A novel approach to eliminate therapy-resistant mantle cell lymphoma: synergistic effects of Vorinostat with Palbociclib

Abstract

Mantle cell lymphoma (MCL) represents an aggressive B-cell lymphoma with frequent relapse and poor survival. Recently, dysregulated histone-deacetylases (HDACs) and cell cycle CDK-Rb pathway have been shown to be commonly associated with MCL pathogenesis, and are considered promising targets for relapsed-lymphoma therapy. Therefore, we investigated the single agents and combination efficacy of HDACs inhibitor Vorinostat, CDK4/6 dual-inhibitor Palbociclib on MCL cell growth/survival and underlying molecular mechanism(s) using MCL cell lines including therapy-resistant MCL cell lines. Our results showed that both inhibitors as single agents or combined, significantly suppressed the cell growth and induced apoptosis in therapy-resistant and parental MCL lines. In addition, the combination of Vorinostat and Palbociclib significantly inhibited the activation of the key molecules of the CDK4/6-Rb pathway and HDAC activity and subsequently decreased the expression of Cyclin-D1 and Bcl-2. These studies demonstrated the potential for combining these two inhibitors as a novel therapeutic approach in refractory MCL therapy.

Keywords:

• Mantle cell lymphoma
• therapy-resistant MCL
• HDAC inhibitor
• CDK4/CDK6 inhibitor

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2018.1520986

Additional information

Funding

This study was supported by the Department of Genetics, Cell Biology and Anatomy Pilot Grant and Lymphoma Research Foundation, NY, New York and University of Nebraska Medical Center (UNMC), College of Medicine, Dean’s Research Funds. The authors thank the Flow Cytometry Core Facility at UNMC for their help in these studies. The authors also thank the Fred and Pamela Buffett Cancer Center supported Core Facilities.