Contribution of lysosomes to concentrative uptake of DX-9065a into rat liver

Murayama, Nobuyuki; Nakaoka, Minoru; Sudo, Kenichi

doi:10.1002/jps.20530

Cited by 2 publications

(1 citation statement)

References 30 publications

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“…In their report, the radioactivity concentration of DX-9065a in the kidney was approximately 50 times greater than the serum level 24 h after the single intravenous injection. 28 Therefore, DX-9065a administered simultaneously with OX-7 injection might remain in renal tissue for a long time at sufficient concentration to suppress local factor Xa activity.…”

Section: Roles Of Factor Xa In Rat Mspgnmentioning

confidence: 99%

Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Nomura

Liu

Nagai

et al. 2007

Laboratory Investigation

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Tissue factor initiates the extrinsic coagulation pathway by activating coagulation factor X to factor Xa, and factor V is a cofactor for the prothrombin activation by factor Xa. As factor Xa is known to promote the proliferation of mesangial cells in culture, the roles of the coagulation pathway and factor Xa were studied in an animal model of mesangioproliferative glomerulonephritis (MsPGN). MsPGN was induced in Wistar rats by an intravenous injection of anti-Thy 1.1 monoclonal antibody, OX-7. To clarify the role of factor Xa in MsPGN, a specific factor Xa inhibitor, DX-9065a, was injected intravenously at 2.5 or 10 mg/kg at the same time as OX-7, and kidney involvement was assessed by immunohistological analyses. We also examined p44/42 mitogen-activated protein (MAP) kinase activation. Time-course study revealed that expressions of tissue factor, factor V, and protease-activated receptor 2 (PAR2) were peaked on day 3, followed by factor X accumulation and mesangial proliferation. DX-9065a treatment significantly ameliorated proteinuria in a dose-dependent manner on day 8. Histological analyses showed a significant reduction in the size of glomeruli, the total number of glomerular cells, and crescent formation by DX-9065a treatment. Macrophage infiltration, which was rapidly observed on day 1 in disease control rats was not inhibited on days 1-3 by DX-9065a treatment, however it was suppressed on days 5-8. The deposition of fibrin, the number of PCNA-positive cells, and phosphorylation of p44/42 MAP kinase were markedly increased in the disease control group, whereas they were significantly reduced in the treatment group. Tissue factor and factor V induction may accelerate MsPGN through the activation and accumulation of factor X via proinflammatory and procoagulant mechanisms, and the inhibition of factor Xa would be a promising method to regulate the disease process.

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Section: Roles Of Factor Xa In Rat Mspgnmentioning

confidence: 99%

Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Nomura

Liu

Nagai

et al. 2007

Laboratory Investigation

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Lysosomal trapping of palbociclib and its functional implications

et al. 2019

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Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) approved for the treatment of some cancers. The main mechanism of action of palbociclib is to induce cell cycle arrest and senescence on responsive cells. Here, we report that palbociclib concentrates in intracellular acidic vesicles, where it can be readily observed due to its intrinsic fluorescence, and it is released from these vesicles upon dilution or washing out of the extracellular medium. This reversible storage of drugs into acidic vesicles is generally known as lysosomal trapping and, based on this, we uncover novel properties of palbociclib. In particular, a short exposure of cells to palbociclib is sufficient to produce a stable cell-cycle arrest and long-term senescence. Moreover, after washing out the drug, palbociclib-treated cells release the drug to the medium and this conditioned medium is active on susceptible cells. Interestingly, cancer cells resistant to palbociclib also accumulate and release the drug producing paracrine senescence on susceptible cells. Finally, other lysosomotropic drugs, such as chloroquine, interfere with the accumulation of palbociclib into lysosomes, thereby reducing the minimal dose of palbociclib required for cell-cycle arrest and senescence. In summary, lysosomal trapping explains the prolonged temporal activity of palbociclib, the paracrine activity of exposed cells, and the cooperation with lysosomotropic drugs. These are important features that may help to improve the therapeutic dosing and efficacy of palbociclib. Finally, two other clinically approved CDK4/6 inhibitors, ribociclib and abemaciclib, present a similar behavior as palbociclib, suggesting that lysosomal trapping is a property common to all three clinically-approved CDK4/6 inhibitors.

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Contribution of lysosomes to concentrative uptake of DX-9065a into rat liver

Cited by 2 publications

References 30 publications

Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Lysosomal trapping of palbociclib and its functional implications

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