Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia/lymphoma.

Abstract

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.

• Authors: Hiba El Hajj, Bariaa Khalil, Botheina Ghandour, Rihab Nasr, Sharif Shahine, Akram Ghantous, Rana Abdel-Samad, Ansam Sinjab, Hideki Hasegawa, Mark Jabbour, William W Hall, Ghazi Zaatari, Ghassan Dbaibo, Claudio Pisano, Ali Bazarbachi, Nadine Darwiche
• Journal: Blood (Blood) Vol. 124 Issue 13 Pg. 2072-80 (Sep 25 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 25035162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• 3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid
• Antineoplastic Agents
• Cinnamates
• Gene Products, tax
• Tumor Suppressor Protein p53
• Caspases
• Adamantane

Topics

• Adamantane (administration & dosage, analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Transformed
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cinnamates (administration & dosage, pharmacology)
• DNA Damage
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Products, tax (genetics, metabolism)
• Humans
• Leukemia-Lymphoma, Adult T-Cell (drug therapy, genetics, metabolism, mortality, pathology)
• Leukemic Infiltration
• Mice
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays