Chemosensitization of hepatocellular carcinoma cells to sorafenib by β-caryophyllene oxide-induced inhibition of ABC export pumps
Several ATP-binding cassette (ABC) proteins reduce intracellular concentrations of antitumor drugs and hence weaken the response of cancer cells to chemotherapy. Accordingly, the inhibition of these export pumps constitutes a promising strategy to chemosensitize highly chemoresistant tumors, such as...
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| Veröffentlicht in: | Archives of toxicology 2019-03, Vol.93 (3), p.623-634 |
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| creator | Di Giacomo, Silvia Briz, Oscar Monte, Maria J. Sanchez-Vicente, Laura Abete, Lorena Lozano, Elisa Mazzanti, Gabriela Di Sotto, Antonella Marin, Jose J. G. |
| description | Several ATP-binding cassette (ABC) proteins reduce intracellular concentrations of antitumor drugs and hence weaken the response of cancer cells to chemotherapy. Accordingly, the inhibition of these export pumps constitutes a promising strategy to chemosensitize highly chemoresistant tumors, such as hepatocellular carcinoma (HCC). Here, we have investigated the ability of β-caryophyllene oxide (CRYO), a naturally occurring sesquiterpene component of many essential oils, to inhibit, at non-toxic doses, ABC pumps and improve the response of HCC cells to sorafenib. First, we have obtained a clonal subline (Alexander/R) derived from human hepatoma cells with enhanced multidrug resistance (MDR) associated to up-regulation (mRNA and protein) of MRP1 and MRP2. Analysis of fluorescent substrates export (flow cytometry) revealed that CRYO did not affect the efflux of fluorescein (MRP3, MRP4 and MRP5) but inhibited that of rhodamine 123 (MDR1) and calcein (MRP1 and MRP2). This ability was higher for CRYO than for other sesquiterpenes assayed. CRYO also inhibited sorafenib efflux, increased its intracellular accumulation (HPLC–MS/MS) and enhanced its cytotoxic response (MTT). For comparison, the effect of known ABC pumps inhibitors was also determined. They induced strong (diclofenac on MRPs), modest (verapamil on MDR1) or null (fumitremorgin C on BCRP) effect on sorafenib efflux and cytotoxicity. In the mouse xenograft model, the response to sorafenib treatment of subcutaneous tumors generated by mouse hepatoma Hepa 1–6/R cells, with marked MDR phenotype, was significantly enhanced by CRYO co-administration. In conclusion, at non-toxic dose, CRYO is able to chemosensitizating liver cancer cells to sorafenib by favoring its intracellular accumulation. |
| doi_str_mv | 10.1007/s00204-019-02395-9 |
| format | Article |
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G.</creator><creatorcontrib>Di Giacomo, Silvia ; Briz, Oscar ; Monte, Maria J. ; Sanchez-Vicente, Laura ; Abete, Lorena ; Lozano, Elisa ; Mazzanti, Gabriela ; Di Sotto, Antonella ; Marin, Jose J. G.</creatorcontrib><description>Several ATP-binding cassette (ABC) proteins reduce intracellular concentrations of antitumor drugs and hence weaken the response of cancer cells to chemotherapy. Accordingly, the inhibition of these export pumps constitutes a promising strategy to chemosensitize highly chemoresistant tumors, such as hepatocellular carcinoma (HCC). Here, we have investigated the ability of β-caryophyllene oxide (CRYO), a naturally occurring sesquiterpene component of many essential oils, to inhibit, at non-toxic doses, ABC pumps and improve the response of HCC cells to sorafenib. First, we have obtained a clonal subline (Alexander/R) derived from human hepatoma cells with enhanced multidrug resistance (MDR) associated to up-regulation (mRNA and protein) of MRP1 and MRP2. Analysis of fluorescent substrates export (flow cytometry) revealed that CRYO did not affect the efflux of fluorescein (MRP3, MRP4 and MRP5) but inhibited that of rhodamine 123 (MDR1) and calcein (MRP1 and MRP2). This ability was higher for CRYO than for other sesquiterpenes assayed. CRYO also inhibited sorafenib efflux, increased its intracellular accumulation (HPLC–MS/MS) and enhanced its cytotoxic response (MTT). For comparison, the effect of known ABC pumps inhibitors was also determined. They induced strong (diclofenac on MRPs), modest (verapamil on MDR1) or null (fumitremorgin C on BCRP) effect on sorafenib efflux and cytotoxicity. In the mouse xenograft model, the response to sorafenib treatment of subcutaneous tumors generated by mouse hepatoma Hepa 1–6/R cells, with marked MDR phenotype, was significantly enhanced by CRYO co-administration. In conclusion, at non-toxic dose, CRYO is able to chemosensitizating liver cancer cells to sorafenib by favoring its intracellular accumulation.</description><identifier>ISSN: 0340-5761</identifier><identifier>EISSN: 1432-0738</identifier><identifier>DOI: 10.1007/s00204-019-02395-9</identifier><identifier>PMID: 30659321</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Accumulation ; Animals ; Antineoplastic Agents - toxicity ; ATP-Binding Cassette Transporters - metabolism ; Biomedical and Life Sciences ; Biomedicine ; Calcein ; Cancer ; Carcinoma, Hepatocellular ; Caryophyllene ; Caryophyllene oxide ; Cell Line, Tumor ; Chemosensitization ; Chemotherapy ; Cytotoxicity ; Diclofenac ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm - drug effects ; Efflux ; Environmental Health ; Essential oils ; Exports ; Flow cytometry ; Fluorescein ; Fluorescence ; Hepatocellular carcinoma ; Hepatocytes ; Hepatoma ; High-performance liquid chromatography ; Humans ; Inhibition ; Inhibitor drugs ; Intracellular ; Liquid chromatography ; Liver ; Liver cancer ; Liver Neoplasms ; MDR1 protein ; Mice ; Molecular Toxicology ; mRNA ; Multidrug resistance ; Multidrug resistant organisms ; Neoplasm Proteins ; Occupational Medicine/Industrial Medicine ; P-Glycoprotein ; Pharmacology/Toxicology ; Phenotypes ; Polycyclic Sesquiterpenes - metabolism ; Proteins ; Pumps ; Rhodamine ; Sesquiterpenes ; Sorafenib - toxicity ; Substrates ; Targeted cancer therapy ; Toxicity ; Tumors ; Xenografts ; Xenotransplantation</subject><ispartof>Archives of toxicology, 2019-03, Vol.93 (3), p.623-634</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2019</rights><rights>Archives of Toxicology is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-2c448cb7fadff9d3252178fe4afdfeb99de1303cd0a62f7983a258d9bb1aead53</citedby><cites>FETCH-LOGICAL-c375t-2c448cb7fadff9d3252178fe4afdfeb99de1303cd0a62f7983a258d9bb1aead53</cites><orcidid>0000-0003-1186-6849</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00204-019-02395-9$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00204-019-02395-9$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30659321$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Di Giacomo, Silvia</creatorcontrib><creatorcontrib>Briz, Oscar</creatorcontrib><creatorcontrib>Monte, Maria J.</creatorcontrib><creatorcontrib>Sanchez-Vicente, Laura</creatorcontrib><creatorcontrib>Abete, Lorena</creatorcontrib><creatorcontrib>Lozano, Elisa</creatorcontrib><creatorcontrib>Mazzanti, Gabriela</creatorcontrib><creatorcontrib>Di Sotto, Antonella</creatorcontrib><creatorcontrib>Marin, Jose J. G.