Molecular insight into human P-glycoprotein allosteric transition from outward- to inward-facing state

In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. Bortezomib-induced cell cycle arrest in the G2/M phase was more pronounced in the S cells than in the R or T cells and was related to the expression levels of cyclins, cyclin-dependent kinases, and their inhibitors. We also observed an increase in the level of polyubiquitinated proteins (via K48-linkage) and a decrease in the gene expression of some deubiquitinases after treatment with bortezomib. Resistant cells expressed higher levels of genes encoding 26S proteasome components and the chaperone HSP90, which is involved in 26S proteasome assembly. After 4 h of preincubation, bortezomib induced a more pronounced depression of proteasome activity in S cells than in R or T cells. However, none of these changes alone or in combination sufficiently suppressed the sensitivity of R or T cells to bortezomib, which remained at a level similar to that of S cells.

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Faculty Opinions recommendation of Structural insight into substrate and inhibitor discrimination by human P-glycoprotein.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735100354.793556897 ◽

2019 ◽

Author(s):

Robert Copeland

Keyword(s):

P Glycoprotein ◽

Structural Insight ◽

Insight Into

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The Differential Absorption of a Series of P-Glycoprotein Substrates in Isolated Perfused Lungs from Mdr1a/1b Genetic Knockout Mice can be Attributed to Distinct Physico-Chemical Properties: an Insight into Predicting Transporter-Mediated, Pulmonary Specific Disposition

Pharmaceutical Research ◽

10.1007/s11095-017-2220-5 ◽

2017 ◽

Vol 34 (12) ◽

pp. 2498-2516 ◽

Cited By ~ 3

Author(s):

Daniel F. Price ◽

Chris N. Luscombe ◽

Peter J. Eddershaw ◽

Chris D. Edwards ◽

Mark Gumbleton

Keyword(s):

Knockout Mice ◽

Chemical Properties ◽

Differential Absorption ◽

Genetic Knockout ◽

P Glycoprotein ◽

Physico Chemical ◽

Insight Into

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Recent Advances in Nanotherapeutic Interventions for the Treatment of Alzheimer’s Disease

Current Pharmaceutical Design ◽

10.2174/1381612826666200422092620 ◽

2020 ◽

Vol 26 (19) ◽

pp. 2257-2279 ◽

Cited By ~ 1

Author(s):

Anmol Dogra ◽

R.S. Narang ◽

Jasjeet K. Narang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Manifestations ◽

Drug Efflux ◽

Factors Associated ◽

P Glycoprotein ◽

Recent Advances ◽

The Central Nervous System ◽

The Common ◽

Insight Into

Alzheimer’s disease (AD), with impairment of learning and memory as the common clinical manifestations, is one of the most challenging diseases affecting individuals, their families and society as a whole. The fact that its prevalence is escalating rapidly, with the total number of AD patients estimated to reach 115.4 million by 2050, has made the disease a very challenging ailment worldwide. Several biological barriers like the bloodbrain barrier (BBB), drug efflux by P-glycoprotein and the blood-cerebrospinal fluid barrier restrict the delivery of conventional AD drugs to the central nervous system (CNS), thereby limiting their effectiveness. In order to overcome the above physiological barriers, the development of nanomedicines has been extensively explored. The present review provides an insight into the pathophysiology of AD and risk factors associated with AD. Besides, various nanoformulations reported in the literature for the diagnosis and treatments of AD have been classified and summarised. The patented nanoformulations for AD and details of nanoformulations which are in clinical trials are also mentioned. The review would be helpful to researchers and scientific community by providing them with information related to the recent advances in nanointerventions for the diagnosis and treatment of AD, which they can further explore for better management of the disease. However, although the nanotherapeutics for managing AD have been extensively explored, the factors which hinder their commercialisation, the toxicity concern being one of them, need to be addressed so that effective nanotherapeutics for AD can be developed for clinical use.

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