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Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma.
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| Zeitschriftentitel: | Blood |
|---|---|
| Personen und Körperschaften: | , , |
| In: | Blood, 114, 2009, 22, S. 1885-1885 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
|
| Schlagwörter: |
| author_facet |
Kikukawa, Yoshitaka Mitsuya, Hiroaki Hata, Hiroyuki Kikukawa, Yoshitaka Mitsuya, Hiroaki Hata, Hiroyuki |
|---|---|
| author |
Kikukawa, Yoshitaka Mitsuya, Hiroaki Hata, Hiroyuki |
| spellingShingle |
Kikukawa, Yoshitaka Mitsuya, Hiroaki Hata, Hiroyuki Blood Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. Cell Biology Hematology Immunology Biochemistry |
| author_sort |
kikukawa, yoshitaka |
| spelling |
Kikukawa, Yoshitaka Mitsuya, Hiroaki Hata, Hiroyuki 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v114.22.1885.1885 <jats:title>Abstract</jats:title> <jats:p>Abstract 1885</jats:p> <jats:p>Poster Board I-908</jats:p> <jats:p>Treatment of MGUS by hesperetin, potentially delaying/blocking the conversion of MGUS to symptomatic myeloma</jats:p> <jats:p>Yoshitaka Kikukawa, Hiroaki Mitsuya, Hiroyuki Hata. Department of Hematology, Kumamoto Unversity Hospital</jats:p> <jats:sec> <jats:title>INTRODUCTION:</jats:title> <jats:p>Although prognosis of multiple myeloma has recently been improved by novel therapeutic regimens, all currently available therapuetics target symptomatic myeloma only. We saw an MGUS patient, experiencing a gradual and continuous decrease of M-protein (IgA-k) from 2,080 mg/dl to 878 mg/dl over 3 years (Fig. 1). History examiantion revealed that the decrease of M-protein initiated when the patient started taking a dietary supplement containing hesperetin-7-glucoside, which is a glycosylated form of hesperetin designated to achive an approximately 104-fold increase of bioavailability comparing to aglycon structure (Hayashibara Biochemical Laboratories, Inc.). Because this compound is eventually metabolized to hesperetin, a possible anti-myeloma effect of hesperetin was examined in vitro.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>Myeloma cells were obtained from myeloma patients and purified with CD138 magnetic beads. Anti-myeloma effects of test compounds on purified myeloma cells or myeloma cell lines were evaluated by WST-8 assay. Apoptosis of myeloma cells was quantified either by annexin V staining or the propidium iodide method, followed by flowcytomerty analysis or by morphological analysis of cytospin slides. Mitochondrial membrane potential was quantified using JC-1 staining Kit (Cayman Chemical Co.) and flow cytometry. Caspase activation and total ubiqutinated protein were analysed by western blotting. Proteasomal chymotrypsin-like activity was measured using 20S Proteasome Assay Kit (Enzo Life Sciences).</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>Hesperetin showed inhibitory effects in a dose-dependent manner on the growth of 4 myeloma cell lines and freshly isolated myeloma cells. Two myeloma cell ines, RPMI8226 and 12PE, were utilized as representative cell lines for further analysis. Hesperetin induced annexin V/PI positive cells, morphological fragmentation of the nucleus of myeloma cells, and activation of caspase-3, 8 and 9, at a concentration around 500 microM, which is clinically achievable with peroral administration of glycosylated hesperetin, suggesting that the observed anti-myeloma effects by hesperitine through apoptotic pathways. Further analysis revealed that hesperetin disrupted mitochondrial membrane potential which leads to release of cytochrome c from mitochondria to cytoplasm as assessed by western blot analysis. Caspase-8 and 9 inhibitors(Z-IETD-fmk and Z-LEHD-fmk, respectively)did not inhibit the hesperetine-induced apoptosis, although they completely inhibited anti-Fas antibody-induced apoptosis, suggesting that the hesperitine-induced apoptosis is not dependent on death receptor signaling. A pan-caspase inhibitor, Z-VAD-fmk, completely blocked the hesperetin-induced apoptosis in 12PE cells, but only partially in RPMI8226 cells, suggesting that hesperetin also mediated caspase-independent apoptosis in RPMI8226 cells. Moreover, western blot showed that hesperetin treatment induced an accumlation of poly-ubiquitine proteins. Analysis of proteasome activity revealed that hesperetin at 500 microM exerted a moderate inhibition of proteasome activity with 72.6% of the inhibition exerted by bortezomib at 40 nM.