Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor
A new targeting chemotherapeutic agent, Pt-Mal-LHRH, was synthesized by linking activated cisplatin to luteinizing hormone releasing hormone (LHRH). The compound’s efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, si...
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| Veröffentlicht in: | Bioconjugate chemistry 2017-02, Vol.28 (2), p.461-470 |
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| creator | Calderon, Lindsay E Keeling, Jonathan K Rollins, Joseph Black, Carrie A Collins, Kendall Arnold, Nova Vance, Diane E Ndinguri, Margaret W |
| description | A new targeting chemotherapeutic agent, Pt-Mal-LHRH, was synthesized by linking activated cisplatin to luteinizing hormone releasing hormone (LHRH). The compound’s efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, since the Pt-Mal-LHRH malonate linker chelates platinum in a similar manner to carboplatin. Breast cancer and normal cell viability were analyzed by an MTT assay comparing Pt-Mal-LHRH with carboplatin. Cells were also treated with either Pt-Mal-LHRH or carboplatin to evaluate platinum uptake by ICP-MS and cell migration using an in vitro scratch–migration assay. Tumor volume and metastasis were evaluated using an in vivo 4T1 mouse tumor model. Mice were administered Pt-Mal-LHRH (carboplatin molar equivalent dosage) through ip injection and compared to those treated with carboplatin (5 (mg/kg)/week), no treatment, and LHRH plus carboplatin (unbound) controls. An MTT assay showed a reduction in cell viability (p < 0.01) in 4T1 and MDA-MB-231 breast cancer cells treated with Pt-Mal-LHRH compared to carboplatin. Pt-Mal-LHRH was confirmed to be cytotoxic by flow cytometry using a propidium iodide stain. Pt-Mal-LHRH displayed a 20-fold increase in 4T1 cellular uptake compared to carboplatin. There was a decrease (p < 0.0001) in 4T1 cell viability compared to 3T3 normal fibroblast cells. Treatment with Pt-Mal-LHRH also resulted in a significant decrease in cell-migration compared to carboplatin. In vivo testing found a significant reduction in tumor volume (p < 0.05) and metastatic tumor colonization in the lungs with Pt-Mal-LHRH compared to carboplatin. There was a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicate that Pt-Mal-LHRH is a more potent and selective chemotherapeutic agent than untargeted carboplatin. |
| doi_str_mv | 10.1021/acs.bioconjchem.6b00610 |
| format | Article |
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The compound’s efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, since the Pt-Mal-LHRH malonate linker chelates platinum in a similar manner to carboplatin. Breast cancer and normal cell viability were analyzed by an MTT assay comparing Pt-Mal-LHRH with carboplatin. Cells were also treated with either Pt-Mal-LHRH or carboplatin to evaluate platinum uptake by ICP-MS and cell migration using an in vitro scratch–migration assay. Tumor volume and metastasis were evaluated using an in vivo 4T1 mouse tumor model. Mice were administered Pt-Mal-LHRH (carboplatin molar equivalent dosage) through ip injection and compared to those treated with carboplatin (5 (mg/kg)/week), no treatment, and LHRH plus carboplatin (unbound) controls. An MTT assay showed a reduction in cell viability (p < 0.01) in 4T1 and MDA-MB-231 breast cancer cells treated with Pt-Mal-LHRH compared to carboplatin. Pt-Mal-LHRH was confirmed to be cytotoxic by flow cytometry using a propidium iodide stain. Pt-Mal-LHRH displayed a 20-fold increase in 4T1 cellular uptake compared to carboplatin. There was a decrease (p < 0.0001) in 4T1 cell viability compared to 3T3 normal fibroblast cells. Treatment with Pt-Mal-LHRH also resulted in a significant decrease in cell-migration compared to carboplatin. In vivo testing found a significant reduction in tumor volume (p < 0.05) and metastatic tumor colonization in the lungs with Pt-Mal-LHRH compared to carboplatin. There was a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicate that Pt-Mal-LHRH is a more potent and selective chemotherapeutic agent than untargeted carboplatin.