Replicative fitness in vivo of HIV-1 variants with multiple drug resistance-associated mutations

2001 ◽  
Vol 65 (2) ◽  
pp. 218-224 ◽  
Author(s):  
Helen L. Devereux ◽  
Vincent C. Emery ◽  
Margaret A. Johnson ◽  
Clive Loveday
Keyword(s):  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
Replicative Fitness ◽  
Hiv 1

Mechanism Research of Reversal of Multidrug Resistance by the Application of 5-Bromotetrandrine and Magnetic Nanoparticle of Fe3O4 Combined with Daunorubicin in a Human-Nude Mice Xenograft Model

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5058-5058
Author(s):  
Bao-An Chen ◽  
Ya-nan Wu ◽  
Jian Cheng ◽  
Feng Gao ◽  
Wen-lin Xu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Nude Mice ◽  
Magnetic Nanoparticle ◽  
Multiple Drug Resistance ◽  
Xenograft Model ◽  
Tumor Formation ◽  
Multiple Drug ◽  
Inhibition Rate ◽  
Group 5

Abstract Objective: To establish the xenograft leukemia model with stable multiple drug resistance in nude mice; to investigate the reversal effect of 5-Bromotetrandrine and Magnetic nanoparticle of Fe3O4 combined with DNR in vivo and to search for the possible reversal mechanisms. Methods: K562 and K562/A02 cells were respectively inoculated subcutaneously into back of athymic nude mice (1×107 cells/each) to establish the xenograft models. The tumor formation was evaluated by animal ultrasonic inspection. Tumors-bearing nude mice were assigned randomly to five groups which were treated with NS (A group); DNR 1mg/kg (B group); nanoparticle of Fe3O4 combined with DNR 0.63mg/kg(C group): 5-BrTet 2.5mg/kg combined with DNR(D group); 5-Bromotetrandrine 2.5mg/kg and Magnetic nanoparticle of Fe3O4 combined with DNR 0.63mg/kg(E group) respectively. The incidence of tumor formation, growth characteristics, weight and volume of tumor were observed. The histopathologic examination of tumors and organs were detected. For resistant tumors, the protein levels of P-glycoprotein (P-gp) were detected by Western blot. Results: The tumor incidence was 100% in the nude mice inoculated with either K562 or K562/A02 cells. In 6 to 9 days,the tumors reached a volume of more than 1 00 mm3. In vivo, MTT assay showed K562/A02 tumor maintained the drug resistance. For K562 cells xenograft tumors, there were no apparent differences in tumor suppression effect between the B AC AD AE group. For K562/A02 cells xenograft tumors, 5-BrTet and Magnetic nanoparticle of Fe3O4 combined with DNR significantly suppressed growth of tumor: the inhibition rate was 62.76% while DNR alone be used, the inhibition rate was 3.68%. Pathologic examination of resistant tumors showed the tumors necrosis obviously in E group. Application of 5-BrTet and Magnetic nanoparticle of Fe3O4 inhibited the overexpression of P-gp. Conclusion: The xenograft leukemia nude mice model was maintain the multiple drug resistance. 5-Bromotetrandrine and Magnetic nanoparticle of Fe3O4 combined with DNR had a significant tumor-suppressing effect on MDR leukemia cells xenograft model.

scholarly journals Augmentation of Human Immunodeficiency Virus Type 1 Subtype E (CRF01_AE) Multiple-Drug Resistance by Insertion of a Foreign 11-Amino-Acid Fragment into the Reverse Transcriptase

2001 ◽  
Vol 75 (12) ◽  
pp. 5604-5613 ◽  
Author(s):  
Hironori Sato ◽  
Yasuhiro Tomita ◽  
Kazuyoshi Ebisawa ◽  
Atsuko Hachiya ◽  
Kayo Shibamura ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
Insertion Mutation ◽  
Immunodeficiency Virus ◽  
High Level ◽  
Hiv 1

ABSTRACT A human immunodeficiency virus type 1 (HIV-1) subtype E (CRF01_AE) variant (99JP-NH3-II) possessing an in-frame 33-nucleotide insertion mutation in the β3-β4 loop coding region of the reverse transcriptase (RT) gene was isolated from a patient who had not responded to nucleoside analogue RT inhibitors. This virus exhibited an extremely high level of multiple nucleoside analog resistance (MNR). Neighbor-joining tree analysis of thepol sequences indicated that the 99JP-NH3-II variant had originated from the swarm of drug-sensitive predecessors in the patient. Population-based sequence analyses of 82 independently cloned RT segments from the patient suggested that the variants with the insertion, three or four 3′-azido-3′-deoxythymidine resistance mutations, and a T69I mutation in combination had strong selective advantages during chemotherapy. Consistently, in vitro mutagenesis of a drug-sensitive predecessor virus clone demonstrated that this mutation set functions cooperatively to confer a high level of MNR without deleterious effects on viral replication capability. Homology modeling of the parental RT and its MNR mutant showed that extension of the β3-β4 loop by an insertion caused reductions in the distances between the loop and the other subdomains, narrowing the template-primer binding cleft and deoxynucleoside triphosphate-binding pocket in a highly flexible manner. The origin of the insert is elusive, as every effort to find a homologue has been unsuccessful. Taken together, these data suggest that (i) HIV-1 tolerates in vivo insertions as long as 33 nucleotides into the highly conserved enzyme gene to survive multiple anti-HIV-1 inhibitors and (ii) the insertion mutation augments multiple-drug resistance, possibly by reducing the biochemical inaccuracy of substrate-enzyme interactions in the active center.

