Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy
Identifieur interne : 000370 ( Pmc/Checkpoint ); précédent : 000369; suivant : 000371Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy
Auteurs : Ida Sofie Gr Nnings Ter ; Hanne Kristin Fredly ; Bj Rn Tore Gjertsen ; Kimberley Joanne Hatfield [Norvège] ; Ystein BruserudSource :
- Cells [ 2073-4409 ] ; 2019.
Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (
Url:
DOI: 10.3390/cells8101229
PubMed: 31658693
PubMed Central: 6829623
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy</title><author><name sortKey="Gr Nnings Ter, Ida Sofie" sort="Gr Nnings Ter, Ida Sofie" uniqKey="Gr Nnings Ter I" first="Ida Sofie" last="Gr Nnings Ter">Ida Sofie Gr Nnings Ter</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author><author><name sortKey="Fredly, Hanne Kristin" sort="Fredly, Hanne Kristin" uniqKey="Fredly H" first="Hanne Kristin" last="Fredly">Hanne Kristin Fredly</name><affiliation><nlm:aff id="af3-cells-08-01229">Department of Medicine, Bærum Hospital, 1346 Bærum, Norway;<email>Harfre@vestreviken.no</email></nlm:aff></affiliation></author><author><name sortKey="Gjertsen, Bj Rn Tore" sort="Gjertsen, Bj Rn Tore" uniqKey="Gjertsen B" first="Bj Rn Tore" last="Gjertsen">Bj Rn Tore Gjertsen</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author><author><name sortKey="Hatfield, Kimberley Joanne" sort="Hatfield, Kimberley Joanne" uniqKey="Hatfield K" first="Kimberley Joanne" last="Hatfield">Kimberley Joanne Hatfield</name><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-cells-08-01229">Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen, Norway</nlm:aff><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen</wicri:regionArea><wicri:noRegion>5021 Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Bruserud, Ystein" sort="Bruserud, Ystein" uniqKey="Bruserud " first=" Ystein" last="Bruserud"> Ystein Bruserud</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31658693</idno><idno type="pmc">6829623</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829623</idno><idno type="RBID">PMC:6829623</idno><idno type="doi">10.3390/cells8101229</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000476</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000476</idno><idno type="wicri:Area/Pmc/Curation">000476</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000476</idno><idno type="wicri:Area/Pmc/Checkpoint">000370</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000370</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy</title><author><name sortKey="Gr Nnings Ter, Ida Sofie" sort="Gr Nnings Ter, Ida Sofie" uniqKey="Gr Nnings Ter I" first="Ida Sofie" last="Gr Nnings Ter">Ida Sofie Gr Nnings Ter</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author><author><name sortKey="Fredly, Hanne Kristin" sort="Fredly, Hanne Kristin" uniqKey="Fredly H" first="Hanne Kristin" last="Fredly">Hanne Kristin Fredly</name><affiliation><nlm:aff id="af3-cells-08-01229">Department of Medicine, Bærum Hospital, 1346 Bærum, Norway;<email>Harfre@vestreviken.no</email></nlm:aff></affiliation></author><author><name sortKey="Gjertsen, Bj Rn Tore" sort="Gjertsen, Bj Rn Tore" uniqKey="Gjertsen B" first="Bj Rn Tore" last="Gjertsen">Bj Rn Tore Gjertsen</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author><author><name sortKey="Hatfield, Kimberley Joanne" sort="Hatfield, Kimberley Joanne" uniqKey="Hatfield K" first="Kimberley Joanne" last="Hatfield">Kimberley Joanne Hatfield</name><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-cells-08-01229">Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen, Norway</nlm:aff><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen</wicri:regionArea><wicri:noRegion>5021 Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Bruserud, Ystein" sort="Bruserud, Ystein" uniqKey="Bruserud " first=" Ystein" last="Bruserud"> Ystein Bruserud</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author></analytic><series><title level="j">Cells</title><idno type="eISSN">2073-4409</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (<italic>p</italic> < 0.05, <italic>q</italic> < 0.05), where the majority of altered metabolites belonged to lipid (especially fatty acid metabolism) and amino acid pathways, including several carnitines. These metabolomic effects, and especially the effects on lipid metabolism, may be important for the antileukemic and epigenetic effects of this treatment.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Steffen, B" uniqKey="Steffen B">B. Steffen</name></author><author><name sortKey="Muller Tidow, C" uniqKey="Muller Tidow C">C. Muller-Tidow</name></author><author><name sortKey="Schwable, J" uniqKey="Schwable J">J. Schwable</name></author><author><name sortKey="Berdel, W E" uniqKey="Berdel W">W.E. Berdel</name></author><author><name sortKey="Serve, H" uniqKey="Serve H">H. