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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1546-1554.
Prepublished online as a Blood First Edition Paper on October 13, 2005; DOI 10.1182/blood-2004-10-4126.
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Submitted October 27, 2004
Accepted September 5, 2005
Upregulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells
Yoko Tabe, Marina Konopleva, Rooha Contractor, Mark Munsell, Wendy D Schober, Linhua Jin, Yuko Tsutsumi-Ishii, Isao Nagaoka, Jun Igari, and Michael Andreeff*
Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA; Departments of Clinical Pathology and Biochemistry, Juntendo University of Medicine, Tokyo, Japan
Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Department of Biostatistics and Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Departments of Clinical Pathology and Biochemistry, Juntendo University of Medicine, Tokyo, Japan
* Corresponding author; email: mandreef{at}mdanderson.org.
The multidrug resistance (MDR1) gene product P-glycoprotein (P-gp) is frequently implicated in cross-resistance of tumors to chemotherapeutic drugs. In contrast, acute promyelocytic leukemia (APL) cells do not express MDR1 and are highly sensitive to anthracyclines. The combination of ATRA and the novel histone deacetylase (HDAC) inhibitor depsipeptide (FK228), induced P-gp expression and prevented growth inhibition and apoptosis in NB4 APL cells subsequently exposed to Doxorubicin (DOX). ATRA/FK228 treatment after exposure to DOX, however, enhanced apoptosis. Both agents, ATRA or FK228, induced MDR1 mRNA. This effect was significantly enhanced by ATRA/FK228 administered in combination, due in part to increased H4 and H3-Lys9 acetylation of the MDR1 promoter and recruitment of the NF-YA transcription activator to the CCAAT box. Co-treatment with specific P-gp inhibitor PSC833 reversed cytoprotective effects of ATRA/FK228. G1 cell cycle arrest and p21 mRNA induction were also observed in response to ATRA/FK228, which may restrict DOX-induced apoptosis of cells in G2 phase. These results indicate that epigenetic mechanisms involving NF-Y transcription factor recruitment and histone acetylation are activated by ATRA and HDACI, induce MDR1 in APL cells, and point to the critical importance of mechanism-based sequential therapy in future clinical trials that combine HDAC inhibitors, ATRA, and anthracyclines.
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