cell Biol., in press) suggested the presence of an amplified gene associated with the MDR phenotype on the long arm of either of the largest CHO chromosomes (1 or Z1) in vincristine-resistant cells. In this study, somatic cell hybrids were constructed between these vincristine-resistant CHO cells and drug-sensitive murine cells to determine the functional relationship between the chromosome bearing the amplified sequences and the MDR phenotype. Hybrids exhibited primary drug resistance and MDR in an incomplete dominant fashion. Hybrid clones and subclones segregated CHO chromosomes. Concordant segregation between vincristine resistance, the MDR phenotype, the presence of the MDR-associated amplified sequences, overexpression of the gene located in those sequences, and CHO chromosome Z1 was consistent with the hypothesis that there is an amplified gene on chromosome Z1 of the vincristine-resistant CHO cells which is responsible for the MDR in these cells. A low level of discordance between CHO chromosomes Z8 and 2 and the drug resistance phenotype suggests that these chromosomes may contain genes involved with the MDR phenotype.

scholarly journals In Vitro Drug Susceptibility of Bedaquiline, Delamanid, Linezolid, Clofazimine, Moxifloxacin, and Gatifloxacin against Extensively Drug-Resistant Tuberculosis in Beijing, China

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Yu Pang ◽  
Zhaojing Zong ◽  
Fengmin Huo ◽  
Wei Jing ◽  
Yifeng Ma ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Fluoroquinolone Resistance ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Genetic Characteristics ◽  
Acquired Drug Resistance ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant

ABSTRACT Extensively drug-resistant tuberculosis (XDR-TB) is a deadly form of TB that can be incurable due to its extreme drug resistance. In this study, we aimed to explore the in vitro susceptibility to bedaquiline (BDQ), delamanid (DMD), linezolid (LZD), clofazimine (CLO), moxifloxacin (MFX), and gatifloxacin (GAT) of 90 XDR-TB strains isolated from patients in China. We also describe the genetic characteristics of XDR-TB isolates with acquired drug resistance. Resistance to MFX, GAT, LZD, CLO, DMD, and BDQ was found in 82 (91.1%), 76 (84.4%), 5 (5.6%), 5 (5.6%), 4 (4.4%), and 3 (3.3%) isolates among the XDR-TB strains, respectively. The most frequent mutations conferring fluoroquinolone resistance occurred in codon 94 of the gyrA gene (57.8%), and the strains with these mutations (69.2%) were associated with high-level MFX resistance compared to strains with mutations in codon 90 (25.0%) (P < 0.01). All 5 CLO-resistant isolates exhibited ≥4-fold upward shifts in the BDQ MIC, which were attributed to mutations of codons 53 (60.0%) and 157 (20.0%) in the Rv0678 gene. Additionally, mutation in codon 318 of the fbiC gene was identified as the sole mutation related to DMD resistance. In conclusion, our data demonstrate that the XDR-TB strains exhibit a strikingly high proportion of resistance to the current anti-TB drugs, whereas BDQ, DMD, LZD, and CLO exhibit excellent in vitro activity against XDR-TB in the National Clinical Center on TB of China. The extensive cross-resistance between OFX and later-generation fluoroquinolones indicates that MFX and GAT may have difficulty in producing the desired effect for XDR-TB 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.

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