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cells</journal-id><journal-id journal-id-type="iso-abbrev">Cells</journal-id><journal-id journal-id-type="publisher-id">cells</journal-id><journal-title-group><journal-title>Cells</journal-title></journal-title-group><issn pub-type="epub">2073-4409</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31658693</article-id><article-id pub-id-type="pmc">6829623</article-id><article-id pub-id-type="doi">10.3390/cells8101229</article-id><article-id pub-id-type="publisher-id">cells-08-01229</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Grønningsæter</surname><given-names>Ida Sofie</given-names></name><xref ref-type="aff" rid="af1-cells-08-01229">1</xref><xref ref-type="aff" rid="af2-cells-08-01229">2</xref></contrib><contrib contrib-type="author"><name><surname>Fredly</surname><given-names>Hanne Kristin</given-names></name><xref ref-type="aff" rid="af3-cells-08-01229">3</xref></contrib><contrib contrib-type="author"><name><surname>Gjertsen</surname><given-names>Bjørn Tore</given-names></name><xref ref-type="aff" rid="af1-cells-08-01229">1</xref><xref ref-type="aff" rid="af2-cells-08-01229">2</xref></contrib><contrib contrib-type="author"><name><surname>Hatfield</surname><given-names>Kimberley Joanne</given-names></name><xref ref-type="aff" rid="af2-cells-08-01229">2</xref><xref ref-type="aff" rid="af4-cells-08-01229">4</xref></contrib><contrib contrib-type="author"><name><surname>Bruserud</surname><given-names>Øystein</given-names></name><xref ref-type="aff" rid="af1-cells-08-01229">1</xref><xref ref-type="aff" rid="af2-cells-08-01229">2</xref><xref rid="c1-cells-08-01229" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-cells-08-01229"><label>1</label>Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</aff><aff id="af2-cells-08-01229"><label>2</label>Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></aff><aff id="af3-cells-08-01229"><label>3</label>Department of Medicine, Bærum Hospital, 1346 Bærum, Norway;<email>Harfre@vestreviken.no</email></aff><aff id="af4-cells-08-01229"><label>4</label>Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen, Norway</aff><author-notes><corresp id="c1-cells-08-01229"><label>*</label>Correspondence: <email>oystein.bruserud@helse-bergen.no</email>; Tel.: +47-55973082; Fax: +47-55972950</corresp></author-notes><pub-date pub-type="epub"><day>10</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>10</month><year>2019</year></pub-date><volume>8</volume><issue>10</issue><elocation-id>1229</elocation-id><history><date date-type="received"><day>13</day><month>9</month><year>2019</year></date><date date-type="accepted"><day>07</day><month>10</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (<italic>p</italic> < 0.05, <italic>q</italic> < 0.05), where the majority of altered metabolites belonged to lipid (especially fatty acid metabolism) and amino acid pathways, including several carnitines. These metabolomic effects, and especially the effects on lipid metabolism, may be important for the antileukemic and epigenetic effects of this treatment.</p></abstract><kwd-group><kwd>acute myeloid leukemia</kwd><kwd>all-trans retinoic acid</kwd><kwd>lipids</kwd><kwd>metabolomics</kwd><kwd>valproic acid</kwd></kwd-group></article-meta></front><floats-group><fig id="cells-08-01229-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Significantly altered metabolites when comparing the pretreatment levels of non-responders with rapidly progressive disease versus non-responders with less aggressive disease to antileukemic treatment based on all-trans retinoic acid (ATRA) and valproic acid. The <italic>p</italic>-values, <italic>q</italic>-values and mean fold change values for each metabolite are listed to the right in the figure (ranked by <italic>p</italic>-value), and a fold change >1 indicates that the levels were increased in non-responder patients with very aggressive disease compared to non-responder patients with less aggressive disease. Levels of serum metabolites in non-responders with less aggressive disease are shown in grey, increased levels found in non-responders with aggressive disease are shown in green, while decreased levels in non-responders with aggressive disease are shown in yellow. Color codes for classification of metabolites are explained at the bottom of the figure. Error bars show Standard deviation (SD). * Nicotidamine SD 6.761, ** Spermidine SD 9.051.