Sanchez-Gonzalez Blanca, Yang Hui, Bueso-Ramos Carlos, Hoshino Koyu, Quintas-Cardama Alfonso, Richon Victoria M, Garcia-Manero Guillermo
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Blood. 2006 Aug 15;108(4):1174-82. doi: 10.1182/blood-2005-09-008086. Epub 2006 May 4.
We studied the cellular and molecular effects of the combination of an anthracycline with 2 different histone deacetylase inhibitors (HDACIs): vorinostat (suberoylanilide hydroxamic acid) and valproic acid (VPA). The 10% inhibitory concentration (IC(10)) of idarubicin was 0.5 nM in MOLT4 and 1.5 nM in HL60 cells. Concentrations above 0.675 microM of vorinostat resulted in at least 80% loss of cell viability in both cell lines. Concentrations of 1.5 to 3 mM of VPA induced 50% to 60% loss in viability in HL60 and 80% in MOLT4 cells. The combination of idarubicin with vorinostat at 0.075 microM or VPA at 0.25 mM resulted in at least an additive loss of cell viability in both lines. Vorinostat (0.35 microM) and VPA (0.25 mM) in combination with idarubicin (0.5 nM) resulted in a significant increase in apoptotic cells in MOLT4 cells. The combination resulted in an increase in histone H3 and H4 acetylation at 24 hours, phosphorylated H2AX, as well as in the induction of p21(CIP1) mRNA. No effect on cell cycle transition was observed. Of importance, the cellular and molecular effects observed were independent of the sequence used. In summary, the combination of an anthracycline with an HDACI should have significant clinical activity in patients with leukemia.
我们研究了一种蒽环类药物与两种不同组蛋白去乙酰化酶抑制剂（HDACIs）：伏立诺他（辛二酰苯胺异羟肟酸）和丙戊酸（VPA）联合使用的细胞和分子效应。伊达比星在MOLT4细胞中的10%抑制浓度（IC(10)）为0.5 nM，在HL60细胞中为1.5 nM。伏立诺他浓度高于0.675 microM时，两种细胞系的细胞活力至少丧失80%。1.5至3 mM的VPA浓度可导致HL60细胞活力丧失50%至60%，MOLT4细胞中丧失80%。伊达比星与0.075 microM的伏立诺他或0.25 mM的VPA联合使用，在两种细胞系中均导致至少相加的细胞活力丧失。伏立诺他（0.35 microM）和VPA（0.25 mM）与伊达比星（0.5 nM）联合使用，导致MOLT4细胞中凋亡细胞显著增加。联合使用导致24小时时组蛋白H3和H4乙酰化增加、磷酸化H2AX增加，以及p21(CIP1) mRNA的诱导。未观察到对细胞周期转换的影响。重要的是，观察到的细胞和分子效应与所用顺序无关。总之，蒽环类药物与HDACI联合使用对白血病患者应具有显著的临床活性。
