Insulin-Like Growth Factor I Receptor Pathway Inhibition by ADW742, Alone or in Combination with Imatinib, Doxorubicin, or Vincristine, Is a Novel Therapeutic Approach in Ewing Tumor
Purpose: Ewing tumor cell survival and proliferation depends on several autocrine loops. Targeting these loops is a promising therapeutic approach. We recently showed the cytostatic role of imatinib, an inhibitor of the SCF-KIT loop, on Ewing tumor cells, and in this study, we intend to analyze the...
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| creator | Martins, Ana S Mackintosh, Carlos Martín, David Herrero Campos, Maria Hernández, Teresa Ordóñez, Jose-Luis de Alava, Enrique |
| description | Purpose: Ewing tumor cell survival and proliferation depends on several autocrine loops. Targeting these loops is a promising therapeutic
approach. We recently showed the cytostatic role of imatinib, an inhibitor of the SCF-KIT loop, on Ewing tumor cells, and
in this study, we intend to analyze the inhibition of the insulin-like growth factor I receptor (IGF1R) loop.
Experimental Design: We analyzed IGF1R blockade by ADW742, a small molecule specific for this receptor, alone and in combination with imatinib,
vincristine, and doxorubicin on Ewing tumor cell lines. We studied the effect on proliferation, apoptosis, cell cycle, pathway
phosphorylation, soft-agar growth, motility, and vascular endothelial growth factor expression levels.
Results: Treatment with ADW742 induced down-regulation of IGF1R/AKT/mammalian target of rapamycin (mTOR) phosphorylation, which was
deeper in cell lines having higher IGF1R activation levels. Treatment also induced dose-dependent inhibition of cell proliferation
(IC 50 = 0.55-1.4 μmol/L), inducing a G 1 phase blockage and apoptosis. Addition of imatinib to ADW742 synergistically augmented these effects and was especially effective
in inhibiting AKT/mTOR phosphorylation and reducing vascular endothelial growth factor expression in cell lines having high
IGF1R activation levels. Combination with usual chemotherapeutic agents vincristine and doxorubicin showed synergistic interactions.
Conclusions: Inhibition of Ewing tumor cell proliferation by ADW742 is mediated through blockade of IGF1R signaling. Combination of ADW742
with imatinib, vincristine, and doxorubicin induces a significant reduction of tumor cell growth, mainly by the increase in
apoptosis with a pattern depending on IGF1R activation levels. This study supports a potential role for ADW742 in the treatment
of Ewing tumor and AKT/mTOR as a possible surrogate marker of response to therapy. |
| doi_str_mv | 10.1158/1078-0432.CCR-05-1778 |
| format | Article |
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approach. We recently showed the cytostatic role of imatinib, an inhibitor of the SCF-KIT loop, on Ewing tumor cells, and
in this study, we intend to analyze the inhibition of the insulin-like growth factor I receptor (IGF1R) loop.
Experimental Design: We analyzed IGF1R blockade by ADW742, a small molecule specific for this receptor, alone and in combination with imatinib,
vincristine, and doxorubicin on Ewing tumor cell lines. We studied the effect on proliferation, apoptosis, cell cycle, pathway
phosphorylation, soft-agar growth, motility, and vascular endothelial growth factor expression levels.
Results: Treatment with ADW742 induced down-regulation of IGF1R/AKT/mammalian target of rapamycin (mTOR) phosphorylation, which was
deeper in cell lines having higher IGF1R activation levels. Treatment also induced dose-dependent inhibition of cell proliferation
(IC 50 = 0.55-1.4 μmol/L), inducing a G 1 phase blockage and apoptosis. Addition of imatinib to ADW742 synergistically augmented these effects and was especially effective
in inhibiting AKT/mTOR phosphorylation and reducing vascular endothelial growth factor expression in cell lines having high
IGF1R activation levels. Combination with usual chemotherapeutic agents vincristine and doxorubicin showed synergistic interactions.
Conclusions: Inhibition of Ewing tumor cell proliferation by ADW742 is mediated through blockade of IGF1R signaling. Combination of ADW742
with imatinib, vincristine, and doxorubicin induces a significant reduction of tumor cell growth, mainly by the increase in
apoptosis with a pattern depending on IGF1R activation levels. This study supports a potential role for ADW742 in the treatment
of Ewing tumor and AKT/mTOR as a possible surrogate marker of response to therapy.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-05-1778</identifier><identifier>PMID: 16740780</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject><![CDATA[ADW742 ; AKT ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Apoptosis - drug effects ; Benzamides ; Bone Neoplasms - drug therapy ; Bone Neoplasms - metabolism ; Cell Cycle - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Down-Regulation - drug effects ; Doxorubicin - administration & dosage ; Drug Screening Assays, Antitumor ; Ewing Tumor ; G1 Phase - drug effects ; Humans ; IGF1R pathway ; Imatinib Mesylate ; Pediatric cancers ; Phosphorylation - drug effects ; Piperazines - administration & dosage ; Protein Kinases - drug effects ; Protein Kinases - metabolism ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - metabolism ; Pyrimidines - administration & dosage ; Pyrimidines - pharmacology ; Pyrimidines - therapeutic use ; Pyrroles - pharmacology ; Pyrroles - therapeutic use ; Receptor, IGF Type 1 - antagonists & inhibitors ; Receptor, IGF Type 1 - metabolism ; Sarcoma, Ewing - drug therapy ; Sarcoma, Ewing - metabolism ; Sarcoma/soft-tissue malignancies ; Structure-Activity Relationship ; TOR Serine-Threonine Kinases ; Vincristine - administration & dosage]]></subject><ispartof>Clinical cancer research, 2006-06, Vol.12 (11), p.3532-3540</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c388t-60dc52c543c84ba3d6b6703e9d7dc9b041cf9a50e3da003ba28b1549fdbe6fd73</citedby><cites>FETCH-LOGICAL-c388t-60dc52c543c84ba3d6b6703e9d7dc9b041cf9a50e3da003ba28b1549fdbe6fd73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,3343,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16740780$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martins, Ana S</creatorcontrib><creatorcontrib>Mackintosh, Carlos</creatorcontrib><creatorcontrib>Martín, David Herrero</creatorcontrib><creatorcontrib>Campos, Maria</creatorcontrib><creatorcontrib>Hernández, Teresa</creatorcontrib><creatorcontrib>Ordóñez, Jose-Luis</creatorcontrib><creatorcontrib>de Alava, Enrique</creatorcontrib><title>Insulin-Like Growth Factor I Receptor Pathway Inhibition by ADW742, Alone or in Combination with Imatinib, Doxorubicin, or Vincristine, Is a Novel Therapeutic Approach in Ewing Tumor</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: Ewing tumor cell survival and proliferation depends on several autocrine loops. Targeting these loops is a promising therapeutic
approach. We recently showed the cytostatic role of imatinib, an inhibitor of the SCF-KIT loop, on Ewing tumor cells, and
in this study, we intend to analyze the inhibition of the insulin-like growth factor I receptor (IGF1R) loop.
Experimental Design: We analyzed IGF1R blockade by ADW742, a small molecule specific for this receptor, alone and in combination with imatinib,
vincristine, and doxorubicin on Ewing tumor cell lines. We studied the effect on proliferation, apoptosis, cell cycle, pathway
phosphorylation, soft-agar growth, motility, and vascular endothelial growth factor expression levels.
Results: Treatment with ADW742 induced down-regulation of IGF1R/AKT/mammalian target of rapamycin (mTOR) phosphorylation, which was
deeper in cell lines having higher IGF1R activation levels. Treatment also induced dose-dependent inhibition of cell proliferation
(IC 50 = 0.55-1.4 μmol/L), inducing a G 1 phase blockage and apoptosis. Addition of imatinib to ADW742 synergistically augmented these effects and was especially effective
in inhibiting AKT/mTOR phosphorylation and reducing vascular endothelial growth factor expression in cell lines having high
IGF1R activation levels. Combination with usual chemotherapeutic agents vincristine and doxorubicin showed synergistic interactions.
