Ubiquinone does not rescue acute myeloid leukemia cells from growth inhibition by statins.
Ubiquinone does not rescue acute myeloid leukemia cells from growth inhibition by statins.
复制标题
泛醌不能使急性髓性白血病细胞免受他汀类药物的生长抑制。
DOI：
10.1038/sj.leu.2402695
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发表时间：
2003
期刊：
影响因子：
11.4
通讯作者：
Perez,RP
中科院分区：
文献类型：
--
作者：
Burke,LP;Lewis,LD;Perez,RP
The HMG-CoA reductase family of drugs (‘statins’), which includes drugs such as mevastatin, lovastatin and atorvastatin, is widely used to treat patients with hypercholesterolemia. Statins inhibit HMG-CoA reductase, blocking the synthesis of mevalonate, a precursor of cholesterol, ubiquinone, and other intracellular moieties. In vitro, lovastatin causes apoptosis in a number of malignant cell lines and acute myeloid leukemia (AML) cell lines are particularly sensitive to this effect. 1, 2 Serum concentrations of ubiquinone, a coenzyme involved in mitochondrial respiratory metabolism, are decreased in patients taking statin drugs. 3 Oral supplementation with ubiquinone may allow patients to tolerate higher doses of statins as may be required for the treatment of AML and other malignancies. 4 Therefore, prior to considering a therapeutic trial of statins for the treatment of leukemia, we wished to determine whether ubiquinone would rescue AML cells from the cytotoxic effects of statins. In preliminary experiments, ubiquinone did not rescue AML cells from the inhibitory effects of statins at either physiologic concentrations (5 μM) or at supraphysiologic concentrations (50 μM), nor did it stimulate cellular proliferation (data not shown). Ubiquinone, 50 μM, did not rescue leukemic cell proliferation from the inhibitory effects of mevastatin in any cell line (see Figure 1). We also examined the effects of ubiquinone on colony formation in bone marrow cultures of cells obtained from patients with AML and myelodysplasia (MDS). As shown in Figure 2a, the number of colonies was decreased in the presence of mevastatin. Ubiquinone did not rescue primary leukemic cells from the inhibitory effects of mevastatin on colony formation. Also, there was no evidence that ubiquinone alone stimulated leukemic cells as it did not increase the numbers of colonies present in cultures without mevastatin. The mechanism of the anti-proliferative effect of statins is not known. One hypothesis is that cell viability is affected by inhibition of prenylation, a post-translational modification of proteins important for activity of intracellular signaling proteins such as Ras. All statins inhibit the production of mevalonate by HMG-CoA reductase, thereby decreasing the production of all synthetic products downstream from mevalonate. In addition to cholesterol and ubiquinone, these include the prenylation precursors, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These lipophilic moieties are added to Ras and other intracellular proteins during post-translational processing and are required for activity. Xia et al5 reported that, of the mevalonate metabolites, only geranylgeranyl pyrophosphate rescued AML cells from statin-induced apoptosis. Therefore, AML cell viability may be critically sensitive to the prenylation status of one of the intracellular proteins that can be activated by geranylgeranylation. Among these are the Rho, Rac, and Ras-related proteins. As an assay for the prenylation status of these proteins, the prenylation state of Ras was determined using X-1146 to separate the lipophilic (membrane) and aqueous (cytosolic) fractions of cell extracts from K562 cells and MEL cells. Ras was detected by immunoblotting with a pan-Ras antibody (Ras Clone 10; Upstate Biotechnologies, Lake Placid, NY, USA) and detected by chemiluminescence. As shown in Figure 2c, Ras from the untreated cells is found primarily in the membrane fraction, suggesting that prenylation was inhibited. Mevastatin caused an increase in the unprenylated fraction as shown by the increase in the proportion of Ras in the cytosolic fraction. Ubiquinone