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUTIONS:</jats:title> <jats:p>This is the first report showing anti-myeloma effect of hesperetin. It showed anti-myeloma effects via caspase-dependent and independent apoptotic pathways and proteasome inhibition activity. Given a fact that hesperitin has been approved by Japanese Goverment as a safe supplementary compound, and the present MGUS case had been taking hesperitin over >3 years without any adverse events, this compound should be well torelated over a long period. If a delay of conversion from either MGUS or asymptomatic myeloma to symptomatic myeloma could be achieved, prognosis of MM could be improve. Based on these findings, an open-label, pilot clinical trial to test the efficacy of hespertin, enroling asymptomatic myeloma patients, has currently been underway (Approved by IRB of Kumamoto Univerisity Hospital).</jats:p> </jats:sec> <jats:sec> <jats:title>Disclosures:</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. Blood |
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10.1182/blood.v114.22.1885.1885 |
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Biologie Medizin Chemie und Pharmazie |
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American Society of Hematology, 2009 |
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American Society of Hematology, 2009 |
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kikukawa2009treatmentofmgusbyhesperetinpotentiallydelayingblockingtheconversionofmgustosymptomaticmyeloma |
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2009 |
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American Society of Hematology |
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49 |
| title |
Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_unstemmed |
Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_full |
Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_fullStr |
Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_full_unstemmed |
Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_short |
Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_sort |
treatment of mgus by hesperetin, potentially delaying/blocking the conversion of mgus to symptomatic myeloma. |
| topic |
Cell Biology Hematology Immunology Biochemistry |
| url |
http://dx.doi.org/10.1182/blood.v114.22.1885.1885 |
| publishDate |
2009 |
| physical |
1885-1885 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Abstract 1885</jats:p>
<jats:p>Poster Board I-908</jats:p>
<jats:p>Treatment of MGUS by hesperetin, potentially delaying/blocking the conversion of MGUS to symptomatic myeloma</jats:p>
<jats:p>Yoshitaka Kikukawa, Hiroaki Mitsuya, Hiroyuki Hata. Department of Hematology, Kumamoto Unversity Hospital</jats:p>
<jats:sec>
<jats:title>INTRODUCTION:</jats:title>
<jats:p>Although prognosis of multiple myeloma has recently been improved by novel therapeutic regimens, all currently available therapuetics target symptomatic myeloma only. We saw an MGUS patient, experiencing a gradual and continuous decrease of M-protein (IgA-k) from 2,080 mg/dl to 878 mg/dl over 3 years (Fig. 1). History examiantion revealed that the decrease of M-protein initiated when the patient started taking a dietary supplement containing hesperetin-7-glucoside, which is a glycosylated form of hesperetin designated to achive an approximately 104-fold increase of bioavailability comparing to aglycon structure (Hayashibara Biochemical Laboratories, Inc.). Because this compound is eventually metabolized to hesperetin, a possible anti-myeloma effect of hesperetin was examined in vitro.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>METHODS:</jats:title>
<jats:p>Myeloma cells were obtained from myeloma patients and purified with CD138 magnetic beads. Anti-myeloma effects of test compounds on purified myeloma cells or myeloma cell lines were evaluated by WST-8 assay. Apoptosis of myeloma cells was quantified either by annexin V staining or the propidium iodide method, followed by flowcytomerty analysis or by morphological analysis of cytospin slides. Mitochondrial membrane potential was quantified using JC-1 staining Kit (Cayman Chemical Co.) and flow cytometry. Caspase activation and total ubiqutinated protein were analysed by western blotting. Proteasomal chymotrypsin-like activity was measured using 20S Proteasome Assay Kit (Enzo Life Sciences).</jats:p>
</jats:sec>
<jats:sec>
<jats:title>RESULTS:</jats:title>
