Efficacy of the Third-generation Bisphosphonate Risedronate Alone and in Combination with Anticancer Drugs Against Osteosarcoma Cell Lines
Background: Bisphosphonates (BPs) are currently the most important class of inhibitors of osteoclast-mediated bone resorption and are widely used in the treatment of osteoporosis and other osteoclast-mediated bone diseases. Recently, there has been increasing evidence that BPs also exhibit direct an...
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| creator | MURAYAMA, Takashi KAWASOE, Yasuomi YAMASHITA, Yoshitaka UENO, Yoshinori MINAMI, Syusaku YOKOUCHI, Masahiro KOMIYA, Setsuro |
| description | Background: Bisphosphonates (BPs) are currently the most important class of inhibitors of osteoclast-mediated bone resorption
and are widely used in the treatment of osteoporosis and other osteoclast-mediated bone diseases. Recently, there has been
increasing evidence that BPs also exhibit direct anti-tumor activity against several cancer cell lines. However, the efficacies
of BPs against osteosarcoma have not yet been fully elucidated, and the anti-osteosarcoma activity of the potent new-generation
BP risedronate, which is widely used clinically, has not been determined. Materials and Methods: The anti-proliferative effects
of the nitrogen-containing BP risedronate on seven osteosarcoma cell lines (LM8, SaOS2, U2OS, HOS, KHOS, MG63 and OST) were
studied. The cell viability was determined by MTT assay. Prenylation of Rap1A and Ras and phosphorylation of Erk1 and 2 were
examined by Western blot analysis. Genomic DNA fragmentation and TUNEL staining assay were performed to determine whether
risedronate induced apoptosis of the osteosarcoma cells. The anti-tumor activities of risedronate in combination with carboplatin,
doxorubicin, vincristine or etoposide were assayed with CalcuSyn (Biosoft). Results: Risedronate inhibited both prenylation
of Rap1A and Ras and phosphorylation of Erk 1 and 2 at a dose of 50 μM for 48 h. Treatment with risedronate induced significant
time- and dose-dependent cytotoxicity in the LM8 cell line. Risedronate treatment also increased intranucleosomal genomic
DNA fragmentation. The TUNEL assay showed that 10 μM and 50 μM risedronate clearly induced apoptosis of osteosarcoma cells.
Risedronate also clearly inhibited LM8, SaOS2 and KHOS cell growth in a time- and dose-dependent fashion, but only weakly
inhibited that of MG63 and U2OS cells. Risedronate augmented the effects of carboplatin, doxorubicin, vincristine and etoposide
synergistically across a wide range of fractions affected (Fa) values. Conclusion: The nitrogen-containing bisphosphonate
risedronate induces apoptosis and inhibits the growth of osteogenic sarcoma through a mechanism involving the down-regulation
of protein prenylation and may be a candidate for combined use with carboplatin, doxorubicin, vincristine or etoposide. |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_19691678</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>19691678</sourcerecordid><originalsourceid>FETCH-LOGICAL-h301t-ae6acddeffc73731f714b9bb59ad8cfdf48e2a682caf1b43164b557daf39084f3</originalsourceid><addsrcrecordid>eNpFkM1O4zAQgKMVaCnsvsLKF7hFsmMndo6lwIJUqRKCczSxx41XiV1sV4hX4KnJqgUOo5nDN9_8_CgWTLaslDWnJ8WCVjUtJaX1WXGe0j9Km6ZV_GdxxpSsGVdqUbzfWus06DcSLMkDkqfBRVNu0WOE7IIn1y7thvA_PGQkjy6hiYd6OQaPBLwhzpNVmHrnDz2vLg9k6fNs9hojuYn7bSLLLTifMtmkjCFB1GECssJxJGvnMf0qTi2MCX8f80XxfHf7tLov15u_D6vluhw4ZbkEbEAbg9ZqySVnVjLRt31ft2CUtsYKhRU0qtJgWS84a0Rf19KA5S1VwvKL4urg3cXwsseUu8klPa8BHsM-daxtWtZINYN_juC-n9B0u-gmiG_d5_dm4PIIQNIw2jhf69IXV9FacCGa74mD2w6vLmKXJhjHWcs7iJXqxHVXMSH5B2Ozibs</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>19691678</pqid></control><display><type>article</type><title>Efficacy of the Third-generation Bisphosphonate Risedronate Alone and in Combination with Anticancer Drugs Against Osteosarcoma Cell Lines</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>MURAYAMA, Takashi ; KAWASOE, Yasuomi ; YAMASHITA, Yoshitaka ; UENO, Yoshinori ; MINAMI, Syusaku ; YOKOUCHI, Masahiro ; KOMIYA, Setsuro</creator><creatorcontrib>MURAYAMA, Takashi ; KAWASOE, Yasuomi ; YAMASHITA, Yoshitaka ; UENO, Yoshinori ; MINAMI, Syusaku ; YOKOUCHI, Masahiro ; KOMIYA, Setsuro</creatorcontrib><description>Background: Bisphosphonates (BPs) are currently the most important class of inhibitors of osteoclast-mediated bone resorption
