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Bortezomib induces thrombocytopenia by the inhibition of proplatelet formation of megakaryocytes
- Source :
- European Journal of Haematology. 93:290-296
- Publication Year :
- 2014
- Publisher :
- Wiley, 2014.
-
Abstract
- Bortezomib is a potent proteasome inhibitor that has been extensively used to treat multiple myeloma. One of the most common grade 3 adverse events is cyclic thrombocytopenia. In this study, we studied the mechanism by which bortezomib induces thrombocytopenia in a mouse model. After the intravenous administration of bortezomib (2.5 mg/kg) via tail vein, platelet counts significantly decreased on days 2-4 and recovered to the normal range on day 6. Bortezomib (2.5 mg/kg) injected into mice in vivo did not affect colony-forming unit-megakaryocytes (CFU-Mk) or megakaryocytes in the bone marrow. However, proplatelet formation (PPF) significantly decreased on days 2 and 4, after bortezomib administration to mice. Meanwhile, CFU-Mk formation and the ploidy distribution of cultured megakaryocytes in vitro were not affected by bortezomib used at concentrations of ≤ 1 ng/mL. The PPF of megakaryocytes in vitro significantly decreased with 0.1, 1, 10, and 100 ng/mL bortezomib. Considering the bortezomib concentration in clinical studies, these data strongly suggest that decreased PPF activity induces thrombocytopenia. To elucidate the mechanism behind decreased PPF, Western blot was performed. Activated Rho expression increased after the incubation of murine platelets with bortezomib. Decreased PPF activity was eliminated by the addition of Y27632, a Rho kinase inhibitor, in vitro. Given that the Rho/Rho kinase pathway is a negative regulator of PPF, bortezomib increases activated Rho, inducing decreased PPF, which results in decreased platelet count.
- Subjects :
- Blood Platelets
Male
Pyridines
Antineoplastic Agents
Pharmacology
Biology
Thrombopoiesis
Bortezomib
Colony-Forming Units Assay
Mice
Megakaryocyte
Bone Marrow
immune system diseases
In vivo
hemic and lymphatic diseases
medicine
Animals
Platelet
Rho-associated protein kinase
Multiple myeloma
Megakaryocyte Progenitor Cells
rho-Associated Kinases
Platelet Count
Hematology
General Medicine
medicine.disease
Amides
Boronic Acids
Thrombocytopenia
Disease Models, Animal
medicine.anatomical_structure
Thrombopoietin
Rho kinase inhibitor
Pyrazines
Immunology
Proteasome inhibitor
Multiple Myeloma
Megakaryocytes
medicine.drug
Subjects
Details
- ISSN :
- 09024441
- Volume :
- 93
- Database :
- OpenAIRE
- Journal :
- European Journal of Haematology
- Accession number :
- edsair.doi.dedup.....4e82f211629949c5df2824ae7dc5fccb