<jats:p>Hesperetin showed inhibitory effects in a dose-dependent manner on the growth of 4 myeloma cell lines and freshly isolated myeloma cells. Two myeloma cell ines, RPMI8226 and 12PE, were utilized as representative cell lines for further analysis. Hesperetin induced annexin V/PI positive cells, morphological fragmentation of the nucleus of myeloma cells, and activation of caspase-3, 8 and 9, at a concentration around 500 microM, which is clinically achievable with peroral administration of glycosylated hesperetin, suggesting that the observed anti-myeloma effects by hesperitine through apoptotic pathways. Further analysis revealed that hesperetin disrupted mitochondrial membrane potential which leads to release of cytochrome c from mitochondria to cytoplasm as assessed by western blot analysis. Caspase-8 and 9 inhibitors(Z-IETD-fmk and Z-LEHD-fmk, respectively)did not inhibit the hesperetine-induced apoptosis, although they completely inhibited anti-Fas antibody-induced apoptosis, suggesting that the hesperitine-induced apoptosis is not dependent on death receptor signaling. A pan-caspase inhibitor, Z-VAD-fmk, completely blocked the hesperetin-induced apoptosis in 12PE cells, but only partially in RPMI8226 cells, suggesting that hesperetin also mediated caspase-independent apoptosis in RPMI8226 cells. Moreover, western blot showed that hesperetin treatment induced an accumlation of poly-ubiquitine proteins. Analysis of proteasome activity revealed that hesperetin at 500 microM exerted a moderate inhibition of proteasome activity with 72.6% of the inhibition exerted by bortezomib at 40 nM.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>CONCLUTIONS:</jats:title>
<jats:p>This is the first report showing anti-myeloma effect of hesperetin. It showed anti-myeloma effects via caspase-dependent and independent apoptotic pathways and proteasome inhibition activity. Given a fact that hesperitin has been approved by Japanese Goverment as a safe supplementary compound, and the present MGUS case had been taking hesperitin over >3 years without any adverse events, this compound should be well torelated over a long period. If a delay of conversion from either MGUS or asymptomatic myeloma to symptomatic myeloma could be achieved, prognosis of MM could be improve. Based on these findings, an open-label, pilot clinical trial to test the efficacy of hespertin, enroling asymptomatic myeloma patients, has currently been underway (Approved by IRB of Kumamoto Univerisity Hospital).</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Disclosures:</jats:title>
<jats:p>No relevant conflicts of interest to declare.</jats:p>
</jats:sec> |
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| author | Kikukawa, Yoshitaka, Mitsuya, Hiroaki, Hata, Hiroyuki |
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| description | <jats:title>Abstract</jats:title> <jats:p>Abstract 1885</jats:p> <jats:p>Poster Board I-908</jats:p> <jats:p>Treatment of MGUS by hesperetin, potentially delaying/blocking the conversion of MGUS to symptomatic myeloma</jats:p> <jats:p>Yoshitaka Kikukawa, Hiroaki Mitsuya, Hiroyuki Hata. Department of Hematology, Kumamoto Unversity Hospital</jats:p> <jats:sec> <jats:title>INTRODUCTION:</jats:title> <jats:p>Although prognosis of multiple myeloma has recently been improved by novel therapeutic regimens, all currently available therapuetics target symptomatic myeloma only. We saw an MGUS patient, experiencing a gradual and continuous decrease of M-protein (IgA-k) from 2,080 mg/dl to 878 mg/dl over 3 years (Fig. 1). History examiantion revealed that the decrease of M-protein initiated when the patient started taking a dietary supplement containing hesperetin-7-glucoside, which is a glycosylated form of hesperetin designated to achive an approximately 104-fold increase of bioavailability comparing to aglycon structure (Hayashibara Biochemical Laboratories, Inc.). Because this compound is eventually metabolized to hesperetin, a possible anti-myeloma effect of hesperetin was examined in vitro.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>Myeloma cells were obtained from myeloma patients and purified with CD138 magnetic beads. Anti-myeloma effects of test compounds on purified myeloma cells or myeloma cell lines were evaluated by WST-8 assay. Apoptosis of myeloma cells was quantified either by annexin V staining or the propidium iodide method, followed by flowcytomerty analysis or by morphological analysis of cytospin slides. Mitochondrial membrane potential was quantified using JC-1 staining Kit (Cayman Chemical Co.) and flow cytometry. Caspase activation and total ubiqutinated protein were analysed by western blotting. Proteasomal chymotrypsin-like activity was measured using 20S Proteasome Assay Kit (Enzo Life Sciences).