scholarly journals In vivo activity of anprocide alone, and in vitro activity in combination with conventional antibiotics against Staphylococcus aureus and Staphylococcus epidermidis biofilms

2009 ◽  
Vol 58 (9) ◽  
pp. 1203-1206 ◽  
Author(s):  
Robin K. Pettit ◽  
Christine A. Weber ◽  
Stacey B. Lawrence ◽  
George R. Pettit ◽  
Melissa J. Kean ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Resistance ◽  
Murine Model ◽  
Staphylococcus Epidermidis ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
In Vitro Activity ◽  
Conventional Antibiotics

The alarming spread of multiple drug resistance in Staphylococcus aureus, combined with the frequent occurrence of S. aureus and Staphylococcus epidermidis in biofilm-type infections, indicates a growing need for new therapies. The experimental steroidal amide anprocide [3β-acetoxy-17β-(l-prolyl)amino-5α-androstane] significantly reduced c.f.u. ml−1 per suture (P <0.0001) in a murine model of topical S. aureus infection. In chequerboard assays with planktonic-grown S. aureus and S. epidermidis, anprocide was synergistic with bacitracin, oxacillin, clindamycin or ceftriaxone. Anprocide was also synergistic in combination with bacitracin or oxacillin against some isolates of biofilm-grown S. aureus and S. epidermidis.

scholarly journals Crizotinib and Doxorubicin Cooperatively Reduces Drug Resistance by Mitigating MDR1 to Increase Hepatocellular Carcinoma Cells Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Ming Shao ◽  
Run Shi ◽  
Zhen-Xing Gao ◽  
Shan-Shan Gao ◽  
Jing-Feng Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Death ◽  
Kinase Inhibitor ◽  
Multiple Drug Resistance ◽  
Autophagic Cell Death ◽  
Multiple Drug ◽  
Parp 1

As the sixth most lethal cancers worldwide, hepatocellular carcinoma (HCC) has been treated with doxorubicin (Dox) for decades. However, chemotherapy resistance, especially for Dox is an even more prominent problem due to its high cardiotoxicity. To find a regimen to reduce Dox resistance, and identify the mechanisms behind it, we tried to identify combination of drugs that can overcome drug resistance by screening tyrosine kinase inhibitor(s) with Dox with various HCC cell lines in vitro and in vivo. We report here that combination of Crizo and Dox has a synergistic effect on inducing HCC cell death. Accordingly, Crizo plus Dox increases Dox accumulation in nucleus 3-16 times compared to Dox only; HCC cell death enhanced at least 50% in vitro and tumor weights reduced ranging from 35 to 65%. Combining these two drugs reduces multiple drug resistance 1 (MDR1) protein as a result of activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), which phosphorylates eIF2α, leading to protein translational repression. Additionally, PERK stimulation activates C-Jun terminal kinase (JNK), resulting in accumulation of unfused autophagosome to enhance autophagic cell death via Poly-ADP-ribosyltransferase (PARP-1) cleavage. When the activity of PERK or JNK is blocked, unfused autophagosome is diminished, cleaved PARP-1 is reduced, and cell death is abated. Therefore, Crizo plus Dox sensitize HCC drug resistance by engaging PERK-p- eIF2α-MDR1, and kill HCC cells by engaging PERK-JNK- autophagic cell death pathways. These newly discovered mechanisms of Crizo plus Dox not only provide a potential treatment for HCC but also point to an approach to overcome MDR1 related drug resistance in other cancers.

Do Multiple Drug Resistance Transporters Interfere with Cell Functioning under Normal Conditions?

2020 ◽  
Vol 85 (12-13) ◽  
pp. 1560-1569
Author(s):  
D. A. Knorre ◽  
K. V. Galkina ◽  
T. Shirokovskikh ◽  
A. Banerjee ◽  
R. Prasad
Keyword(s):  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Multiple Drug

scholarly journals Amelioration of the Cost of Conjugative Plasmid Carriage in Eschericha coli K12

Genetics ◽  
2003 ◽  
Vol 165 (4) ◽  
pp. 1641-1649
Author(s):  
Cecilia Dahlberg ◽  
Lin Chao
Keyword(s):  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Conjugative Plasmid ◽  
Energetic Cost ◽  
Multiple Drug ◽  
Genetic Changes ◽  
Batch Cultures ◽  
Transfer Rates ◽  
Bacterial Plasmid ◽  
The Cost

Abstract Although plasmids can provide beneficial functions to their host bacteria, they might confer a physiological or energetic cost. This study examines how natural selection may reduce the cost of carrying conjugative plasmids with drug-resistance markers in the absence of antibiotic selection. We studied two plasmids, R1 and RP4, both of which carry multiple drug resistance genes and were shown to impose an initial fitness cost on Escherichia coli. To determine if and how the cost could be reduced, we subjected plasmid-containing bacteria to 1100 generations of evolution in batch cultures. Analysis of the evolved populations revealed that plasmid loss never occurred, but that the cost was reduced through genetic changes in both the plasmids and the bacteria. Changes in the plasmids were inferred by the demonstration that evolved plasmids no longer imposed a cost on their hosts when transferred to a plasmid-free clone of the ancestral E. coli. Changes in the bacteria were shown by the lowered cost when the ancestral plasmids were introduced into evolved bacteria that had been cured of their (evolved) plasmids. Additionally, changes in the bacteria were inferred because conjugative transfer rates of evolved R1 plasmids were lower in the evolved host than in the ancestral host. Our results suggest that once a conjugative bacterial plasmid has invaded a bacterial population it will remain even if the original selection is discontinued.

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