Conclusions: Inhibition of Ewing tumor cell proliferation by ADW742 is mediated through blockade of IGF1R signaling. Combination of ADW742
with imatinib, vincristine, and doxorubicin induces a significant reduction of tumor cell growth, mainly by the increase in
apoptosis with a pattern depending on IGF1R activation levels. This study supports a potential role for ADW742 in the treatment
of Ewing tumor and AKT/mTOR as a possible surrogate marker of response to therapy.</description><subject>ADW742</subject><subject>AKT</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Apoptosis - drug effects</subject><subject>Benzamides</subject><subject>Bone Neoplasms - drug therapy</subject><subject>Bone Neoplasms - metabolism</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Down-Regulation - drug effects</subject><subject>Doxorubicin - administration & dosage</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Ewing Tumor</subject><subject>G1 Phase - drug effects</subject><subject>Humans</subject><subject>IGF1R pathway</subject><subject>Imatinib Mesylate</subject><subject>Pediatric cancers</subject><subject>Phosphorylation - drug effects</subject><subject>Piperazines - administration & dosage</subject><subject>Protein Kinases - drug effects</subject><subject>Protein Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Pyrimidines - administration & dosage</subject><subject>Pyrimidines - pharmacology</subject><subject>Pyrimidines - therapeutic use</subject><subject>Pyrroles - pharmacology</subject><subject>Pyrroles - therapeutic use</subject><subject>Receptor, IGF Type 1 - antagonists & inhibitors</subject><subject>Receptor, IGF Type 1 - metabolism</subject><subject>Sarcoma, Ewing - drug therapy</subject><subject>Sarcoma, Ewing - metabolism</subject><subject>Sarcoma/soft-tissue malignancies</subject><subject>Structure-Activity Relationship</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Vincristine - administration & dosage</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkd1u1DAQRiMEoqXwCCBfISFtih3bSfZylf5FWgGqFri0bGe2MSR2aieEfTGerw67iCuPNWe-GekkyVuCLwnh5UeCizLFjGaXVXWfYp6SoiifJeeE8yKlWc6fx_ofc5a8CuEHxoQRzF4mZyQvWOzh8-RPbcPUGZtuzU9At97NY4tupB6dRzW6Bw3DUn6RYzvLA6pta5QZjbNIHdDm6nvBshXadM4CipixqHK9Mlb-RWYTw-o-fqxRK3Tlfjs_KaONXS30N2O1NyF2YYXqgCT65H5Bh3YteDnANBqNNsPgndTtEn09G_uAdlPv_OvkxV52Ad6c3ovk6831rrpLt59v62qzTTUtyzHNcaN5pjmjumRK0iZXeYEprJui0WuFGdH7teQYaCMxpkpmpSKcrfeNgnzfFPQieX_MjVc8ThBG0ZugoeukBTcFkZc4LspZBPkR1N6F4GEvBm966Q-CYLEIE4sMscgQUZjAXCzC4ty704JJ9dD8nzoZisCHI9Cah3Y2HoSWVoP3EEB63QqSxXxBOc3oE804oZg</recordid><startdate>20060601</startdate><enddate>20060601</enddate><creator>Martins, Ana S</creator><creator>Mackintosh, Carlos</creator><creator>Martín, David Herrero</creator><creator>Campos, Maria</creator><creator>Hernández, Teresa</creator><creator>Ordóñez, Jose-Luis</creator><creator>de Alava, Enrique</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20060601</creationdate><title>Insulin-Like Growth Factor I Receptor Pathway Inhibition by ADW742, Alone or in Combination with Imatinib, Doxorubicin, or Vincristine, Is a Novel Therapeutic Approach in Ewing Tumor</title><author>Martins, Ana S ; Mackintosh, Carlos ; Martín, David Herrero ; Campos, Maria ; Hernández, Teresa ; Ordóñez, Jose-Luis ; de Alava, Enrique</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c388t-60dc52c543c84ba3d6b6703e9d7dc9b041cf9a50e3da003ba28b1549fdbe6fd73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>ADW742</topic><topic>AKT</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Apoptosis - drug effects</topic><topic>Benzamides</topic><topic>Bone Neoplasms - drug therapy</topic><topic>Bone Neoplasms - metabolism</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Down-Regulation - drug effects</topic><topic>Doxorubicin - administration & dosage</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Ewing Tumor</topic><topic>G1 Phase - drug effects</topic><topic>Humans</topic><topic>IGF1R pathway</topic><topic>Imatinib Mesylate</topic><topic>Pediatric cancers</topic><topic>Phosphorylation - drug effects</topic><topic>Piperazines - administration & dosage</topic><topic>Protein Kinases - drug effects</topic><topic>Protein Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Pyrimidines - administration & dosage</topic><topic>Pyrimidines - pharmacology</topic><topic>Pyrimidines - therapeutic use</topic><topic>Pyrroles - pharmacology</topic><topic>Pyrroles - therapeutic use</topic><topic>Receptor, IGF Type 1 - antagonists & inhibitors</topic><topic>Receptor, IGF Type 1 - metabolism</topic><topic>Sarcoma, Ewing - drug therapy</topic><topic>Sarcoma, Ewing - metabolism</topic><topic>Sarcoma/soft-tissue