Retinoid arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

• Published in: Leukemia Vol. 19; no. 10; pp. 1806 - 1811
• Main Authors: TARKANYI, I, DUDOGNON, C, HILLION, J, PENDINO, F, LANOTTE, M, ARADI, J, SEGAL-BENDIRDJIAN, E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.10.2005; Nature Publishing Group
• Subjects: Acute promyeloid leukemia; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Arsenic; Arsenic trioxide; Arsenicals - administration & dosage; Biological and medical sciences; Cell death; Cell differentiation; Combination therapy; Combinatorial analysis; Differentiation (biology); DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm; Hematologic and hematopoietic diseases; Humans; Leukemia; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - enzymology; Leukemia, Promyelocytic, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Neoplasm Proteins - metabolism; Oncogene Proteins, Fusion - metabolism; Oxides - administration & dosage; Patients; Promyeloid leukemia; Remission Induction; Retinoic acid; Side effects; Synergism; Synergistic effect; Telomerase; Telomerase - metabolism; Telomere - metabolism; Telomeres; Therapy; Tretinoin - administration & dosage; Tumor Cells, Cultured; Antineoplastic agent; Promyelocytic leukemia; Hematology; Enzyme; Acute; Promyelocyte; Retinoid; Arsenic trioxide; Malignant hemopathy; Induction treatment; Cell death; Combined treatment; ATRA; Telomerase; APL; Apoptosis; Tretinoin
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2403923

Acute promyelocytic leukemia (APL) is efficiently treated with a cell differentiation inducer, all-trans retinoic acid (ATRA). However, a significant percentage of patients still develop resistance to this treatment. Recently, arsenic trioxide (As2O3), alone or in combination with ATRA, has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. Previous investigations restricted the mechanism of this synergism to the modulation and/or degradation of PML-RARalpha oncoprotein through distinct pathways. In this study, using several ATRA maturation-resistant APL cell lines, we demonstrate in vitro that the success of ATRA/As2O3 treatment in APL pathology can be explained, at least in part, by a synergistic effect of these two drugs in triggering downregulation of telomerase efficient enough to cause telomere shortening and subsequent cell death. Such long-term low-dose combinatorial therapy strategies, developed also to avoid acute side effects, reinforce the notion that the antitelomerase strategy, based on a combination of active agents, should now be considered and evaluated not only in APL but also in other malignancies.