</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>Hesperetin showed inhibitory effects in a dose-dependent manner on the growth of 4 myeloma cell lines and freshly isolated myeloma cells. Two myeloma cell ines, RPMI8226 and 12PE, were utilized as representative cell lines for further analysis. Hesperetin induced annexin V/PI positive cells, morphological fragmentation of the nucleus of myeloma cells, and activation of caspase-3, 8 and 9, at a concentration around 500 microM, which is clinically achievable with peroral administration of glycosylated hesperetin, suggesting that the observed anti-myeloma effects by hesperitine through apoptotic pathways. Further analysis revealed that hesperetin disrupted mitochondrial membrane potential which leads to release of cytochrome c from mitochondria to cytoplasm as assessed by western blot analysis. Caspase-8 and 9 inhibitors(Z-IETD-fmk and Z-LEHD-fmk, respectively)did not inhibit the hesperetine-induced apoptosis, although they completely inhibited anti-Fas antibody-induced apoptosis, suggesting that the hesperitine-induced apoptosis is not dependent on death receptor signaling. A pan-caspase inhibitor, Z-VAD-fmk, completely blocked the hesperetin-induced apoptosis in 12PE cells, but only partially in RPMI8226 cells, suggesting that hesperetin also mediated caspase-independent apoptosis in RPMI8226 cells. Moreover, western blot showed that hesperetin treatment induced an accumlation of poly-ubiquitine proteins. Analysis of proteasome activity revealed that hesperetin at 500 microM exerted a moderate inhibition of proteasome activity with 72.6% of the inhibition exerted by bortezomib at 40 nM.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUTIONS:</jats:title> <jats:p>This is the first report showing anti-myeloma effect of hesperetin. It showed anti-myeloma effects via caspase-dependent and independent apoptotic pathways and proteasome inhibition activity. Given a fact that hesperitin has been approved by Japanese Goverment as a safe supplementary compound, and the present MGUS case had been taking hesperitin over >3 years without any adverse events, this compound should be well torelated over a long period. If a delay of conversion from either MGUS or asymptomatic myeloma to symptomatic myeloma could be achieved, prognosis of MM could be improve. Based on these findings, an open-label, pilot clinical trial to test the efficacy of hespertin, enroling asymptomatic myeloma patients, has currently been underway (Approved by IRB of Kumamoto Univerisity Hospital).</jats:p> </jats:sec> <jats:sec> <jats:title>Disclosures:</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> |
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| imprint | American Society of Hematology, 2009 |
| imprint_str_mv | American Society of Hematology, 2009 |
| institution | DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229 |
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| physical | 1885-1885 |
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| spelling | Kikukawa, Yoshitaka Mitsuya, Hiroaki Hata, Hiroyuki 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v114.22.1885.1885 <jats:title>Abstract</jats:title> <jats:p>Abstract 1885</jats:p> <jats:p>Poster Board I-908</jats:p> <jats:p>Treatment of MGUS by hesperetin, potentially delaying/blocking the conversion of MGUS to symptomatic myeloma</jats:p> <jats:p>Yoshitaka Kikukawa, Hiroaki Mitsuya, Hiroyuki Hata. Department of Hematology, Kumamoto Unversity Hospital</jats:p> <jats:sec> <jats:title>INTRODUCTION:</jats:title> <jats:p>Although prognosis of multiple myeloma has recently been improved by novel therapeutic regimens, all currently available therapuetics target symptomatic myeloma only. We saw an MGUS patient, experiencing a gradual and continuous decrease of M-protein (IgA-k) from 2,080 mg/dl to 878 mg/dl over 3 years (Fig. 1). History examiantion revealed that the decrease of M-protein initiated when the patient started taking a dietary supplement containing hesperetin-7-glucoside, which is a glycosylated form of hesperetin designated to achive an approximately 104-fold increase of bioavailability comparing to aglycon structure (Hayashibara Biochemical Laboratories, Inc.). Because this compound is eventually metabolized to hesperetin, a possible anti-myeloma effect of hesperetin was examined in vitro.