multiple myeloma
Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.
The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.
And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.
Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.
First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.
Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.
When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.
The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.
However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.
Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.
In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.
The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.
The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.
