Analysis of P-Glycoprotein Transport Cycle Reveals a New Way to Identify Efflux Inhibitors

Grigoreva, Tatyana A.; Ворона, Светлана В.; Novikova, Daria; Трибулович, В. Г.

doi:10.1021/acsomega.2c04768

Cited by 6 publications

(4 citation statements)

References 55 publications

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“…For the MDR characteristic in malignant neoplasms and many other diseases, ABC transporters plays important role, and influences severely the chemotherapy effects [ 37 , 38 ]. The multi-drug resistance gene MDR1 and its encoded P-glycoprotein (P-gp) were considered to be the most noteworthy mechanisms of MDR [ 39 , 40 ]. Based on our previous and present study, we revealed an important GRP75’s upstream transcriptional regulator, NF-κB [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Involvement and targeted intervention of benzo(a)pyrene-regulated apoptosis related proteome modification and muti-drug resistance in hepatocellular carcinoma

et al. 2023

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During the development of hepatocellular carcinoma (HCC), the mutual adaptation and interaction of HCC cells and the microenvironment play an important role. Benzo(a)pyrene (B[a]P) is a common environmental pollutant, which can induce the initiation of various malignant tumors, including HCC. However, the effects of B[a]P exposure on progression of HCC and the potential mechanisms remains largely uninvestigated. Here we found that, after the long-term exposure of HCC cells to low dose of B[a]P, it activated glucose-regulated protein 75 (GRP75), which then induced a modification of apoptosis-related proteome. Among them, we identified the X-linked inhibitor of apoptosis protein (XIAP) as a key downstream factor. XIAP further blocked the caspase cascade activation and promoted the acquisition of the anti-apoptosis abilities, ultimately leading to multi-drug resistance (MDR) in HCC. Furthermore, the abovementioned effects were markedly attenuated when we inhibited GRP75 by using 3,4-dihydroxycinnamic acid (caffeic acid, CaA). Collectively, our present study revealed the effects of B[a]P exposure on the progression of HCC, and identified GRP75 was a meaningful factor involved in.

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Section: Discussionmentioning

confidence: 99%

Involvement and targeted intervention of benzo(a)pyrene-regulated apoptosis related proteome modification and muti-drug resistance in hepatocellular carcinoma

et al. 2023

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“…In particular, these transporters release drugs such as doxorubicin, paclitaxel, etc. [ 43 , 44 , 45 ]. We also previously noted that an increase in the expression level of ABCB1 is observed in HCT116 cells in response to long-term treatment with Nutlin-3a [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

New Insights into Chemoresistance Mediated by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics

Grigoreva,

Sagaidak,

Novikova

et al. 2024

Biomedicines

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The inhibition of the Mdm2-p53 protein–protein interaction is a promising strategy for anticancer therapy. However, the problem of developing secondary chemoresistance in tumors treated with such drugs has not yet been sufficiently studied. In this work, we compared the properties of a drug-resistant cell line obtained during long-term cultivation in the presence of an Mdm2 inhibitor, Nutlin-3a, with a similarly obtained line insensitive to the cytostatic drug paclitaxel. We first confirmed the higher safety levels of Mdm2 inhibitors when compared with cytostatics in terms of the development of secondary chemoresistance. We showed that Nutlin-3a affects both the targeted p53-mediated cellular machinery and the universal ABC-mediated efflux mechanism. While both targeted and general defense mechanisms are activated by the Mdm2 inhibitor, it still increases the susceptibility of tumor cells to other drugs. The results obtained indicate that the risks of developing chemoresistance under the therapy with a targeted agent are fundamentally lower than during cytotoxic therapy.

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“…In the case of full-length ASO, the method of conformational search implemented in MacroModel force field-based molecular modeling tool that uses brief MD simulations followed by minimization and normal-mode search steps was used. For structures consisting of 4–6 bases, the LigPrep tool and MacroModel minimization were used using OPLS3e force field with the generation of tautomers and stereoisomers. − …”

Section: Methodsmentioning

confidence: 99%

Rational Design Problematics of Peptide Nucleic Acids as SARS-CoV-2 Inhibitors

Grigoreva,

Vorona,

Novikova

et al. 2024

ACS Omega

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The use of viral protein inhibitors has shown to be insufficiently effective in the case of highly variable SARS-CoV-2. In this work, we examined the possibility of designing agents that bind to a highly conserved region of coronavirus (+)RNA. We demonstrated that while the design of antisense RNAs is based on the complementary interaction of nitrogenous bases, it is possible to use semirigid docking methods in the case of unnatural peptide nucleic acids. The transition from N-(2-aminoethyl)glycine chain to a more conformationally rigid piperidinecontaining backbone allowed us to significantly increase the affinity of structures to the target RNA.

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Analysis of P-Glycoprotein Transport Cycle Reveals a New Way to Identify Efflux Inhibitors

Cited by 6 publications

References 55 publications

Involvement and targeted intervention of benzo(a)pyrene-regulated apoptosis related proteome modification and muti-drug resistance in hepatocellular carcinoma

Involvement and targeted intervention of benzo(a)pyrene-regulated apoptosis related proteome modification and muti-drug resistance in hepatocellular carcinoma

New Insights into Chemoresistance Mediated by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics

Rational Design Problematics of Peptide Nucleic Acids as SARS-CoV-2 Inhibitors

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