Stimuli-responsive nanostructures have shown great promise for intracellular delivery of anticancer compounds. A critical challenge remains in the exploration of stimuli-responsive nanoparticles for fast cytoplasmic delivery. Herein, near-infrared (NIR) light-responsive nanoparticles were rationally designed to generate highly efficient cytoplasmic delivery of anticancer agents for synergistic thermo-chemotherapy. The drug-loaded polymeric nanoparticles of selenium-inserted copolymer (I/D-Se-NPs) were rapidly dissociated in several minutes through reactive oxygen species (ROS)-mediated selenium oxidation upon NIR light exposure, and this irreversible dissociation of I/D-Se-NPs upon such a short irradiation promoted continuous drug release. Moreover, I/D-Se-NPs facilitated cytoplasmic drug translocation through ROS-triggered lysosomal disruption and thus resulted in highly preferable distribution to the nucleus even in 5 min postirradiation, which was further integrated with light-triggered hyperthermia fo...

Light-Responsive Nanoparticles for Highly Efficient Cytoplasmic Delivery of Anticancer Agents.

Discovery of traditional Chinese medicine monomers and their synthetic intermediates, analogs or derivatives for battling P-gp-mediated multi-drug resistance

P-glycoprotein (P-gp) is a critical determinant of multidrug resistance in cancer We previously reported that MAPK inhibition downregulates P-gp expression and that P-gp undergoes ubiquitin–proteasomal degradation regulated by UBE2R1 and SCFFbx15 Here, we investigated the crosstalk between MAPK inhibition and the ubiquitin–proteasomal degradation of P-gp Proteasome inhibitors or knockdown of FBXO15 and/or UBE2R1 cancelled MEK inhibitor-induced P-gp downregulation RSK1 phosphorylated Thr162 on UBE2R1 but did not phosphorylate FBXO15 MEK and RSK inhibitors increased UBE2R1-WT but not UBE2R1-T162D and -T162A expression UBE2R1-T162D showed higher self-ubiquitination and destabilisation than UBE2R1-WT and -T162A Unlike UBE2R1-WT and -T162A, UBE2R1-T162D did not induce P-gp ubiquitination UBE2R1-WT or -T162A downregulated P-gp expression and upregulated rhodamine 123 level and sensitivity to vincristine and doxorubicin However, UBE2R1-T162D did not confer any change in P-gp expression, rhodamine 123 accumulation and sensitivity to the drugs These results suggest that RSK1 protects P-gp against ubiquitination by reducing UBE2R1 stability

/pdf/rsk1-protects-p-glycoprotein-abcb1-against-ubiquitin-4k5tlqvvmd.pdf

RSK1 protects P-glycoprotein/ABCB1 against ubiquitin–proteasomal degradation by downregulating the ubiquitin-conjugating enzyme E2 R1

The co-administration of hydroxychloroquine with azithromycin is proposed in COVID-19 therapy. We hypothesize a new mechanism supporting the synergistic interaction between these drugs. Azithromycin is a substrate of ABCB1 (P-glycoprotein) which is localized in endosomes and lysosomes with a polarized substrate transport from the cell cytosol into the vesicle interior. SARS-CoV-2 and drugs meet in these acidic organelles and both basic drugs, which are potent lysosomotropic compounds, will become protonated and trapped within these vesicles. Consequently, their intra-vesicular concentrations can attain low micromolar effective cytotoxic concentrations on SARS-CoV-2 while concomitantly increase the intra-vesicular pH up to around neutrality. This last effect inhibits lysosomal enzyme activities responsible in virus entry and replication cycle. Based on these considerations, we hypothesize that ABCB1 could be a possible enhancer by confining azithromycin more extensively than expected when the trapping is solely dependent on the passive diffusion. This additional mechanism may therefore explain the synergistic effect when azithromycin is added to hydroxychloroquine, leading to apparently more rapid virus clearance and better clinical benefit, when compared to monotherapy with hydroxychloroquine alone.

/pdf/intracellular-abcb1-as-a-possible-mechanism-to-explain-the-4cp0yqzlj6.pdf

Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy.

Objective—SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2), expressed on the endothelial cell surface, functions as a novel coreceptor for VEGFR2 (vascular endothelial growth factor rece...

https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.117.310506

Inhibition of Endothelial SCUBE2 (Signal Peptide-CUB-EGF Domain-Containing Protein 2), a Novel VEGFR2 (Vascular Endothelial Growth Factor Receptor 2) Coreceptor, Suppresses Tumor Angiogenesis.

Revealing the fate of cell surface human P-glycoprotein (ABCB1): The lysosomal degradation pathway

ATP-binding cassette (ABC) drug transporters have both physiological and pharmacological importance in humans. They not only protect the cells from xenobiotics, but also alter the pharmacokinetics and toxicity of drugs that are substrates for these transporters. P-glycoprotein (P-gp) was the first human ABC transporter to be discovered, almost four decades ago. Drug transport using the energy harvested by ATP hydrolysis is a hallmark of ABC drug transporters and has been extensively studied to determine its mechanism of substrate specificity and transport activity. Structural information from a number of human P-gp homologs highlights the existence of multiple drug-binding sites that can interact with a diverse set of chemically or structurally unrelated compounds. Tyrosine kinase inhibitors (TKIs) comprise a class of drugs that interact with ABC transporters with high affinity and are reported to be transport substrates of several ABC transporters. A number of preclinical and clinical studies have shown that ABC transporters influence the disposition of several TKIs that include altered pharmacokinetics and safety profiles and have a role in the development of resistance to this class of therapeutics. Structural details regarding the TKIs’ effect on ABC transporters have not been thoroughly explored. This review summarizes preclinical and clinical observations on the interaction of TKIs with ABC drug transporters. In addition, we provide structural information on the interaction of two TKIs, nilotinib and imatinib, at the drug-binding regions within P-gp and ABCG2. This information could help to generate a novel scaffold that would be an ideal TKI with potent inhibition of kinases, but minimal interactions with ABC drug transporters.

Atish Patel

Papers

Revealing the fate of cell surface human P-glycoprotein (ABCB1): The lysosomal degradation pathway

Mechanistic and Pharmacological Insights into Modulation of ABC Drug Transporters by Tyrosine Kinase Inhibitors