The effect of calcium channel blockers on the outcome of acute myeloid leukemia

Chae, Young Kwang; Dimou, Anastasios; Pierce, Sherry; Kantarjian, Hagop M.; Andreeff, Michael

doi:10.3109/10428194.2014.901513

Cited by 18 publications

(11 citation statements)

References 30 publications

(28 reference statements)

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“…A lot of GO terms detected for TSS down methylated genes were connected to calcium ion transport and sequestering (for example: GO:0051283, GO:0051282, GO:0060402, GO:0070588, GO:0060401, GO:0010857, GO:0009931 ) which is consistent with literature findings where the alteration in calcium processes in AML is very commonly reported [ 40 ]. The second group of GO terms detected for TSS down methylated genes are processes concerning immune system, which is concordant with AML as an immune system disease.…”

Section: Resultssupporting

confidence: 89%

Region-Specific Methylation Profiling in Acute Myeloid Leukemia

Cecotka

Polańska

2018

Interdiscip Sci Comput Life Sci

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Alteration of DNA methylation level in cancer diseases leads to deregulation of gene expression—silencing of tumor suppressor genes and enhancing of protooncogenes. There are several tools devoted to the problem of identification of CpG sites' demethylation but majority of them focuses on single site level and does not allow for quantification of region methylation changes. The aim was to create an adaptive algorithm supporting detection of differentially methylated CpG sites and genomic regions specific for acute myeloid leukemia. Knowledge on AML methylation fingerprint helps in better understanding the epigenetics of leukemogenesis. Proposed algorithm is data driven and does not use predefined quantification thresholds. Gaussian mixture modeling supports classification of CpG sites to several levels of demethylation. p value integration allows for translation from single site demethylation to the demethylation of gene promoter and body regions. Methylation profiles of healthy controls and AML patients were examined (GEO:GSE63409). The differences in whole genome methylation profiles were observed. The methylation profile differs significantly among genomic regions. The lowest methylation level was observed for promoter regions, while sites from intergenic regions were by average higher methylated. The observed number of AML related down methylated sites has not substantially exceeded the expected number by chance. Intergenic regions were characterized by the highest percentage of AML up methylated sites. Methylation enhancement/diminution is the most frequent for intergenic region while methylation compensation (positive or negative) is specific for promoter regions. Functional analysis performed for AML down methylated or extreme high up methylated genes showed strong connection to the leukemic processes.Electronic supplementary materialThe online version of this article (10.1007/s12539-018-0285-4) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 89%

Region-Specific Methylation Profiling in Acute Myeloid Leukemia

Cecotka

Polańska

2018

Interdiscip Sci Comput Life Sci

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“…We further excluded four studies (Fletcher et al, 1993;Shah et al, 2011;Springate et al, 2015;Wong et al, 2015) that compared the effect of β blockers with that of other antihypertensive medications. Finally, 20 cohort studies (Hole et al, 1993;Powe et al, 2010;Barron et al, 2011;Lemeshow et al, 2011;Melhem-Bertrandt et al, 2011;Diaz et al, 2012;Yusuf et al, 2012;Aydiner et al, 2013;Botteri et al, 2013;Holmes et al, 2013aHolmes et al, , 2013bJohannesdottir et al, 2013;Livingstone et al, 2013;Wang et al, 2013;Assayag et al, 2014;Cata et al, 2014;Chae et al, 2014;De Giorgi et al, 2014;Grytli et al, 2014;Jansen et al, 2014) and four case-control studies Hicks et al, 2013;McCourt et al, 2014) involving 76 538 participants were selected for metaanalysis. Table 1 shows the characteristics of the studies included.…”

Section: Resultsmentioning

confidence: 99%

β-Blocker use and mortality in cancer patients: systematic review and meta-analysis of observational studies