</p></caption><graphic xlink:href="cells-08-01229-g001"></graphic></fig><fig id="cells-08-01229-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Random forest analysis based on pretreatment serum metabolites when comparing non-responders with rapidly progressive disease versus non-responders with less aggressive disease to antileukemic treatment based on ATRA and valproic acid. The figure shows the 30 top-ranked metabolites from this analysis, which can segregate the two patient groups with a predictive accuracy of 77%. Amino acid and lipid metabolites constituted the majority of the top-ranked metabolites. Color codes for classification of metabolites are shown to the lower right. This analysis included 26 metabolites with a <italic>p</italic>-value < 0.05 (see <xref ref-type="fig" rid="cells-08-01229-f001">Figure 1</xref>; six amino acid metabolites, 16 lipid metabolites, and four other metabolites). Abbreviations; NR-Agg, non-responders aggressive disease (i.e., rapidly progressive); NR-NAgg, non-responders non-aggressive disease.</p></caption><graphic xlink:href="cells-08-01229-g002"></graphic></fig><fig id="cells-08-01229-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Pathway enrichment analysis based on altered metabolites between non-responder patients with rapidly progressive disease (i.e., aggressive disease) versus non-responders with less aggressive disease. This analysis was based on significantly altered metabolites <italic>p</italic> < 0.05 (see <xref ref-type="fig" rid="cells-08-01229-f001">Figure 1</xref>). Only pathways with an enrichment value greater than two and at least two metabolites within each pathway are shown in the figure.</p></caption><graphic xlink:href="cells-08-01229-g003"></graphic></fig><fig id="cells-08-01229-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>The effect of ATRA monotherapy on the serum metabolomic profiles of patients after two days of treatment. Fifty-four metabolites were significantly altered after ATRA treatment (<italic>p <</italic> 0.05). The <italic>p</italic>-values, <italic>q</italic>-values, and mean fold change values for each metabolite are listed to the right in the figure (ranked by <italic>p</italic>-value), and a fold change >1 indicates that the levels were increased in responders compared with non-responders. Pretherapy levels of serum metabolites for the ten patients are presented in grey, increased levels during ATRA treatment are presented in green and decreased levels presented in yellow. Color codes for classification of metabolites are explained at the bottom of the figure. Error bars show Standard deviation (SD). * Androstenediol (3 beta, 17 beta) pre-ATRA SD 3.862, ** Androstenediol (3 beta,17 beta) post-ATRA SD 2.542.</p></caption><graphic xlink:href="cells-08-01229-g004"></graphic></fig><fig id="cells-08-01229-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Identification and classification of serum metabolites that differed significantly when comparing samples taken prior to treatment and after seven days of valproic acid (VPA) therapy. Thirty-six metabolites differed significantly between untreated and VPA-treated samples (<italic>p</italic> < 0.05, Welch′s two sample <italic>t</italic>-test), with <italic>q</italic>-value < 0.1 (the upper 23 metabolites with <italic>q</italic> < 0.05). The <italic>p</italic>-values, <italic>q</italic>-values, and mean fold change for each metabolite are listed to the right in the figure (ranked by <italic>p</italic> and <italic>q</italic>-value), and a fold change >1 indicates that the levels were increased after valproic acid therapy. Metabolite levels found in pretreatment samples are shown in grey, while increased levels during treatment are shown in green (22/36 increased) and decreased levels during treatment are shown in orange (14/36 decreased). Color codes for classification of metabolites are explained at the bottom of the figure. Error bars show Standard deviation (SD). *Adipoylcranitine (C6-DC) SD 6.928 **Suberoylcarnitine (C8-DC) SD 8.50.</p></caption><graphic xlink:href="cells-08-01229-g005"></graphic></fig><fig id="cells-08-01229-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>The effect of 7-day valproic acid (VPA) monotherapy on the serum metabolomic profiles for ten patients (five responders and five non-responders). The random forest analysis was based on the identification of 886 metabolites in pretherapy samples and samples collected after seven days of valproic acid monotherapy. The analysis showed a predictive accuracy of 90% (see the insert table) after exclusion of the four valproic acid metabolites. The top-30 most important metabolites for separation of the two groups are shown in ranking order. Color codes indicate the classification of individual metabolites at the lower right part of the figure.</p></caption><graphic xlink:href="cells-08-01229-g006"></graphic></fig><fig id="cells-08-01229-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Pathway enrichment analysis based on metabolites altered after seven days of valproic acid treatment compared to pretherapy levels. This analysis was based on significant altered metabolites <italic>p</italic> < 0.05 (see <xref ref-type="app" rid="app1-cells-08-01229">Figure S5</xref>), and only pathways with an enrichment value greater than two and at least two metabolites within each pathway are shown. The most significant pathway is shown in red and less significant pathways in light yellow.