Growth inhibition and proapoptotic activity induction by IIF and valproic acid on RA-resistant leukemia cells.
Growth inhibition and proapoptotic activity induction by IIF and valproic acid on RA-resistant leukemia cells.
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发表时间：
2008
影响因子：
2
通讯作者：
G. Bartolini;M. Orlandi;A. Papi;K. Ammar;R. Tonelli;M. Franzoni;A. Pession;P. Rocchi;A. Ferreri-A.-Fer
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作者：
G. Bartolini;M. Orlandi;A. Papi;K. Ammar;R. Tonelli;M. Franzoni;A. Pession;P. Rocchi;A. Ferreri-A.-Fer
全反式维甲酸(RA)可诱导高比例的急性早幼粒细胞白血病(APL)患者完全缓解。然而，这些患者中的大多数都会出现RA耐药和复发。为了模拟临床治疗白血病的条件，建立了稳定耐RA的人早幼粒细胞白血病细胞系HL60(HL60-R)的亚克隆，研究了维甲酸IIF(6-OH-11-O-羟基苯三烯)与RA的抗增殖和促凋亡作用。此外，还评价了组蛋白脱乙酰酶(HDAC)活性抑制剂丙戊酸(VPA)是否能增强HL60-R细胞对维甲酸的敏感性。最后观察IIF对多药耐药相关蛋白1(MRP1)和P糖蛋白(P Gp)表达的影响。结果发现，IIF强烈抑制细胞增殖(通过生长曲线测定)和诱导细胞凋亡(通过DNA片段化和Annexin V检测)，而RA几乎没有作用。在IIF中加入VPA可增强IIF单独的抗增殖作用，并增加细胞凋亡；VPA与RA联合使用可使细胞生长停滞。此外，Western blotting显示，IIF可降低跨膜转运蛋白的表达，尤其是P-gp的表达。我们的结果表明，IIF可能有助于控制RA耐药白血病细胞的增殖，特别是与HDAC抑制剂(如VPA)联合使用时。
All-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). Nevertheless, most of these patients develop RA resistance and relapse. In an attemp to mimic clinical conditions for the treatment of leukemia, a stably RA-resistant subclone of the human promyelocytic leukemia cell line HL60 (HL60-R) was developed to study the antiproliferative and proapoptotic effect of the retinoid IIF (6-OH-11-O-hydroxyphenantrene) in comparison with RA. Moreover whether the inhibitor of histone deacetylase (HDAC) activity, valproic acid (VPA), could enhance sensitivity to retinoids in HL60-R cells was evaluated. Finally, the effect of IIF on the expression of multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (P-gp) was evaluated. It was found that IIF strongly suppressed cell proliferation (as measured by growth curves) and induced apoptosis (as measured by DNA fragmentation and Annexin V detection assays), while RA was practically ineffective. The addition of VPA to IIF accentuated the antiproliferative effect of IIF alone and increased apoptosis; the combination of VPA with RA allowed growth arrest. Moreover IIF caused a reduction of transmembrane transporter expression, particularly of P-gp, as shown by Western blotting. Our results suggest that IIF may be useful in controlling the proliferation of RA-resistant leukemia cells, especially in combination with an HDAC inhibitor, such as VPA.