Zhong

Yu²,

Zhang³

et al. 2016

European Journal of Cancer Prevention

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A number of epidemiologic studies have attempted to link the use of β blockers to mortality in cancer patients, but their findings have been inconclusive. A meta-analysis was carried out to derive a more precise estimation. Relevant studies were identified by searching PubMed and EMBASE to May 2015. We calculated the summary hazard ratios (HRs) and 95% confidence intervals (CIs) using random-effects models. Twenty cohort studies and four case-control studies involving 76 538 participants were included. The overall results showed that patients who used β blockers after diagnosis had an HR of 0.89 (95% CI 0.81-0.98) for all-cause mortality compared with nonusers. Those who used β blockers after diagnosis (vs. nonusers) had an HR of 0.89 (95% CI 0.79-0.99) for cancer-specific mortality. Prediagnostic use of β blockers showed no beneficial effect on all-cause mortality or cancer-specific mortality. Stratifying by cancer type, only breast cancer patients who used β blockers after diagnosis had a prolonged overall survival. A linear but nonsignificant trend was found between postdiagnostic β-blocker use and mortality of cancer patients. In conclusion, the average effect of β-blocker use after diagnosis but not before diagnosis is beneficial for the survival of cancer patients.

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“…A range of drug candidates (including tyrosine kinase inhibitors, farnesyltransferase inhibitors, histone deacetylase inhibitors, multidrug-resistance inhibitors, and deoxyadenosine analogues) is now in clinical development [ 18 , 88 ]. Interestingly, treatment with Ca 2+ channel blockers (such as amlodipine or diltiazem) is predictive of worse survival in patients with AML [ 89 ]. When administered to mice, NGR-peptide-1 does not induce apparent toxicity and is not immunogenic [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

The CNGRC-GG-D(KLAKLAK)2 peptide induces a caspase-independent, Ca2+-dependent death in human leukemic myeloid cells by targeting surface aminopeptidase N/CD13

et al. 2015

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The CD13 antigen's binding site for the Asn-Gly-Arg (NGR) motif enables NGR-containing chemotherapeutic drugs to be delivered to CD13-positive tumours. Human CD13-positive acute myeloid leukemia (AML) cells proliferate abnormally and escape death. Here, we show that the CNGRC-GG-D(KLAKLAK)2 peptide induces death in AML cell lines (U937, THP-1, NB4, HL-60) and primary blood cells from AML patients. Cell death was characterized as a caspase-independent mechanism, without DNA fragmentation, but phosphatidylserine externalization and membrane disruption. Our results demonstrate in U937 cells that (i) the NGR-peptide triggers the loss of mitochondrial potential(ΔΨm) and generates superoxide anion (O2−), (ii) N-acetyl-L-cysteine (NAC) and extra/intracellular Ca2+ chelators (BAPTA) prevent both O2− production and cell death, (iii) the Ca2+-channel blocker nifedipine prevents cell death (indicating that Ca2+ influx is the initial death trigger), and (iv) BAPTA, but not NAC, prevents ΔΨm loss (suggesting O2− is a mitochondrial downstream effector). AML cell lines and primary blasts responding to the lethal action of NGR-peptide express promatrix metalloproteinase-12 (proMMP-12) and its substrate progranulin (an 88 kDa cell survival factor). A cell-free assay highlighted proMMP-12 activation by O2−. Accordingly, NGR-peptide's downregulation of 88 kDa progranulin protein was prevented by BAPTA and NAC. Conversely, AML blast resistance to NGR-peptide is associated with the expression of a distinct, 105 kDa progranulin isoform. These results indicate that CNGRC-GG-D(KLAKLAK)2 induces death in AML cells through the Ca2+-mitochondria-O2.-pathway, and support the link between proMMP-12 activation and progranulin cleavage during cell death. Our findings may have implications for the understanding of tumour biology and treatment.

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The effect of calcium channel blockers on the outcome of acute myeloid leukemia

Cited by 18 publications

References 30 publications

Region-Specific Methylation Profiling in Acute Myeloid Leukemia

Region-Specific Methylation Profiling in Acute Myeloid Leukemia

β-Blocker use and mortality in cancer patients: systematic review and meta-analysis of observational studies

The CNGRC-GG-D(KLAKLAK)2 peptide induces a caspase-independent, Ca2+-dependent death in human leukemic myeloid cells by targeting surface aminopeptidase N/CD13

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