</p></caption><graphic xlink:href="cells-08-01229-g007"></graphic></fig><table-wrap id="cells-08-01229-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-01229-t001_Table 1</object-id><label>Table 1</label><caption><p>An overview of significantly altered serum metabolites (<italic>p</italic> < 0.05 and <italic>q</italic> < 0.05) after seven-day valproic acid therapy.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Biochemical Name</th><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Classification</th><th colspan="3" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">During VPA Therapy/Pretherapy </th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>p</italic>-Value</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>q</italic>-Value</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fold Change</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>RESPONDERS</bold></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Valproate</td><td align="center" valign="middle" rowspan="1" colspan="1">Drug concentration</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*2-propyl-2-pentenoate (2-ene-valproate)</td><td align="center" valign="middle" rowspan="1" colspan="1">Valproic acid metabolite</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">55.81</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*5-hydroxyvalproate</td><td align="center" valign="middle" rowspan="1" colspan="1">Valproic acid metabolite</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">13.83</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*3-hydroxyvalproate</td><td align="center" valign="middle" rowspan="1" colspan="1">Valproic acid metabolite</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">25.77</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Glucuronide of C8H16O2 (1)*</td><td align="center" valign="middle" rowspan="1" colspan="1">Partially characterized</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">28.34</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Suberoylcarnitine (C8-DC)</td><td align="center" valign="middle" rowspan="1" colspan="1">Fatty acid metabolism, acyl carnitine</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">30.82</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Phenylacetylcarnitine</td><td align="center" valign="middle" rowspan="1" colspan="1">Acetylated peptide</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">17.30</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">*Adipoylcarnitine (C6-DC)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fatty acid metabolism</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">17.06</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*3-methylglutarylcarnitine (2)</td><td align="center" valign="middle" rowspan="1" colspan="1">Leucine/isoleucin/valine metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.18</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Adipate (C6-DC)</td><td align="center" valign="middle" rowspan="1" colspan="1">Fatty acid, dicarboxylate</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0027</td><td align="center" valign="middle" rowspan="1" colspan="1">3.41</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">10-undecenoate (11:1n1)</td><td align="center" valign="middle" rowspan="1" colspan="1">Medium chain fatty acid</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0001</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0043</td><td align="center" valign="middle" rowspan="1" colspan="1">0.49</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Isobutyrylca′rnitine (C4)</td><td align="center" valign="middle" rowspan="1" colspan="1">Leucine/isoleucin/valine metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0001</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0093</td><td align="center" valign="middle" rowspan="1" colspan="1">3.06</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Glucuronide of C14H22O4 (2)</td><td align="center" valign="middle" rowspan="1" colspan="1">Partially characterized</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0003</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0182</td><td align="center" valign="middle" rowspan="1" colspan="1">0.22</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">4-hydroxycinnamate sulfate</td><td align="center" valign="middle" rowspan="1" colspan="1">Tyrosine metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0004</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0259</td><td align="center" valign="middle" rowspan="1" colspan="1">3.00</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Isoeugenol sulfate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Food