and are widely used in the treatment of osteoporosis and other osteoclast-mediated bone diseases. Recently, there has been
increasing evidence that BPs also exhibit direct anti-tumor activity against several cancer cell lines. However, the efficacies
of BPs against osteosarcoma have not yet been fully elucidated, and the anti-osteosarcoma activity of the potent new-generation
BP risedronate, which is widely used clinically, has not been determined. Materials and Methods: The anti-proliferative effects
of the nitrogen-containing BP risedronate on seven osteosarcoma cell lines (LM8, SaOS2, U2OS, HOS, KHOS, MG63 and OST) were
studied. The cell viability was determined by MTT assay. Prenylation of Rap1A and Ras and phosphorylation of Erk1 and 2 were
examined by Western blot analysis. Genomic DNA fragmentation and TUNEL staining assay were performed to determine whether
risedronate induced apoptosis of the osteosarcoma cells. The anti-tumor activities of risedronate in combination with carboplatin,
doxorubicin, vincristine or etoposide were assayed with CalcuSyn (Biosoft). Results: Risedronate inhibited both prenylation
of Rap1A and Ras and phosphorylation of Erk 1 and 2 at a dose of 50 μM for 48 h. Treatment with risedronate induced significant
time- and dose-dependent cytotoxicity in the LM8 cell line. Risedronate treatment also increased intranucleosomal genomic
DNA fragmentation. The TUNEL assay showed that 10 μM and 50 μM risedronate clearly induced apoptosis of osteosarcoma cells.
Risedronate also clearly inhibited LM8, SaOS2 and KHOS cell growth in a time- and dose-dependent fashion, but only weakly
inhibited that of MG63 and U2OS cells. Risedronate augmented the effects of carboplatin, doxorubicin, vincristine and etoposide
synergistically across a wide range of fractions affected (Fa) values. Conclusion: The nitrogen-containing bisphosphonate
risedronate induces apoptosis and inhibits the growth of osteogenic sarcoma through a mechanism involving the down-regulation
of protein prenylation and may be a candidate for combined use with carboplatin, doxorubicin, vincristine or etoposide.</description><identifier>ISSN: 0250-7005</identifier><identifier>EISSN: 1791-7530</identifier><identifier>PMID: 18751388</identifier><language>eng</language><publisher>Attiki: International Institute of Anticancer Research</publisher><subject><![CDATA[Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Apoptosis - drug effects ; Biological and medical sciences ; Bone Density Conservation Agents - administration & dosage ; Bone Density Conservation Agents - pharmacology ; Bone Neoplasms - drug therapy ; Bone Neoplasms - metabolism ; Bone Neoplasms - pathology ; Carboplatin - administration & dosage ; Cell Line, Tumor ; Diseases of the osteoarticular system ; Doxorubicin - administration & dosage ; Drug Synergism ; Etidronic Acid - administration & dosage ; Etidronic Acid - analogs & derivatives ; Etidronic Acid - pharmacology ; Etoposide - administration & dosage ; GTP-Binding Proteins - metabolism ; Humans ; Medical sciences ; Osteosarcoma - drug therapy ; Osteosarcoma - metabolism ; Osteosarcoma - pathology ; Prenylation - drug effects ; Risedronate Sodium ; Tumors ; Tumors of striated muscle and skeleton ; Vincristine - administration & dosage]]></subject><ispartof>Anticancer research, 2008-07, Vol.28 (4B), p.2147-2154</ispartof><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20543446$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18751388$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MURAYAMA, Takashi</creatorcontrib><creatorcontrib>KAWASOE, Yasuomi</creatorcontrib><creatorcontrib>YAMASHITA, Yoshitaka</creatorcontrib><creatorcontrib>UENO, Yoshinori</creatorcontrib><creatorcontrib>MINAMI, Syusaku</creatorcontrib><creatorcontrib>YOKOUCHI, Masahiro</creatorcontrib><creatorcontrib>KOMIYA, Setsuro</creatorcontrib><title>Efficacy of the Third-generation Bisphosphonate Risedronate Alone and in Combination with Anticancer Drugs Against Osteosarcoma Cell Lines</title><title>Anticancer research</title><addtitle>Anticancer Res</addtitle><description>Background: Bisphosphonates (BPs) are currently the most important class of inhibitors of osteoclast-mediated bone resorption
and are widely used in the treatment of osteoporosis and other osteoclast-mediated bone diseases. Recently, there has been
increasing evidence that BPs also exhibit direct anti-tumor activity against several cancer cell lines. However, the efficacies
of BPs against osteosarcoma have not yet been fully elucidated, and the anti-osteosarcoma activity of the potent new-generation
BP risedronate, which is widely used clinically, has not been determined. Materials and Methods: The anti-proliferative effects
of the nitrogen-containing BP risedronate on seven osteosarcoma cell lines (LM8, SaOS2, U2OS, HOS, KHOS, MG63 and OST) were
studied. The cell viability was determined by MTT assay. Prenylation of Rap1A and Ras and phosphorylation of Erk1 and 2 were
examined by Western blot analysis. Genomic DNA fragmentation and TUNEL staining assay were performed to determine whether
risedronate induced apoptosis of the osteosarcoma cells. The anti-tumor activities of risedronate in combination with carboplatin,
doxorubicin, vincristine or etoposide were assayed with CalcuSyn (Biosoft). Results: Risedronate inhibited both prenylation
of Rap1A and Ras and phosphorylation of Erk 1 and 2 at a dose of 50 μM for 48 h. Treatment with risedronate induced significant
time- and dose-dependent cytotoxicity in the LM8 cell line. Risedronate treatment also increased intranucleosomal genomic
DNA fragmentation. The TUNEL assay showed that 10 μM and 50 μM risedronate clearly induced apoptosis of osteosarcoma cells.
Risedronate also clearly inhibited LM8, SaOS2 and KHOS cell growth in a time- and dose-dependent fashion, but only weakly
inhibited that of MG63 and U2OS cells. Risedronate augmented the effects of carboplatin, doxorubicin, vincristine and etoposide
synergistically across a wide range of fractions affected (Fa) values. Conclusion: The nitrogen-containing bisphosphonate
risedronate induces apoptosis and inhibits the growth of osteogenic sarcoma through a mechanism involving the down-regulation
of protein prenylation and may be a candidate for combined use with carboplatin, doxorubicin, vincristine or etoposide.</description><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Bone Density Conservation Agents - administration & dosage</subject><subject>Bone Density Conservation Agents - pharmacology</subject><subject>Bone Neoplasms - drug therapy</subject><subject>Bone Neoplasms - metabolism</subject><subject>Bone Neoplasms - pathology</subject><subject>Carboplatin - administration & dosage</subject><subject>Cell Line, Tumor</subject><subject>Diseases of the osteoarticular system</subject><subject>Doxorubicin - administration & dosage</subject><subject>Drug Synergism</subject><subject>Etidronic Acid - administration & dosage</subject><subject>Etidronic Acid - analogs & derivatives</subject><subject>Etidronic Acid - pharmacology</subject><subject>Etoposide - administration & dosage</subject><subject>GTP-Binding Proteins - metabolism</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Osteosarcoma - drug therapy</subject><subject>Osteosarcoma - metabolism</subject><subject>Osteosarcoma - pathology</subject><subject>Prenylation - drug effects</subject><subject>Risedronate Sodium</subject><subject>Tumors</subject><subject>Tumors of striated muscle and skeleton</subject><subject>Vincristine - administration & dosage</subject><issn>0250-7005</issn><issn>1791-7530</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkM1O4zAQgKMVaCnsvsLKF7hFsmMndo6lwIJUqRKCczSxx41XiV1sV4hX4KnJqgUOo5nDN9_8_CgWTLaslDWnJ8WCVjUtJaX1WXGe0j9Km6ZV_GdxxpSsGVdqUbzfWus06DcSLMkDkqfBRVNu0WOE7IIn1y7thvA_PGQkjy6hiYd6OQaPBLwhzpNVmHrnDz2vLg9k6fNs9hojuYn7bSLLLTifMtmkjCFB1GECssJxJGvnMf0qTi2MCX8f80XxfHf7tLov15u_D6vluhw4ZbkEbEAbg9ZqySVnVjLRt31ft2CUtsYKhRU0qtJgWS84a0Rf19KA5S1VwvKL4urg3cXwsseUu8klPa8BHsM-daxtWtZINYN_juC-n9B0u-gmiG_d5_dm4PIIQNIw2jhf69IXV9FacCGa74mD2w6vLmKXJhjHWcs7iJXqxHVXMSH5B2Ozibs</recordid><startdate>20080701</startdate><enddate>20080701</enddate><creator>MURAYAMA, Takashi</creator><creator>KAWASOE, Yasuomi</creator><creator>YAMASHITA, Yoshitaka</creator><creator>UENO, Yoshinori</creator><creator>MINAMI, Syusaku</creator><creator>YOKOUCHI, Masahiro</creator><creator>KOMIYA, Setsuro</creator><general>International Institute of Anticancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QO</scope><scope>7QP</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20080701</creationdate><title>Efficacy of the Third-generation Bisphosphonate Risedronate Alone and in Combination with Anticancer Drugs Against Osteosarcoma Cell Lines</title><author>MURAYAMA, Takashi ; KAWASOE, Yasuomi ; YAMASHITA, Yoshitaka ; UENO, Yoshinori ; MINAMI, Syusaku ; YOKOUCHI, Masahiro ; KOMIYA, Setsuro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h301t-ae6acddeffc73731f714b9bb59ad8cfdf48e2a682caf1b43164b557daf39084f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Biological and medical sciences</topic><topic>Bone Density Conservation Agents - administration & dosage</topic><topic>Bone Density Conservation Agents - pharmacology</topic><topic>Bone Neoplasms - drug therapy</topic><topic>Bone Neoplasms - metabolism</topic><topic>Bone Neoplasms - pathology</topic><topic>Carboplatin - administration & dosage</topic><topic>Cell Line, Tumor</topic><topic>Diseases of the osteoarticular system</topic><topic>Doxorubicin - administration & dosage</topic><topic>Drug Synergism</topic><topic>Etidronic Acid - administration & dosage</topic><topic>Etidronic Acid - analogs & derivatives</topic><topic>Etidronic Acid - pharmacology</topic><topic>Etoposide - administration & dosage</topic><topic>GTP-Binding Proteins - metabolism</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Osteosarcoma - drug therapy</topic><topic>Osteosarcoma - metabolism</topic><topic>Osteosarcoma - pathology</topic><topic>Prenylation - drug effects</topic><topic>Risedronate Sodium</topic><topic>Tumors</topic><topic>Tumors of striated muscle and skeleton</topic><topic>Vincristine - administration & dosage</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MURAYAMA, Takashi</creatorcontrib><creatorcontrib>KAWASOE, Yasuomi</creatorcontrib><creatorcontrib>YAMASHITA, Yoshitaka</creatorcontrib><creatorcontrib>UENO, Yoshinori</creatorcontrib><creatorcontrib>MINAMI, Syusaku</creatorcontrib><creatorcontrib>YOKOUCHI, Masahiro</creatorcontrib><creatorcontrib>KOMIYA, Setsuro</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Anticancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MURAYAMA, Takashi</au><au>KAWASOE, Yasuomi</au><au>YAMASHITA, Yoshitaka</au><au>UENO, Yoshinori</au><au>MINAMI, Syusaku</au><au>YOKOUCHI, Masahiro</au><au>KOMIYA, Setsuro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficacy of the Third-generation Bisphosphonate Risedronate Alone and in Combination with Anticancer Drugs Against Osteosarcoma Cell Lines</atitle><jtitle>Anticancer research</jtitle><addtitle>Anticancer Res</addtitle><date>2008-07-01</date><risdate>2008</risdate><volume>28</volume><issue>4B</issue><spage>2147</spage><epage>2154</epage><pages>2147-2154</pages><issn>0250-7005</issn><eissn>1791-7530</eissn><abstract>Background: Bisphosphonates (BPs) are currently the most important class of inhibitors of osteoclast-mediated bone resorption
