in the bone marrow
Researchers say they’ve identified a previously unknown but crucial component of the platelet production process.
And this discovery could help spare multiple myeloma (MM) patients from thrombocytopenia induced by the proteasome inhibitor bortezomib.
The researchers found that proteasome inhibition blocked platelet production in vitro and in vivo.
But fasudil, a Rho kinase inhibitor that is approved for use outside the US, restored platelet counts.
The researchers believe these findings, published in The Journal of Clinical Investigation, could translate to MM patients.
“A low platelet count is a big issue for people who receive bortezomib for this cancer,” said study author Andrew S. Weyrich, PhD, of the University of Utah in Salt Lake City.
“When platelet levels drop too low, it can mean interrupting treatment to allow the platelet count to recover. Fasudil potentially could help keep platelet counts normal while multiple myeloma patients receive bortezomib.”
Dr Weyrich and his colleagues found that bortezomib-induced proteasome inhibition prevented the production of proplatelets in both human and mouse megakaryocytes.
Megakaryocytes isolated from mice lacking PSMC1, an essential subunit of the 26S proteasome, also failed to produce proplatelets.
Further study revealed that the megakaryocytes’ inability to generate platelets was caused by the hyperactivation of RhoA, a protein that helps megakaryocytes maintain the proper shape to produce platelets.
When the researchers inhibited RhoA or its downstream target, Rho-associated protein kinase, in vitro, they were able to restore megakaryocyte proplatelet formation in the setting of proteasome inhibition.
Likewise, the Rho kinase inhibitor fasudil restored platelet counts in adult mice that had thrombocytopenia induced by proteasome inhibition.
Fasudil is approved in Japan and elsewhere to treat cerebral vasospasms, or constricted arteries that arise as a complication of brain aneurysms.
The drug is under investigation in US clinical trials for treating high blood pressure, diabetic macular edema, and other health issues.
There are no trials investigating fasudil’s effects on thrombocytopenia, but Dr Weyrich and his colleagues hope their study might change that. And if clinical trials produce favorable results, fasudil might be made available for MM patients much faster than a new drug.
“If the Food and Drug Administration did approve fasudil for use by multiple myeloma patients, it could, in principle, be moved to the clinic relatively fast in the United States,” Dr Weyrich said.
