adarotene and Leukemic-Infiltration

Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1-positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL.

Topics: Adamantane; Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Cycle Checkpoints; Cell Line, Transformed; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cinnamates; Disease Models, Animal; DNA Damage; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Gene Products, tax; Humans; Leukemia-Lymphoma, Adult T-Cell; Leukemic Infiltration; Mice; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays