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The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo.
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| Zeitschriftentitel: | Blood |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , |
| In: | Blood, 106, 2005, 11, S. 3357-3357 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
|
| Schlagwörter: |
| author_facet |
Burger, Renate Legouill, Steven Tai, Yu-Tzu Shringarpure, Reshma Podar, Klaus Catley, Laurence Tassone, Pierfrancesco Neri, Paola Hideshima, Teru Chauhan, Dharminder Caulder, Eian Vaddi, Kris Neilan, Claire L. Gramatzki, Martin Fridman, Jordan S. Anderson, Kenneth C. Burger, Renate Legouill, Steven Tai, Yu-Tzu Shringarpure, Reshma Podar, Klaus Catley, Laurence Tassone, Pierfrancesco Neri, Paola Hideshima, Teru Chauhan, Dharminder Caulder, Eian Vaddi, Kris Neilan, Claire L. Gramatzki, Martin Fridman, Jordan S. Anderson, Kenneth C. |
|---|---|
| author |
Burger, Renate Legouill, Steven Tai, Yu-Tzu Shringarpure, Reshma Podar, Klaus Catley, Laurence Tassone, Pierfrancesco Neri, Paola Hideshima, Teru Chauhan, Dharminder Caulder, Eian Vaddi, Kris Neilan, Claire L. Gramatzki, Martin Fridman, Jordan S. Anderson, Kenneth C. |
| spellingShingle |
Burger, Renate Legouill, Steven Tai, Yu-Tzu Shringarpure, Reshma Podar, Klaus Catley, Laurence Tassone, Pierfrancesco Neri, Paola Hideshima, Teru Chauhan, Dharminder Caulder, Eian Vaddi, Kris Neilan, Claire L. Gramatzki, Martin Fridman, Jordan S. Anderson, Kenneth C. Blood The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. Cell Biology Hematology Immunology Biochemistry |
| author_sort |
burger, renate |
| spelling |
Burger, Renate Legouill, Steven Tai, Yu-Tzu Shringarpure, Reshma Podar, Klaus Catley, Laurence Tassone, Pierfrancesco Neri, Paola Hideshima, Teru Chauhan, Dharminder Caulder, Eian Vaddi, Kris Neilan, Claire L. Gramatzki, Martin Fridman, Jordan S. Anderson, Kenneth C. 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v106.11.3357.3357 <jats:title>Abstract</jats:title> <jats:p>In multiple myeloma (MM), IL-6 plays an important role for tumor cell growth, survival, and drug resistance. Janus kinases (JAKs) are protein tyrosine kinases and constitutively associated with the gp130 chain of the IL-6 receptor complex. Their activation is one of the first steps in cytokine receptor-mediated signaling and critical for virtually all subsequent downstream signaling cascades. INCB20 is a small-molecule synthetic compound which, in biochemical assays, potently inhibited all four JAKs with IC50 values between 0.3 nM and 1.2 nM (for comparison, IC50 of AG490, another JAK inhibitor, was &gt;50 μM). Consistent with the central role of JAKs in gp130-mediated signaling, INCB20 inhibited IL-6 induced phosphorylation of SHP-2, STAT1, STAT3, ERK1/2, and AKT in MM1.S cells. In contrast, AKT phosphorylation induced by IGF-1 remained unchanged. Evaluation of the cellular efficacy of INCB20 was performed using the IL-6 dependent INA -6 cell line. Growth of INA-6 cells was inhibited in a dose-dependent manner with an IC50 of approx. 0.5 μM, as measured by [3H]-thymidine uptake and an MTS-based assay (for comparison, the cellular IC50 of AG490 was 15–20 μM). This correlated with an increase in the percentage of apoptotic cells, as evaluated by Apo2.7 staining after 48 hours. Importantly, INA-6 growth was inhibited in the presence of bone marrow stromal cells accompanied by a decrease in phospho-STAT3 levels. Furthermore, in a subcutaneous INA-6-SCID model, INCB20 inhibited tumor growth (and phosphorylated STAT3) in a dose-dependent manner. Our studies provide the conceptual basis for the use of JAK inhibitors as a therapeutic approach in MM.</jats:p> The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. Blood |
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10.1182/blood.v106.11.3357.3357 |
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| title |
The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_unstemmed |
The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_full |
The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_fullStr |
The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_full_unstemmed |
The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_short |
The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_sort |
the jak inhibitor incb20 induces antiproliferative and apoptotic effects in human myeloma cells in vitro and in vivo. |
| topic |
Cell Biology Hematology Immunology Biochemistry |
| url |
http://dx.doi.org/10.1182/blood.v106.11.3357.3357 |
| publishDate |
2005 |
| physical |
3357-3357 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>In multiple myeloma (MM), IL-6 plays an important role for tumor cell growth, survival, and drug resistance. Janus kinases (JAKs) are protein tyrosine kinases and constitutively associated with the gp130 chain of the IL-6 receptor complex. Their activation is one of the first steps in cytokine receptor-mediated signaling and critical for virtually all subsequent downstream signaling cascades. INCB20 is a small-molecule synthetic compound which, in biochemical assays, potently inhibited all four JAKs with IC50 values between 0.3 nM and 1.2 nM (for comparison, IC50 of AG490, another JAK inhibitor, was &gt;50 μM). Consistent with the central role of JAKs in gp130-mediated signaling, INCB20 inhibited IL-6 induced phosphorylation of SHP-2, STAT1, STAT3, ERK1/2, and AKT in MM1.S cells. In contrast, AKT phosphorylation induced by IGF-1 remained unchanged. Evaluation of the cellular efficacy of INCB20 was performed using the IL-6 dependent INA -6 cell line. Growth of INA-6 cells was inhibited in a dose-dependent manner with an IC50 of approx. 0.5 μM, as measured by [3H]-thymidine uptake and an MTS-based assay (for comparison, the cellular IC50 of AG490 was 15–20 μM). This correlated with an increase in the percentage of apoptotic cells, as evaluated by Apo2.7 staining after 48 hours. Importantly, INA-6 growth was inhibited in the presence of bone marrow stromal cells accompanied by a decrease in phospho-STAT3 levels. Furthermore, in a subcutaneous INA-6-SCID model, INCB20 inhibited tumor growth (and phosphorylated STAT3) in a dose-dependent manner. Our studies provide the conceptual basis for the use of JAK inhibitors as a therapeutic approach in MM.</jats:p> |
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| author | Burger, Renate, Legouill, Steven, Tai, Yu-Tzu, Shringarpure, Reshma, Podar, Klaus, Catley, Laurence, Tassone, Pierfrancesco, Neri, Paola, Hideshima, Teru, Chauhan, Dharminder, Caulder, Eian, Vaddi, Kris, Neilan, Claire L., Gramatzki, Martin, Fridman, Jordan S., Anderson, Kenneth C. |
| author_facet | Burger, Renate, Legouill, Steven, Tai, Yu-Tzu, Shringarpure, Reshma, Podar, Klaus, Catley, Laurence, Tassone, Pierfrancesco, Neri, Paola, Hideshima, Teru, Chauhan, Dharminder, Caulder, Eian, Vaddi, Kris, Neilan, Claire L., Gramatzki, Martin, Fridman, Jordan S., Anderson, Kenneth C., Burger, Renate, Legouill, Steven, Tai, Yu-Tzu, Shringarpure, Reshma, Podar, Klaus, Catley, Laurence, Tassone, Pierfrancesco, Neri, Paola, Hideshima, Teru, Chauhan, Dharminder, Caulder, Eian, Vaddi, Kris, Neilan, Claire L., Gramatzki, Martin, Fridman, Jordan S., Anderson, Kenneth C. |
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| description | <jats:title>Abstract</jats:title> <jats:p>In multiple myeloma (MM), IL-6 plays an important role for tumor cell growth, survival, and drug resistance. Janus kinases (JAKs) are protein tyrosine kinases and constitutively associated with the gp130 chain of the IL-6 receptor complex. Their activation is one of the first steps in cytokine receptor-mediated signaling and critical for virtually all subsequent downstream signaling cascades. INCB20 is a small-molecule synthetic compound which, in biochemical assays, potently inhibited all four JAKs with IC50 values between 0.3 nM and 1.2 nM (for comparison, IC50 of AG490, another JAK inhibitor, was &gt;50 μM). Consistent with the central role of JAKs in gp130-mediated signaling, INCB20 inhibited IL-6 induced phosphorylation of SHP-2, STAT1, STAT3, ERK1/2, and AKT in MM1.S cells. In contrast, AKT phosphorylation induced by IGF-1 remained unchanged. Evaluation of the cellular efficacy of INCB20 was performed using the IL-6 dependent INA -6 cell line. Growth of INA-6 cells was inhibited in a dose-dependent manner with an IC50 of approx. 