component, plant</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0005</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0264</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.04</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>NON-RESPONDERS</bold></td><td colspan="4" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Valproate</td><td align="center" valign="middle" rowspan="1" colspan="1">Drug concentration</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*2-propyl-2-pentenoate (2-ene-valproate)</td><td align="center" valign="middle" rowspan="1" colspan="1">Valproic acic metabolite</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">48.32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*5-hydroxyvalproate</td><td align="center" valign="middle" rowspan="1" colspan="1">Valproic acic metabolite</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">31.58</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*3-hydroxyvalproate</td><td align="center" valign="middle" rowspan="1" colspan="1">Valproic acic metabolite</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">93.38</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Glucuronide of C8H16O2 (1)</td><td align="center" valign="middle" rowspan="1" colspan="1">Partially characterized</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">16.16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Suberoylcarnitine (C8-DC)</td><td align="center" valign="middle" rowspan="1" colspan="1">Fatty acid, dicarboxylate</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">12.96</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Adipoylcarnitine (C6-DC)</td><td align="center" valign="middle" rowspan="1" colspan="1">Fatty acid metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">7.34</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Adipate (C6-DC)</td><td align="center" valign="middle" rowspan="1" colspan="1">Fatty acid, dicarboxylate</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0001</td><td align="center" valign="middle" rowspan="1" colspan="1">4.33</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*3-methylglutarylcarnitine (2)</td><td align="center" valign="middle" rowspan="1" colspan="1">Leucine/isoleucin/valine metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0001</td><td align="center" valign="middle" rowspan="1" colspan="1">0.25</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Suberate (C8-DC)</td><td align="center" valign="middle" rowspan="1" colspan="1">Fatty acid, dicarboxylate</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0000</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0022</td><td align="center" valign="middle" rowspan="1" colspan="1">3.43</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">3-carboxy-4-methyl-5-pentyl-2-Furanpropionate (3-Cmpfp)</td><td align="center" valign="middle" rowspan="1" colspan="1">Fatty acid metabolism, dicarboxylate</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0001</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0054</td><td align="center" valign="middle" rowspan="1" colspan="1">0.44</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Hexanoylglycine</td><td align="center" valign="middle" rowspan="1" colspan="1">Fatty acid metabolism, acyl glycine</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0001</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0077</td><td align="center" valign="middle" rowspan="1" colspan="1">3.03</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">3-hydroxyhexanoate</td><td align="center" valign="middle" rowspan="1" colspan="1">Fatty acid metabolism, monohydroxy</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0001</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0100</td><td align="center" valign="middle" rowspan="1" colspan="1">2.03</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Androstenediol (3beta,17beta) disulfate (1)</td><td align="center" valign="middle" rowspan="1" colspan="1">Androgenic steroid</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0003</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0197</td><td align="center" valign="middle" rowspan="1" colspan="1">1.45</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">*Isobutyrylcarnitine (C4)</td><td align="center" valign="middle" rowspan="1" colspan="1">Leucine/isoleucin/valine metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0004</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0208</td><td align="center" valign="middle" rowspan="1" colspan="1">3.15</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Gamma-CEHC</td><td align="center" valign="middle" rowspan="1" colspan="1">Cofactors/vitamins</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0004</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0234</td><td