Ubiquinone does not rescue acute myeloid leukemia cells from growth inhibition by statins

Burke, Lillian; Lewis, Lionel D.; Perez, Raymond P.

doi:10.1038/sj.leu.2402695

Cited by 3 publications

(2 citation statements)

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“…The second correlated expression profile with statin use was a signature of improved prognosis among pediatric acute myeloid leukemia patients (AML). In tumor cell lines, statins were shown to inhibit the growth of acute myeloid leukemia cells [ 51 ], to synergistically increase the killing of the human erythroleukemia cell line K562 by the chemotherapeutic agent cytosine arabinoside [ 52 ], and to inhibit the proliferation and cytotoxicity of a human leukemic natural killer cell line [ 53 ]. The third correlated signature with statin use was a signature of Parkinson’s disease (PD) patients when compared with healthy or neurodegenerative disease controls[ 54 ].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Statins on Blood Gene Expression in COPD

et al. 2015

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BackgroundCOPD is currently the fourth leading cause of death worldwide. Statins are lipid lowering agents with documented cardiovascular benefits. Observational studies have shown that statins may have a beneficial role in COPD. The impact of statins on blood gene expression from COPD patients is largely unknown.ObjectiveIdentify blood gene signature associated with statin use in COPD patients, and the pathways underpinning this signature that could explain any potential benefits in COPD.MethodsWhole blood gene expression was measured on 168 statin users and 451 non-users from the ECLIPSE study using the Affymetrix Human Gene 1.1 ST microarray chips. Factor Analysis for Robust Microarray Summarization (FARMS) was used to process the expression data. Differential gene expression analysis was undertaken using the Linear Models for Microarray data (Limma) package adjusting for propensity score and surrogate variables. Similarity of the expression signal with published gene expression profiles was performed in ProfileChaser.Results25 genes were differentially expressed between statin users and non-users at an FDR of 10%, including LDLR, CXCR2, SC4MOL, FAM108A1, IFI35, FRYL, ABCG1, MYLIP, and DHCR24. The 25 genes were significantly enriched in cholesterol homeostasis and metabolism pathways. The resulting gene signature showed correlation with Huntington’s disease, Parkinson’s disease and acute myeloid leukemia gene signatures.ConclusionThe blood gene signature of statins’ use in COPD patients was enriched in cholesterol homeostasis pathways. Further studies are needed to delineate the role of these pathways in lung biology.

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Section: Discussionmentioning

confidence: 99%

The Effect of Statins on Blood Gene Expression in COPD

et al. 2015

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“…In addition, statins may have potent anti-tumor properties [11,12]. Investigations using tumor cell lines noted that statins inhibited the growth of acute myeloid leukemia cells [13], induced apoptosis in IM-9 human lymphoblasts [14], and increased the killing of the human erythroleukemia cell line K562 by a commonly used chemotherapeutic agent [15]. …”

Section: Introductionmentioning

confidence: 99%

Statins inhibit proliferation and cytotoxicity of a human leukemic natural killer cell line

et al. 2013

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BackgroundNatural killer cells comprise the body’s first line of defense against virus-infected cells. As is true of all lymphocytes, natural killer cell malignancies can develop, however natural killer cell leukemias can be very difficult to treat due to their intrinsic resistance to chemotherapeutic agents. With the recent understanding that statin drugs may have anti-cancer properties, our investigations have focused on the ability of statins to inhibit the growth and cytotoxicity of the YT-INDY natural killer cell leukemia cell line.ResultsOur findings indicate that several statin compounds can inhibit YT-INDY proliferation disrupt cell cycle progression and abrogate natural killer cell cytotoxicity. Since natural killer cell leukemia cytotoxicity may play a role in the pulmonary damage seen in these patients, this is an important finding. Cytotoxicity, proliferation and cell cycle progression could be restored by the addition of mevalonate, signifying that the statin effects are brought about through HMG CoA reductase inhibition. The mevalonate pathway intermediate geranylgeranyl pyrophosphate, but not other intermediates in the mevalonate pathway, partially reversed statin-induced inhibition of YT-INDY proliferation and cytotoxicity. These results suggest that blockage of products made in the latter part of the mevalonate pathway may account for the observed inhibitory effects on YT-INDY proliferation and cytotoxicity. However, geranylgeranyl pyrophosphate could not reverse the statin-induced inhibition of the cell cycle.ConclusionsThese results suggest that the statin drugs should be investigated as a potential therapeutic strategy for human natural killer cell leukemias possibly in combination with chemotherapeutic agents.

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Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies

Holstein

Knapp

Clamon

et al. 2005

Cancer Chemother Pharmacol

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Lovastatin, an inhibitor of the rate-limiting enzyme in the cholesterol biosynthetic pathway, hydroxymethylglutaryl coenzyme A reductase, has shown interesting antiproliferative activities in cell culture and in animal models of cancer. The goal of the current study is to determine whether lovastatin bioactivity levels, in a range equivalent to those used in in vitro and preclinical studies, can be safely achieved in human subjects. Here we present the findings from a dose-escalating trial of lovastatin in subjects with advanced malignancies. Lovastatin was administered every 6 h for 96 h in 4-week cycles in doses ranging from 10 mg/m2 to 415 mg/m2. Peak plasma lovastatin bioactivity levels of 0.06-12.3 microM were achieved in a dose-independent manner. Cholesterol levels decreased during treatment and normalized during the rest period. A dose-limiting toxicity was not reached and there were no clinically significant increases in creatine phosphokinase or serum hepatic aminotransferases levels. No antitumor responses were observed. These results demonstrate that high doses of lovastatin, given every 4 h for 96 h, are well-tolerated and in select cases, bioactivity levels in the range necessary for antiproliferative activity were achieved.

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Ubiquinone does not rescue acute myeloid leukemia cells from growth inhibition by statins

Cited by 3 publications

References 5 publications

The Effect of Statins on Blood Gene Expression in COPD

The Effect of Statins on Blood Gene Expression in COPD

Statins inhibit proliferation and cytotoxicity of a human leukemic natural killer cell line

Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies

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