The Effect of a Histone Deacetylase Inhibitor (AR-42) and Zoledronic Acid on Adult T-Cell Leukemia/Lymphoma Osteolytic Bone Tumors

SIMPLE SUMMARY: Adult T-cell leukemia (ATL) Leukemia is an aggressive, peripheral blood (T-cell) neoplasm associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Recent studies have implicated dysregulated histone deacetylases in ATL pathogenesis. ATL modulates the bone microenvironment of patients and activates osteoclasts (bone resorbing cells) that cause severe bone loss. The objective of this study was to assess the individual and dual effects of AR-42 (HDACi) and zoledronic acid (Zol) on the growth of ATL cells in vitro and in vivo. AR-42 and Zol reduced the viability of ATL cells in vitro. Additionally, Zol and Zol/AR-42 decreased ATL tumor growth and halted osteolysis in bone tumor xenografts in immunodeficient mice in vivo. Our study suggests that dual targeting of ATL cells (using HDACi) and bone osteoclasts (using bisphosphonates) may be exploited as a valuable approach to reduce bone tumor burden and improve the life quality of ATL patients. ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is an intractable disease affecting nearly 4% of Human T-cell Leukemia Virus Type 1 (HTLV-1) carriers. Acute ATL has a unique interaction with bone characterized by aggressive bone invasion, osteolytic metastasis, and hypercalcemia. We hypothesized that dual tumor and bone-targeted therapies would decrease tumor burden in bone, the incidence of metastasis, and ATL-associated osteolysis. Our goal was to evaluate dual targeting of both ATL bone tumors and the bone microenvironment using an anti-tumor HDACi (AR-42) and an osteoclast inhibitor (zoledronic acid, Zol), alone and in combination. Our results showed that AR-42, Zol, and AR-42/Zol significantly decreased the viability of multiple ATL cancer cell lines in vitro. Zol and AR-42/Zol decreased tumor growth in vivo. Zol ± AR-42 significantly decreased ATL-associated bone resorption and promoted new bone formation. AR-42-treated ATL cells had increased mRNA levels of PTHrP, ENPP2 (autotaxin) and MIP-1α, and TAX viral gene expression. AR-42 alone had no significant effect on tumor growth or osteolysis in mice. These findings indicate that Zol adjuvant therapy has the potential to reduce growth of ATL in bone and its associated osteolysis.