</description><identifier>ISSN: 1043-1802</identifier><identifier>EISSN: 1520-4812</identifier><identifier>DOI: 10.1021/acs.bioconjchem.6b00610</identifier><identifier>PMID: 27997127</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>3T3 Cells ; Animals ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Breast - drug effects ; Breast - metabolism ; Breast - pathology ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Cell Movement - drug effects ; Cells ; Chemical synthesis ; Cisplatin - administration & dosage ; Cisplatin - chemistry ; Cisplatin - pharmacokinetics ; Cisplatin - therapeutic use ; Drug Delivery Systems ; Female ; Gene expression ; Gonadotropin-Releasing Hormone - administration & dosage ; Gonadotropin-Releasing Hormone - chemistry ; Gonadotropin-Releasing Hormone - pharmacokinetics ; Gonadotropin-Releasing Hormone - therapeutic use ; Humans ; Lung - drug effects ; Lung - pathology ; Lung Neoplasms - drug therapy ; Lung Neoplasms - pathology ; Lung Neoplasms - secondary ; Metastasis ; Mice ; Mice, Inbred BALB C ; Receptors, LHRH - metabolism ; Tumors ; Up-Regulation - drug effects</subject><ispartof>Bioconjugate chemistry, 2017-02, Vol.28 (2), p.461-470</ispartof><rights>Copyright © 2016 American Chemical Society</rights><rights>Copyright American Chemical Society Feb 15, 2017</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a418t-f57a3ba27ce7402b7e8b05d245fff2db748cc6b92fd6f8f6ef09ac3b2471ed213</citedby><cites>FETCH-LOGICAL-a418t-f57a3ba27ce7402b7e8b05d245fff2db748cc6b92fd6f8f6ef09ac3b2471ed213</cites><orcidid>0000-0002-1773-9368</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.6b00610$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.bioconjchem.6b00610$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27997127$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Calderon, Lindsay E</creatorcontrib><creatorcontrib>Keeling, Jonathan K</creatorcontrib><creatorcontrib>Rollins, Joseph</creatorcontrib><creatorcontrib>Black, Carrie A</creatorcontrib><creatorcontrib>Collins, Kendall</creatorcontrib><creatorcontrib>Arnold, Nova</creatorcontrib><creatorcontrib>Vance, Diane E</creatorcontrib><creatorcontrib>Ndinguri, Margaret W</creatorcontrib><title>Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor</title><title>Bioconjugate chemistry</title><addtitle>Bioconjugate Chem</addtitle><description>A new targeting chemotherapeutic agent, Pt-Mal-LHRH, was synthesized by linking activated cisplatin to luteinizing hormone releasing hormone (LHRH). The compound’s efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, since the Pt-Mal-LHRH malonate linker chelates platinum in a similar manner to carboplatin. Breast cancer and normal cell viability were analyzed by an MTT assay comparing Pt-Mal-LHRH with carboplatin. Cells were also treated with either Pt-Mal-LHRH or carboplatin to evaluate platinum uptake by ICP-MS and cell migration using an in vitro scratch–migration assay. Tumor volume and metastasis were evaluated using an in vivo 4T1 mouse tumor model. Mice were administered Pt-Mal-LHRH (carboplatin molar equivalent dosage) through ip injection and compared to those treated with carboplatin (5 (mg/kg)/week), no treatment, and LHRH plus carboplatin (unbound) controls. An MTT assay showed a reduction in cell viability (p < 0.01) in 4T1 and MDA-MB-231 breast cancer cells treated with Pt-Mal-LHRH compared to carboplatin. Pt-Mal-LHRH was confirmed to be cytotoxic by flow cytometry using a propidium iodide stain. Pt-Mal-LHRH displayed a 20-fold increase in 4T1 cellular uptake compared to carboplatin. There was a decrease (p < 0.0001) in 4T1 cell viability compared to 3T3 normal fibroblast cells. Treatment with Pt-Mal-LHRH also resulted in a significant decrease in cell-migration compared to carboplatin. In vivo testing found a significant reduction in tumor volume (p < 0.05) and metastatic tumor colonization in the lungs with Pt-Mal-LHRH compared to carboplatin. There was a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicate that Pt-Mal-LHRH is a more potent and selective chemotherapeutic agent than untargeted carboplatin.