Home Blog of Signal Transduction Proteases Autophagy Inhibition of proteasome restores bortesomib-induced thrombocytopenia

Category

Archives

Popular Post

ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

Inhibition of proteasome restores bortesomib-induced thrombocytopenia

 

Bortesomib is a effective proteasome inhibitor used in the therapy against multiple myeloma, however, it often induces thrombocytopenia, a decrease of platelet count, within a short term of therapy initiation. This effect can be recovered after cessation of bortezomib treatment. Due to the unknown mechanism of how bortezomib affects thrombopoiesis, several studies aim to find out the role of proteasome in platelet formation. Shi et al. reported clinical proteasome inhibitor enable to block proplatelet formation by megakaryocytes in human and mouse model. The article was published in The Journal of Clinical Investigation.

 

Researchers found the systemic or platelet-specific lacking of PSMC1 , a subunit of the 26S proteasome, caused failure of proplatelet production by megakaryocytes or thrombocytopenia-induced death, respectively. Mechanically, they found the failure of proplatelet production in PSMC1 deficient megakaryocytes is caused by aberrant increase of RhoA, a small GTPase. The formation of proplatelet can be restored by either inhibiting RhoA or its downstream target, Rho-associated protein kinase (ROCK). A ROCK inhibitor, fasudil, restored thrombopoiesis in mice with thrombocytopenic induced by the suppression of proteasome activity resulted from tamoxifen usage. The findings revealed the important role of RhoA and ROCK signaling in mediating proplatelet formation by megakaryocutes, and made them potential targets for treatment of bortezomib-induced thrombocytopenia in multiple myeloma patients.

 

Reference:
J Clin Invest. 2014 Sep;124(9):3757-66. 

Related Products

Cat.No. Product Name Information
S1013 Bortezomib Bortezomib is a potent 20S proteasome inhibitor with Ki of 0.6 nM. It exhibits favorable selectivity towards tumor cells over normal cells. Bortezomib (PS-341) inhibits NF-κB and induces ERK phosphorylation to suppress cathepsin B and inhibit the catalytic process of autophagy in ovarian cancer and other solid tumors.
S1573 Fasudil HCl Fasudil HCl, a potent and selective inhibitor of Rho kinase, displays less potent inhibiton over PKA, PKG, PKC and MLCK with Ki of 1.6, 1.6, 3.3, and 36 μM in cell-free assays, respectively. Fasudil is also a calcium channel blocker.

Related Targets

Autophagy ROCK Proteasome