align="center" valign="middle" rowspan="1" colspan="1">1.56</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Isoursodeoxycholate</td><td align="center" valign="middle" rowspan="1" colspan="1">Secondary bile acid metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0005</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0278</td><td align="center" valign="middle" rowspan="1" colspan="1">0.06</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Indoleacetylglutamine</td><td align="center" valign="middle" rowspan="1" colspan="1">Tryptophane metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0006</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0298</td><td align="center" valign="middle" rowspan="1" colspan="1">0.09</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">4-hydroxyphenylacetylglutamine</td><td align="center" valign="middle" rowspan="1" colspan="1">Acetylated peptide</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0008</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0352</td><td align="center" valign="middle" rowspan="1" colspan="1">0.28</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">1-palmitoyl-2-linoleoyl-GPI (16:0/18:2)</td><td align="center" valign="middle" rowspan="1" colspan="1">Phosphatidylinositole</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0008</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0352</td><td align="center" valign="middle" rowspan="1" colspan="1">1.51</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">5-bromotryptophan</td><td align="center" valign="middle" rowspan="1" colspan="1">Tryptophane metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0010</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0387</td><td align="center" valign="middle" rowspan="1" colspan="1">0.49</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">4-allylphenol sulfate</td><td align="center" valign="middle" rowspan="1" colspan="1">Food component, plant</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0010</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0387</td><td align="center" valign="middle" rowspan="1" colspan="1">0.29</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>N</italic>-acetyltyrosine</td><td align="center" valign="middle" rowspan="1" colspan="1">Tyrosine metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0011</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0413</td><td align="center" valign="middle" rowspan="1" colspan="1">2.42</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Trans-4-hydroxyproline</td><td align="center" valign="middle" rowspan="1" colspan="1">Urea cycle. Proline metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0011</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0411</td><td align="center" valign="middle" rowspan="1" colspan="1">1.73</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Galactonate</td><td align="center" valign="middle" rowspan="1" colspan="1">Carbohydrate metabolism</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0012</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0430</td><td align="center" valign="middle" rowspan="1" colspan="1">0.38</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3-aminoisobutyrate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pyrimidine metabolism, thymine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0013</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0433</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.86</td></tr></tbody></table><table-wrap-foot><fn><p>The metabolites are ranked according to their <italic>p</italic>- and <italic>q</italic>-values, and the metabolites that were altered in responders and non-responders to the antileukemic AML-stabilizing therapy are listed separately. Overlapping metabolites between these two groups are marked with *. VPA, valproic acid.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Norvège</li></country></list><tree><noCountry><name sortKey="Bruserud, Ystein" sort="Bruserud, Ystein" uniqKey="Bruserud " first=" Ystein" last="Bruserud"> Ystein Bruserud</name><name sortKey="Fredly, Hanne Kristin" sort="Fredly, Hanne Kristin" uniqKey="Fredly H" first="Hanne Kristin" last="Fredly">Hanne Kristin Fredly</name><name sortKey="Gjertsen, Bj Rn Tore" sort="Gjertsen, Bj Rn Tore" uniqKey="Gjertsen B" first="Bj Rn Tore" last="Gjertsen">Bj Rn Tore Gjertsen</name><name sortKey="Gr Nnings Ter, Ida Sofie" sort="Gr Nnings Ter, Ida Sofie" uniqKey="Gr Nnings Ter I" first="Ida Sofie" last="Gr Nnings Ter">Ida Sofie Gr Nnings Ter</name></noCountry><country name="Norvège"><noRegion><name sortKey="Hatfield, Kimberley Joanne" sort="Hatfield, Kimberley Joanne" uniqKey="Hatfield K" first="Kimberley Joanne" last="Hatfield">Kimberley Joanne Hatfield</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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