Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia
Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia
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DOI：
10.1371/journal.pone.0008147
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发表时间：
2009-12-07
期刊：
影响因子：
3.7
通讯作者：
Bunce, Chris M.
中科院分区：
文献类型：
--
作者：
Khanim, Farhat L.;Hayden, Rachel E.;Bunce, Chris M.
背景：大多数急性髓性白血病（AML）患者年龄超过60岁。在目前的治疗方案下，这些患者以及那些复发的年轻患者的生存率仍然很低，迫切需要新的治疗方法。特别是，具有抗白血病活性的疗法，但与传统的化疗不同，不损害正常的haemopoiesis.Principal Findings：在这里，我们证明了有效的抗白血病活性的组合的调脂药物苯扎贝特（BEZ）和性激素醋酸甲羟孕酮（MPA）对AML细胞系和原代AML细胞。BEZ和MPA（B/M）的联合活性集中于前列腺素D-2（PGD（2））合成增加和代谢减少，导致下游高生物活性、抗肿瘤前列腺素15-脱氧Delta（12，14）PGJ（2）（15 d-PGJ（2））水平升高。BEZ通过产生活性氧（ROS）和激活脂质过氧化途径增加PGD（2）合成。MPA通过抑制醛酮还原酶AKR 1C 3的PGD（2）11 β-酮还原酶活性（将PGD（2）代谢为9 α 11 β-PGF（2 α）），将前列腺素合成导向15 d-PGJ（2）。B/M处理导致AML细胞系和原代AML细胞的生长停滞、细胞凋亡和细胞分化，这些作用通过15 d-PGJ处理重现（2）。重要的是，B/M的作用对正常成人髓系祖细胞的存活几乎没有影响。意义：总的来说，我们的数据表明，B/M治疗AML细胞增加了ROS，并传递了15 d-PGJ的抑制作用（2）。这些观察结果为B/M在老年和复发AML中的重新部署提供了机制依据。
Background: The majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis.Principal Findings: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D-2 (PGD(2)) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Delta(12,14) PGJ(2) (15d-PGJ(2)). BEZ increased PGD(2) synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ(2) by inhibiting the PGD(2) 11 beta-ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD(2) to 9 alpha 11 beta-PGF(2 alpha). B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ(2). Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors.Significance: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the antineoplastic actions of 15d-PGJ(2). These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML.