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Downregulation of Renal MRPs Transporters in Acute Lymphoblastic Leukemia Mediated by the IL-6/STAT3/PXR Signaling
Yue Zhou1, Ai-Qing Nie1, Shang Chen2
1Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
Purpose:
Considering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL.
Subjects And Methods:
ALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).
Results:
Plasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway.
Conclusion:
Inflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments.
Insights
Interleukin-6 (IL-6) signaling in acute lymphoblastic leukemia (ALL) reduces key drug transporters, affecting chemotherapy. Blocking this pathway may improve ALL treatment outcomes.
Area of Science:
- Pharmacology
- Oncology
- Cell Biology
Background:
- Multidrug resistance-associated proteins (MRPs) 2 and 4 are crucial for drug transport.
- Reductions in MRP2 and MRP4 expression are observed in acute lymphoblastic leukemia (ALL).
- The IL-6/STAT3/PXR signaling pathway is implicated in these transporter changes.
Purpose of the Study:
- To investigate the mechanisms behind IL-6/STAT3/PXR-mediated changes in MRP2 and MRP4 expression in ALL.
- To understand how inflammation affects drug pharmacokinetics in ALL.
Main Methods:
- Established ALL xenograft mouse models.
- Utilized Western blotting and immunocytochemistry to assess protein expression.
- Quantified plasma methotrexate concentrations using HPLC-MS/MS.
Main Results:
- Elevated plasma IL-6 levels were found in ALL patients and mice.
- IL-6 treatment decreased MRP2, MRP4, and PXR expression while increasing p-STAT3 in HK-2 cells.
- Blocking the IL-6/STAT3/PXR pathway attenuated these effects.
Conclusions:
- Inflammation, via IL-6, significantly alters pharmacokinetics in ALL.
- IL-6 signaling pathways are key to understanding adverse outcomes in ALL.
- Targeting IL-6 may offer therapeutic implications for ALL treatment.
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