and are widely used in the treatment of osteoporosis and other osteoclast-mediated bone diseases. Recently, there has been
increasing evidence that BPs also exhibit direct anti-tumor activity against several cancer cell lines. However, the efficacies
of BPs against osteosarcoma have not yet been fully elucidated, and the anti-osteosarcoma activity of the potent new-generation
BP risedronate, which is widely used clinically, has not been determined. Materials and Methods: The anti-proliferative effects
of the nitrogen-containing BP risedronate on seven osteosarcoma cell lines (LM8, SaOS2, U2OS, HOS, KHOS, MG63 and OST) were
studied. The cell viability was determined by MTT assay. Prenylation of Rap1A and Ras and phosphorylation of Erk1 and 2 were
examined by Western blot analysis. Genomic DNA fragmentation and TUNEL staining assay were performed to determine whether
risedronate induced apoptosis of the osteosarcoma cells. The anti-tumor activities of risedronate in combination with carboplatin,
doxorubicin, vincristine or etoposide were assayed with CalcuSyn (Biosoft). Results: Risedronate inhibited both prenylation
of Rap1A and Ras and phosphorylation of Erk 1 and 2 at a dose of 50 μM for 48 h. Treatment with risedronate induced significant
time- and dose-dependent cytotoxicity in the LM8 cell line. Risedronate treatment also increased intranucleosomal genomic
DNA fragmentation. The TUNEL assay showed that 10 μM and 50 μM risedronate clearly induced apoptosis of osteosarcoma cells.
Risedronate also clearly inhibited LM8, SaOS2 and KHOS cell growth in a time- and dose-dependent fashion, but only weakly
inhibited that of MG63 and U2OS cells. Risedronate augmented the effects of carboplatin, doxorubicin, vincristine and etoposide
synergistically across a wide range of fractions affected (Fa) values. Conclusion: The nitrogen-containing bisphosphonate
risedronate induces apoptosis and inhibits the growth of osteogenic sarcoma through a mechanism involving the down-regulation
of protein prenylation and may be a candidate for combined use with carboplatin, doxorubicin, vincristine or etoposide.</abstract><cop>Attiki</cop><pub>International Institute of Anticancer Research</pub><pmid>18751388</pmid><tpages>8</tpages></addata></record> |
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| ispartof | Anticancer research, 2008-07, Vol.28 (4B), p.2147-2154 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis - drug effects Biological and medical sciences Bone Density Conservation Agents - administration & dosage Bone Density Conservation Agents - pharmacology Bone Neoplasms - drug therapy Bone Neoplasms - metabolism Bone Neoplasms - pathology Carboplatin - administration & dosage Cell Line, Tumor Diseases of the osteoarticular system Doxorubicin - administration & dosage Drug Synergism Etidronic Acid - administration & dosage Etidronic Acid - analogs & derivatives Etidronic Acid - pharmacology Etoposide - administration & dosage GTP-Binding Proteins - metabolism Humans Medical sciences Osteosarcoma - drug therapy Osteosarcoma - metabolism Osteosarcoma - pathology Prenylation - drug effects Risedronate Sodium Tumors Tumors of striated muscle and skeleton Vincristine - administration & dosage |
| title | Efficacy of the Third-generation Bisphosphonate Risedronate Alone and in Combination with Anticancer Drugs Against Osteosarcoma Cell Lines |
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