malignancies</topic><topic>Structure-Activity Relationship</topic><topic>TOR Serine-Threonine Kinases</topic><topic>Vincristine - administration & dosage</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martins, Ana S</creatorcontrib><creatorcontrib>Mackintosh, Carlos</creatorcontrib><creatorcontrib>Martín, David Herrero</creatorcontrib><creatorcontrib>Campos, Maria</creatorcontrib><creatorcontrib>Hernández, Teresa</creatorcontrib><creatorcontrib>Ordóñez, Jose-Luis</creatorcontrib><creatorcontrib>de Alava, Enrique</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martins, Ana S</au><au>Mackintosh, Carlos</au><au>Martín, David Herrero</au><au>Campos, Maria</au><au>Hernández, Teresa</au><au>Ordóñez, Jose-Luis</au><au>de Alava, Enrique</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Insulin-Like Growth Factor I Receptor Pathway Inhibition by ADW742, Alone or in Combination with Imatinib, Doxorubicin, or Vincristine, Is a Novel Therapeutic Approach in Ewing Tumor</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2006-06-01</date><risdate>2006</risdate><volume>12</volume><issue>11</issue><spage>3532</spage><epage>3540</epage><pages>3532-3540</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: Ewing tumor cell survival and proliferation depends on several autocrine loops. Targeting these loops is a promising therapeutic
approach. We recently showed the cytostatic role of imatinib, an inhibitor of the SCF-KIT loop, on Ewing tumor cells, and
in this study, we intend to analyze the inhibition of the insulin-like growth factor I receptor (IGF1R) loop.
Experimental Design: We analyzed IGF1R blockade by ADW742, a small molecule specific for this receptor, alone and in combination with imatinib,
vincristine, and doxorubicin on Ewing tumor cell lines. We studied the effect on proliferation, apoptosis, cell cycle, pathway
phosphorylation, soft-agar growth, motility, and vascular endothelial growth factor expression levels.
Results: Treatment with ADW742 induced down-regulation of IGF1R/AKT/mammalian target of rapamycin (mTOR) phosphorylation, which was
deeper in cell lines having higher IGF1R activation levels. Treatment also induced dose-dependent inhibition of cell proliferation
(IC 50 = 0.55-1.4 μmol/L), inducing a G 1 phase blockage and apoptosis. Addition of imatinib to ADW742 synergistically augmented these effects and was especially effective
in inhibiting AKT/mTOR phosphorylation and reducing vascular endothelial growth factor expression in cell lines having high
IGF1R activation levels. Combination with usual chemotherapeutic agents vincristine and doxorubicin showed synergistic interactions.
Conclusions: Inhibition of Ewing tumor cell proliferation by ADW742 is mediated through blockade of IGF1R signaling. Combination of ADW742
with imatinib, vincristine, and doxorubicin induces a significant reduction of tumor cell growth, mainly by the increase in
apoptosis with a pattern depending on IGF1R activation levels. This study supports a potential role for ADW742 in the treatment
of Ewing tumor and AKT/mTOR as a possible surrogate marker of response to therapy.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>16740780</pmid><doi>10.1158/1078-0432.CCR-05-1778</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2006-06, Vol.12 (11), p.3532-3540 |
| issn | 1078-0432 1557-3265 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | ADW742 AKT Antineoplastic Combined Chemotherapy Protocols - therapeutic use Apoptosis - drug effects Benzamides Bone Neoplasms - drug therapy Bone Neoplasms - metabolism Cell Cycle - drug effects Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Down-Regulation - drug effects Doxorubicin - administration & dosage Drug Screening Assays, Antitumor Ewing Tumor G1 Phase - drug effects Humans IGF1R pathway Imatinib Mesylate Pediatric cancers Phosphorylation - drug effects Piperazines - administration & dosage Protein Kinases - drug effects Protein Kinases - metabolism Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Pyrimidines - administration & dosage Pyrimidines - pharmacology Pyrimidines - therapeutic use Pyrroles - pharmacology Pyrroles - therapeutic use Receptor, IGF Type 1 - antagonists & inhibitors Receptor, IGF Type 1 - metabolism Sarcoma, Ewing - drug therapy Sarcoma, Ewing - metabolism Sarcoma/soft-tissue malignancies Structure-Activity Relationship TOR Serine-Threonine Kinases Vincristine - administration & dosage |
| title | Insulin-Like Growth Factor I Receptor Pathway Inhibition by ADW742, Alone or in Combination with Imatinib, Doxorubicin, or Vincristine, Is a Novel Therapeutic Approach in Ewing Tumor |
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