</description><subject>3T3 Cells</subject><subject>Animals</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Breast - drug effects</subject><subject>Breast - metabolism</subject><subject>Breast - pathology</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>Cells</subject><subject>Chemical synthesis</subject><subject>Cisplatin - administration & dosage</subject><subject>Cisplatin - chemistry</subject><subject>Cisplatin - pharmacokinetics</subject><subject>Cisplatin - therapeutic use</subject><subject>Drug Delivery Systems</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gonadotropin-Releasing Hormone - administration & dosage</subject><subject>Gonadotropin-Releasing Hormone - chemistry</subject><subject>Gonadotropin-Releasing Hormone - pharmacokinetics</subject><subject>Gonadotropin-Releasing Hormone - therapeutic use</subject><subject>Humans</subject><subject>Lung - drug effects</subject><subject>Lung - pathology</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - pathology</subject><subject>Lung Neoplasms - secondary</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Receptors, LHRH - metabolism</subject><subject>Tumors</subject><subject>Up-Regulation - drug effects</subject><issn>1043-1802</issn><issn>1520-4812</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1uEzEYRUeIipbCK4AlNiyYYHt-bC9LBA1S2qIS1iPb87mZaMae2h5KeAoeGadJAbGBlS353HtlnSx7SfCMYEreSh1mqnPa2Y1ewzCrFcY1wY-yE1JRnJec0MfpjssiJxzT4-xpCBuMsSCcPsmOKROCEcpOsh-fYn4h-3y5uF68QRJdwl2_RZ-3Nq4hdN-hRXM3jG6yLTqLEewkY2dv0DsPMkQ0l1aDR6tpcB6de3cX10gm9AJiepahC0ht0Ur6G7iPXX0FD99GDyF0ziJnUJpBu210DRrG6Pyz7MjIPsDzw3maffnwfjVf5Mur84_zs2UuS8JjbiomCyUp08BKTBUDrnDV0rIyxtBWsZJrXStBTVsbbmowWEhdKFoyAi0lxWn2et87enc7QYjN0AUNfS8tuCk0hDPGC1ZR8R9oRagQRVEn9NVf6MZN3qaPJKoWnImKV4lie0p7F4IH04y-G6TfNgQ3O79N8tv84bc5-E3JF4f-SQ3Q_so9CE1AsQd2Db-3_1H7EyoiuGs</recordid><startdate>20170215</startdate><enddate>20170215</enddate><creator>Calderon, Lindsay E</creator><creator>Keeling, Jonathan K</creator><creator>Rollins, Joseph</creator><creator>Black, Carrie A</creator><creator>Collins, Kendall</creator><creator>Arnold, Nova</creator><creator>Vance, Diane E</creator><creator>Ndinguri, Margaret W</creator><general>American Chemical Society</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>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1773-9368</orcidid></search><sort><creationdate>20170215</creationdate><title>Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor</title><author>Calderon, Lindsay E ; Keeling, Jonathan K ; Rollins, Joseph ; Black, Carrie A ; Collins, Kendall ; Arnold, Nova ; Vance, Diane E ; Ndinguri, Margaret W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a418t-f57a3ba27ce7402b7e8b05d245fff2db748cc6b92fd6f8f6ef09ac3b2471ed213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>3T3 Cells</topic><topic>Animals</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Breast - drug effects</topic><topic>Breast - metabolism</topic><topic>Breast - pathology</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - drug effects</topic><topic>Cells</topic><topic>Chemical synthesis</topic><topic>Cisplatin - administration & dosage</topic><topic>Cisplatin - chemistry</topic><topic>Cisplatin - pharmacokinetics</topic><topic>Cisplatin - therapeutic use</topic><topic>Drug Delivery Systems</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gonadotropin-Releasing Hormone - administration & dosage</topic><topic>Gonadotropin-Releasing Hormone - chemistry</topic><topic>Gonadotropin-Releasing Hormone - pharmacokinetics</topic><topic>Gonadotropin-Releasing Hormone - therapeutic use</topic><topic>Humans</topic><topic>Lung - drug effects</topic><topic>Lung - pathology</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - pathology</topic><topic>Lung Neoplasms - secondary</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Receptors, LHRH - metabolism</topic><topic>Tumors</topic><topic>Up-Regulation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Calderon, Lindsay