Tan, L.; Gao, P.; Li, Z.; Gao, C.; Geng, X.; Wang, Q.; Tang, D.; Wang, F.; Liu, J. The Reversal Effect of P-Glycoprotein-Mediated Tumor Multidrug Resistance by Pyxinol and 24S-Pyxinol Amino Acid Ester Derivatives. Preprints2023, 2023100013. https://doi.org/10.20944/preprints202310.0013.v1
APA Style
Tan, L., Gao, P., Li, Z., Gao, C., Geng, X., Wang, Q., Tang, D., Wang, F., & Liu, J. (2023). The Reversal Effect of P-Glycoprotein-Mediated Tumor Multidrug Resistance by Pyxinol and 24S-Pyxinol Amino Acid Ester Derivatives. Preprints. https://doi.org/10.20944/preprints202310.0013.v1
Chicago/Turabian Style
Tan, L., Fang Wang and Jinping Liu. 2023 "The Reversal Effect of P-Glycoprotein-Mediated Tumor Multidrug Resistance by Pyxinol and 24S-Pyxinol Amino Acid Ester Derivatives" Preprints. https://doi.org/10.20944/preprints202310.0013.v1
Abstract
(1) Background: The typical transporter protein, P-glycoprotein (P-gp), has been proven to be associated with multidrug resistance (MDR). Pyxinol and 24S-Pyxinol amino acid ester derivatives had been demonstrated to be promising P-gp inhibitors for reversal of tumor MDR in KBV cells, however, their roles in MDR reversal in other tumor-resistant cells are still unclear. (2) Methods: In the present study, we synthesized 40 amino acid ester derivatives of Pyxinol and 24S-Pyxinol. The MDR reversal effects of these derivatives were evaluated in A549/Tax, MCF-7/ADR, and HCT-8/VCR cells using the CCK-8 assay. Subsequently, western blot assay, intracellular Rhodamine123 (Rh123) accumulation assay and P-gp ATPase activity assay were utilized to investigate the effects of active compound on P-gp. Molecular docking was used to predict the possible binding patterns of active compound to P-gp. Moreover, based on UPLC-Q/TOF-MS cellular metabolomics technology to identify endogenous differential metabolites and metabolic pathways associated with tumor MDR effects of the active compound. (3) Results: The results of the CCK-8 assay showed that compounds 8, 14, 16, 17, 18, 23, 25, 34, 36, 37 exhibited strong MDR reversal effect in A549/Tax, MCF-7/ADR and HCT-8/VCR cells, which were screened by reversal fold (RF) greater than 5. Among them, 10 μM of derivative 37 (new compound) showed the outstanding activity (RF: 15.31) in reversing MDR in A549/Tax cells. Compound 37 could act as a substrate for P-gp and inhibit the efflux function of P-gp by competitively binding to the binding site of antitumor drugs. Meanwhile, the molecular docking results confirmed that compound 37 was identified to under-go high-affinity binding to the drug binding site of P-gp. In addition, 14 endogenous differential metabolites and 6 metabolic pathways involved closely associated with the reversal of tumor MDR effects of compound 37 were identified. (4) Conclusions: Overall, a new candidate compound 37 (24S-3-L-threonyl-Pyxinol) could be provided for reversing tumor MDR by this study.
Medicine and Pharmacology, Medicine and Pharmacology
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