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>Myeloma cells were obtained from myeloma patients and purified with CD138 magnetic beads. Anti-myeloma effects of test compounds on purified myeloma cells or myeloma cell lines were evaluated by WST-8 assay. Apoptosis of myeloma cells was quantified either by annexin V staining or the propidium iodide method, followed by flowcytomerty analysis or by morphological analysis of cytospin slides. Mitochondrial membrane potential was quantified using JC-1 staining Kit (Cayman Chemical Co.) and flow cytometry. Caspase activation and total ubiqutinated protein were analysed by western blotting. Proteasomal chymotrypsin-like activity was measured using 20S Proteasome Assay Kit (Enzo Life Sciences).</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>Hesperetin showed inhibitory effects in a dose-dependent manner on the growth of 4 myeloma cell lines and freshly isolated myeloma cells. Two myeloma cell ines, RPMI8226 and 12PE, were utilized as representative cell lines for further analysis. Hesperetin induced annexin V/PI positive cells, morphological fragmentation of the nucleus of myeloma cells, and activation of caspase-3, 8 and 9, at a concentration around 500 microM, which is clinically achievable with peroral administration of glycosylated hesperetin, suggesting that the observed anti-myeloma effects by hesperitine through apoptotic pathways. Further analysis revealed that hesperetin disrupted mitochondrial membrane potential which leads to release of cytochrome c from mitochondria to cytoplasm as assessed by western blot analysis. Caspase-8 and 9 inhibitors(Z-IETD-fmk and Z-LEHD-fmk, respectively)did not inhibit the hesperetine-induced apoptosis, although they completely inhibited anti-Fas antibody-induced apoptosis, suggesting that the hesperitine-induced apoptosis is not dependent on death receptor signaling. A pan-caspase inhibitor, Z-VAD-fmk, completely blocked the hesperetin-induced apoptosis in 12PE cells, but only partially in RPMI8226 cells, suggesting that hesperetin also mediated caspase-independent apoptosis in RPMI8226 cells. Moreover, western blot showed that hesperetin treatment induced an accumlation of poly-ubiquitine proteins. Analysis of proteasome activity revealed that hesperetin at 500 microM exerted a moderate inhibition of proteasome activity with 72.6% of the inhibition exerted by bortezomib at 40 nM.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUTIONS:</jats:title> <jats:p>This is the first report showing anti-myeloma effect of hesperetin. It showed anti-myeloma effects via caspase-dependent and independent apoptotic pathways and proteasome inhibition activity. Given a fact that hesperitin has been approved by Japanese Goverment as a safe supplementary compound, and the present MGUS case had been taking hesperitin over >3 years without any adverse events, this compound should be well torelated over a long period. If a delay of conversion from either MGUS or asymptomatic myeloma to symptomatic myeloma could be achieved, prognosis of MM could be improve. Based on these findings, an open-label, pilot clinical trial to test the efficacy of hespertin, enroling asymptomatic myeloma patients, has currently been underway (Approved by IRB of Kumamoto Univerisity Hospital).</jats:p> </jats:sec> <jats:sec> <jats:title>Disclosures:</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. Blood |
| spellingShingle | Kikukawa, Yoshitaka, Mitsuya, Hiroaki, Hata, Hiroyuki, Blood, Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma., Cell Biology, Hematology, Immunology, Biochemistry |
| title | Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_full | Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_fullStr | Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_full_unstemmed | Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_short | Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| title_sort | treatment of mgus by hesperetin, potentially delaying/blocking the conversion of mgus to symptomatic myeloma. |
| title_unstemmed | Treatment of MGUS by Hesperetin, potentially Delaying/Blocking the Conversion of MGUS to Symptomatic Myeloma. |
| topic | Cell Biology, Hematology, Immunology, Biochemistry |
| url | http://dx.doi.org/10.1182/blood.v114.22.1885.1885 |