E</creatorcontrib><creatorcontrib>Keeling, Jonathan K</creatorcontrib><creatorcontrib>Rollins, Joseph</creatorcontrib><creatorcontrib>Black, Carrie A</creatorcontrib><creatorcontrib>Collins, Kendall</creatorcontrib><creatorcontrib>Arnold, Nova</creatorcontrib><creatorcontrib>Vance, Diane E</creatorcontrib><creatorcontrib>Ndinguri, Margaret W</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioconjugate chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Calderon, Lindsay E</au><au>Keeling, Jonathan K</au><au>Rollins, Joseph</au><au>Black, Carrie A</au><au>Collins, Kendall</au><au>Arnold, Nova</au><au>Vance, Diane E</au><au>Ndinguri, Margaret W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor</atitle><jtitle>Bioconjugate chemistry</jtitle><addtitle>Bioconjugate Chem</addtitle><date>2017-02-15</date><risdate>2017</risdate><volume>28</volume><issue>2</issue><spage>461</spage><epage>470</epage><pages>461-470</pages><issn>1043-1802</issn><eissn>1520-4812</eissn><abstract>A new targeting chemotherapeutic agent, Pt-Mal-LHRH, was synthesized by linking activated cisplatin to luteinizing hormone releasing hormone (LHRH). The compound’s efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, since the Pt-Mal-LHRH malonate linker chelates platinum in a similar manner to carboplatin. Breast cancer and normal cell viability were analyzed by an MTT assay comparing Pt-Mal-LHRH with carboplatin. Cells were also treated with either Pt-Mal-LHRH or carboplatin to evaluate platinum uptake by ICP-MS and cell migration using an in vitro scratch–migration assay. Tumor volume and metastasis were evaluated using an in vivo 4T1 mouse tumor model. Mice were administered Pt-Mal-LHRH (carboplatin molar equivalent dosage) through ip injection and compared to those treated with carboplatin (5 (mg/kg)/week), no treatment, and LHRH plus carboplatin (unbound) controls. An MTT assay showed a reduction in cell viability (p < 0.01) in 4T1 and MDA-MB-231 breast cancer cells treated with Pt-Mal-LHRH compared to carboplatin. Pt-Mal-LHRH was confirmed to be cytotoxic by flow cytometry using a propidium iodide stain. Pt-Mal-LHRH displayed a 20-fold increase in 4T1 cellular uptake compared to carboplatin. There was a decrease (p < 0.0001) in 4T1 cell viability compared to 3T3 normal fibroblast cells. Treatment with Pt-Mal-LHRH also resulted in a significant decrease in cell-migration compared to carboplatin. In vivo testing found a significant reduction in tumor volume (p < 0.05) and metastatic tumor colonization in the lungs with Pt-Mal-LHRH compared to carboplatin. There was a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicate that Pt-Mal-LHRH is a more potent and selective chemotherapeutic agent than untargeted carboplatin.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27997127</pmid><doi>10.1021/acs.bioconjchem.6b00610</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-1773-9368</orcidid></addata></record> |
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| ispartof | Bioconjugate chemistry, 2017-02, Vol.28 (2), p.461-470 |
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| subjects | 3T3 Cells Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Breast - drug effects Breast - metabolism Breast - pathology Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Line, Tumor Cell Movement - drug effects Cells Chemical synthesis Cisplatin - administration & dosage Cisplatin - chemistry Cisplatin - pharmacokinetics Cisplatin - therapeutic use Drug Delivery Systems Female Gene expression Gonadotropin-Releasing Hormone - administration & dosage Gonadotropin-Releasing Hormone - chemistry Gonadotropin-Releasing Hormone - pharmacokinetics Gonadotropin-Releasing Hormone - therapeutic use Humans Lung - drug effects Lung - pathology Lung Neoplasms - drug therapy Lung Neoplasms - pathology Lung Neoplasms - secondary Metastasis Mice Mice, Inbred BALB C Receptors, LHRH - metabolism Tumors Up-Regulation - drug effects |
| title | Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor |
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