0.5 μM, as measured by [3H]-thymidine uptake and an MTS-based assay (for comparison, the cellular IC50 of AG490 was 15–20 μM). This correlated with an increase in the percentage of apoptotic cells, as evaluated by Apo2.7 staining after 48 hours. Importantly, INA-6 growth was inhibited in the presence of bone marrow stromal cells accompanied by a decrease in phospho-STAT3 levels. Furthermore, in a subcutaneous INA-6-SCID model, INCB20 inhibited tumor growth (and phosphorylated STAT3) in a dose-dependent manner. Our studies provide the conceptual basis for the use of JAK inhibitors as a therapeutic approach in MM.</jats:p> |
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| imprint | American Society of Hematology, 2005 |
| imprint_str_mv | American Society of Hematology, 2005 |
| institution | DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15 |
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| spelling | Burger, Renate Legouill, Steven Tai, Yu-Tzu Shringarpure, Reshma Podar, Klaus Catley, Laurence Tassone, Pierfrancesco Neri, Paola Hideshima, Teru Chauhan, Dharminder Caulder, Eian Vaddi, Kris Neilan, Claire L. Gramatzki, Martin Fridman, Jordan S. Anderson, Kenneth C. 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v106.11.3357.3357 <jats:title>Abstract</jats:title> <jats:p>In multiple myeloma (MM), IL-6 plays an important role for tumor cell growth, survival, and drug resistance. Janus kinases (JAKs) are protein tyrosine kinases and constitutively associated with the gp130 chain of the IL-6 receptor complex. Their activation is one of the first steps in cytokine receptor-mediated signaling and critical for virtually all subsequent downstream signaling cascades. INCB20 is a small-molecule synthetic compound which, in biochemical assays, potently inhibited all four JAKs with IC50 values between 0.3 nM and 1.2 nM (for comparison, IC50 of AG490, another JAK inhibitor, was &gt;50 μM). Consistent with the central role of JAKs in gp130-mediated signaling, INCB20 inhibited IL-6 induced phosphorylation of SHP-2, STAT1, STAT3, ERK1/2, and AKT in MM1.S cells. In contrast, AKT phosphorylation induced by IGF-1 remained unchanged. Evaluation of the cellular efficacy of INCB20 was performed using the IL-6 dependent INA -6 cell line. Growth of INA-6 cells was inhibited in a dose-dependent manner with an IC50 of approx. 0.5 μM, as measured by [3H]-thymidine uptake and an MTS-based assay (for comparison, the cellular IC50 of AG490 was 15–20 μM). This correlated with an increase in the percentage of apoptotic cells, as evaluated by Apo2.7 staining after 48 hours. Importantly, INA-6 growth was inhibited in the presence of bone marrow stromal cells accompanied by a decrease in phospho-STAT3 levels. Furthermore, in a subcutaneous INA-6-SCID model, INCB20 inhibited tumor growth (and phosphorylated STAT3) in a dose-dependent manner. Our studies provide the conceptual basis for the use of JAK inhibitors as a therapeutic approach in MM.</jats:p> The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. Blood |
| spellingShingle | Burger, Renate, Legouill, Steven, Tai, Yu-Tzu, Shringarpure, Reshma, Podar, Klaus, Catley, Laurence, Tassone, Pierfrancesco, Neri, Paola, Hideshima, Teru, Chauhan, Dharminder, Caulder, Eian, Vaddi, Kris, Neilan, Claire L., Gramatzki, Martin, Fridman, Jordan S., Anderson, Kenneth C., Blood, The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo., Cell Biology, Hematology, Immunology, Biochemistry |
| title | The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_full | The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_fullStr | The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_full_unstemmed | The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_short | The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| title_sort | the jak inhibitor incb20 induces antiproliferative and apoptotic effects in human myeloma cells in vitro and in vivo. |
| title_unstemmed | The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo. |
| topic | Cell Biology, Hematology, Immunology, Biochemistry |
| url | http://dx.doi.org/10.1182/blood.v106.11.3357.3357 |