Combination of 13-Cis Retinoic Acid and Lovastatin: Marked Antitumor Potential In Vivo in a Pheochromocytoma Allograft Model in Female Athymic Nude Mice
Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggre...
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| Veröffentlicht in: | Endocrinology (Philadelphia) 2014-07, Vol.155 (7), p.2377-2390 |
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| creator | Nölting, Svenja Giubellino, Alessio Tayem, Yasin Young, Karen Lauseker, Michael Bullova, Petra Schovanek, Jan Anver, Miriam Fliedner, Stephanie Korbonits, Márta Göke, Burkhard Vlotides, George Grossman, Ashley Pacak, Karel |
| description | Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of α-smooth muscle actin. The combination of high microvessel density and low α-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventive option for malignant PCC. |
| doi_str_mv | 10.1210/en.2014-1027 |
| format | Article |
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Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of α-smooth muscle actin. The combination of high microvessel density and low α-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventive option for malignant PCC.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2014-1027</identifier><identifier>PMID: 24762141</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Actin ; Actins - metabolism ; Adrenal Gland Neoplasms - drug therapy ; Adrenal Gland Neoplasms - metabolism ; Adrenal Gland Neoplasms - pathology ; Allografts ; Animals ; Antigens, CD34 - metabolism ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Antiproliferatives ; Antitumor activity ; Bioluminescence ; Cancer-Oncogenes ; Cell growth ; Cell Line, Tumor ; Cell Survival - drug effects ; Chromogranin A - metabolism ; Density ; Female ; Immunohistochemistry ; Immunosuppressive agents ; Isotretinoin - administration & dosage ; Isotretinoin - pharmacology ; Lovastatin ; Lovastatin - administration & dosage ; Lovastatin - pharmacology ; Lung Neoplasms - metabolism ; Lung Neoplasms - prevention & control ; Lung Neoplasms - secondary ; Metastases ; Mice ; Mice, Nude ; Muscle, Smooth - chemistry ; Muscles ; Necrosis ; Paraganglioma ; Pheochromocytoma ; Pheochromocytoma - drug therapy ; Pheochromocytoma - metabolism ; Pheochromocytoma - pathology ; Retinoic acid ; Smooth muscle ; Succinate dehydrogenase ; Time Factors ; Transplantation, Homologous ; Treatment Outcome ; Tumor Burden - drug effects ; Tumors ; Tyrosine 3-Monooxygenase - metabolism</subject><ispartof>Endocrinology (Philadelphia), 2014-07, Vol.155 (7), p.2377-2390</ispartof><rights>Copyright © 2014 by the Endocrine Society</rights><rights>Copyright © 2014 by the Endocrine Society 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-e4f1fa828f1b3b82ca5a93b02b8e7efca3ae8830003081471b12af7edbe145913</citedby><cites>FETCH-LOGICAL-c488t-e4f1fa828f1b3b82ca5a93b02b8e7efca3ae8830003081471b12af7edbe145913</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24762141$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nölting, Svenja</creatorcontrib><creatorcontrib>Giubellino, Alessio</creatorcontrib><creatorcontrib>Tayem, Yasin</creatorcontrib><creatorcontrib>Young, Karen</creatorcontrib><creatorcontrib>Lauseker, Michael</creatorcontrib><creatorcontrib>Bullova, Petra</creatorcontrib><creatorcontrib>Schovanek, Jan</creatorcontrib><creatorcontrib>Anver, Miriam</creatorcontrib><creatorcontrib>Fliedner, Stephanie</creatorcontrib><creatorcontrib>Korbonits, Márta</creatorcontrib><creatorcontrib>Göke, Burkhard</creatorcontrib><creatorcontrib>Vlotides, George</creatorcontrib><creatorcontrib>Grossman, Ashley</creatorcontrib><creatorcontrib>Pacak, Karel</creatorcontrib><title>Combination of 13-Cis Retinoic Acid and Lovastatin: Marked Antitumor Potential In Vivo in a Pheochromocytoma Allograft Model in Female Athymic Nude Mice</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of α-smooth muscle actin. The combination of high microvessel density and low α-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventive option for malignant PCC.</description><subject>Actin</subject><subject>Actins - metabolism</subject><subject>Adrenal Gland Neoplasms - drug therapy</subject><subject>Adrenal Gland Neoplasms - metabolism</subject><subject>Adrenal Gland Neoplasms - pathology</subject><subject>Allografts</subject><subject>Animals</subject><subject>Antigens, CD34 - metabolism</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Antiproliferatives</subject><subject>Antitumor activity</subject><subject>Bioluminescence</subject><subject>Cancer-Oncogenes</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Chromogranin A - metabolism</subject><subject>Density</subject><subject>Female</subject><subject>Immunohistochemistry</subject><subject>Immunosuppressive agents</subject><subject>Isotretinoin - administration & dosage</subject><subject>Isotretinoin - pharmacology</subject><subject>Lovastatin</subject><subject>Lovastatin - administration & dosage</subject><subject>Lovastatin - pharmacology</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - prevention & control</subject><subject>Lung Neoplasms - secondary</subject><subject>Metastases</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Muscle, Smooth - chemistry</subject><subject>Muscles</subject><subject>Necrosis</subject><subject>Paraganglioma</subject><subject>Pheochromocytoma</subject><subject>Pheochromocytoma - drug therapy</subject><subject>Pheochromocytoma - metabolism</subject><subject>Pheochromocytoma - pathology</subject><subject>Retinoic acid</subject><subject>Smooth muscle</subject><subject>Succinate dehydrogenase</subject><subject>Time Factors</subject><subject>Transplantation, Homologous</subject><subject>Treatment Outcome</subject><subject>Tumor Burden - drug effects</subject><subject>Tumors</subject><subject>Tyrosine 3-Monooxygenase - metabolism</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFuEzEQhlcIREPhxhlZ4sCFLR7b6TockKKIQqUEKgRcLa93tnHZ9QSvN1LepI9bRwkFJDhZI3_-5rf-ongO_AwE8DcYzgQHVQIX1YNiAjM1LSuo-MNiwjnIshKiOimeDMNNHpVS8nFxIlR1LkDBpLhdUF_7YJOnwKhl-cHCD-wLJh_IOzZ3vmE2NGxJWzukzIW3bGXjD2zYPCSfxp4iu6KEebAduwzsu98S84FZdrVGcutIPbldot6yedfRdbRtYitqsNtTF9jbDtk8rXd93vdpbJCtvMOnxaPWdgM-O56nxbeL918XH8vl5w-Xi_mydErrVKJqobVa6BZqWWvh7NTOZM1FrbHC1llpUWvJOZdcg6qgBmHbCpsaQU1nIE-LdwfvZqx7bFz-R7Sd2UTf27gzZL35-yb4tbmmrVH8nIOeZcHLoyDSzxGHZG5ojCFnNhIkr0BwPc3U6wPlIg1DxPZ-A3Cz79FgMPsezb7HjL_4M9U9_Ku4DLw6ADRu_qcqjyp5IDE05KIPuIk4DL9T_jPAHYFKt1U</recordid><startdate>20140701</startdate><enddate>20140701</enddate><creator>Nölting, Svenja</creator><creator>Giubellino, Alessio</creator><creator>Tayem, Yasin</creator><creator>Young, Karen</creator><creator>Lauseker, Michael</creator><creator>Bullova, Petra</creator><creator>Schovanek, Jan</creator><creator>Anver, Miriam</creator><creator>Fliedner, Stephanie</creator><creator>Korbonits, Márta</creator><creator>Göke, Burkhard</creator><creator>Vlotides, George</creator><creator>Grossman, Ashley</creator><creator>Pacak, Karel</creator><general>Endocrine Society</general><general>Oxford University Press</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>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20140701</creationdate><title>Combination of 13-Cis Retinoic Acid and Lovastatin: Marked Antitumor Potential In Vivo in a Pheochromocytoma Allograft Model in Female Athymic Nude Mice</title><author>Nölting, Svenja ; Giubellino, Alessio ; Tayem, Yasin ; Young, Karen ; Lauseker, Michael ; Bullova, Petra ; Schovanek, Jan ; Anver, Miriam ; Fliedner, Stephanie ; Korbonits, Márta ; Göke, Burkhard ; Vlotides, George ; Grossman, Ashley ; Pacak, Karel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c488t-e4f1fa828f1b3b82ca5a93b02b8e7efca3ae8830003081471b12af7edbe145913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Actin</topic><topic>Actins - metabolism</topic><topic>Adrenal Gland Neoplasms - drug therapy</topic><topic>Adrenal Gland Neoplasms - metabolism</topic><topic>Adrenal Gland Neoplasms - pathology</topic><topic>Allografts</topic><topic>Animals</topic><topic>Antigens, CD34 - metabolism</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Antiproliferatives</topic><topic>Antitumor activity</topic><topic>Bioluminescence</topic><topic>Cancer-Oncogenes</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Chromogranin A - metabolism</topic><topic>Density</topic><topic>Female</topic><topic>Immunohistochemistry</topic><topic>Immunosuppressive agents</topic><topic>Isotretinoin - administration & dosage</topic><topic>Isotretinoin - pharmacology</topic><topic>Lovastatin</topic><topic>Lovastatin - administration & dosage</topic><topic>Lovastatin - pharmacology</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - 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Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of α-smooth muscle actin. The combination of high microvessel density and low α-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventive option for malignant PCC.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>24762141</pmid><doi>10.1210/en.2014-1027</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Journals@Ovid Complete; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Actin Actins - metabolism Adrenal Gland Neoplasms - drug therapy Adrenal Gland Neoplasms - metabolism Adrenal Gland Neoplasms - pathology Allografts Animals Antigens, CD34 - metabolism Antineoplastic Combined Chemotherapy Protocols - therapeutic use Antiproliferatives Antitumor activity Bioluminescence Cancer-Oncogenes Cell growth Cell Line, Tumor Cell Survival - drug effects Chromogranin A - metabolism Density Female Immunohistochemistry Immunosuppressive agents Isotretinoin - administration & dosage Isotretinoin - pharmacology Lovastatin Lovastatin - administration & dosage Lovastatin - pharmacology Lung Neoplasms - metabolism Lung Neoplasms - prevention & control Lung Neoplasms - secondary Metastases Mice Mice, Nude Muscle, Smooth - chemistry Muscles Necrosis Paraganglioma Pheochromocytoma Pheochromocytoma - drug therapy Pheochromocytoma - metabolism Pheochromocytoma - pathology Retinoic acid Smooth muscle Succinate dehydrogenase Time Factors Transplantation, Homologous Treatment Outcome Tumor Burden - drug effects Tumors Tyrosine 3-Monooxygenase - metabolism |
| title | Combination of 13-Cis Retinoic Acid and Lovastatin: Marked Antitumor Potential In Vivo in a Pheochromocytoma Allograft Model in Female Athymic Nude Mice |
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