</creatorcontrib><title>Chemosensitization of hepatocellular carcinoma cells to sorafenib by β-caryophyllene oxide-induced inhibition of ABC export pumps</title><title>Archives of toxicology</title><addtitle>Arch Toxicol</addtitle><addtitle>Arch Toxicol</addtitle><description>Several ATP-binding cassette (ABC) proteins reduce intracellular concentrations of antitumor drugs and hence weaken the response of cancer cells to chemotherapy. Accordingly, the inhibition of these export pumps constitutes a promising strategy to chemosensitize highly chemoresistant tumors, such as hepatocellular carcinoma (HCC). Here, we have investigated the ability of β-caryophyllene oxide (CRYO), a naturally occurring sesquiterpene component of many essential oils, to inhibit, at non-toxic doses, ABC pumps and improve the response of HCC cells to sorafenib. First, we have obtained a clonal subline (Alexander/R) derived from human hepatoma cells with enhanced multidrug resistance (MDR) associated to up-regulation (mRNA and protein) of MRP1 and MRP2. Analysis of fluorescent substrates export (flow cytometry) revealed that CRYO did not affect the efflux of fluorescein (MRP3, MRP4 and MRP5) but inhibited that of rhodamine 123 (MDR1) and calcein (MRP1 and MRP2). This ability was higher for CRYO than for other sesquiterpenes assayed. CRYO also inhibited sorafenib efflux, increased its intracellular accumulation (HPLC–MS/MS) and enhanced its cytotoxic response (MTT). For comparison, the effect of known ABC pumps inhibitors was also determined. They induced strong (diclofenac on MRPs), modest (verapamil on MDR1) or null (fumitremorgin C on BCRP) effect on sorafenib efflux and cytotoxicity. In the mouse xenograft model, the response to sorafenib treatment of subcutaneous tumors generated by mouse hepatoma Hepa 1–6/R cells, with marked MDR phenotype, was significantly enhanced by CRYO co-administration. In conclusion, at non-toxic dose, CRYO is able to chemosensitizating liver cancer cells to sorafenib by favoring its intracellular accumulation.</description><subject>Accumulation</subject><subject>Animals</subject><subject>Antineoplastic Agents - toxicity</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Calcein</subject><subject>Cancer</subject><subject>Carcinoma, Hepatocellular</subject><subject>Caryophyllene</subject><subject>Caryophyllene oxide</subject><subject>Cell Line, Tumor</subject><subject>Chemosensitization</subject><subject>Chemotherapy</subject><subject>Cytotoxicity</subject><subject>Diclofenac</subject><subject>Drug Resistance, Multiple</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Efflux</subject><subject>Environmental Health</subject><subject>Essential oils</subject><subject>Exports</subject><subject>Flow cytometry</subject><subject>Fluorescein</subject><subject>Fluorescence</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatocytes</subject><subject>Hepatoma</subject><subject>High-performance liquid chromatography</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Inhibitor drugs</subject><subject>Intracellular</subject><subject>Liquid chromatography</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Liver Neoplasms</subject><subject>MDR1 protein</subject><subject>Mice</subject><subject>Molecular Toxicology</subject><subject>mRNA</subject><subject>Multidrug resistance</subject><subject>Multidrug resistant organisms</subject><subject>Neoplasm Proteins</subject><subject>Occupational Medicine/Industrial Medicine</subject><subject>P-Glycoprotein</subject><subject>Pharmacology/Toxicology</subject><subject>Phenotypes</subject><subject>Polycyclic Sesquiterpenes - metabolism</subject><subject>Proteins</subject><subject>Pumps</subject><subject>Rhodamine</subject><subject>Sesquiterpenes</subject><subject>Sorafenib - toxicity</subject><subject>Substrates</subject><subject>Targeted cancer therapy</subject><subject>Toxicity</subject><subject>Tumors</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>0340-5761</issn><issn>1432-0738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kMFO3DAQhi1UBFvaF-BQWerZdGwnm_gIq9JWQuJCz5Zjj1mjxE7tRGJ75JH6IDxTQxfKjdNIM9_8o_kIOeVwxgGaLwVAQMWAKwZCqpqpA7LilRQMGtm-IyuQFbC6WfNj8r6UOwAuWiWPyLGEda2k4CvysNnikArGEqbw20whRZo83eJopmSx7-feZGpNtiGmwdCnVqFToiVl4zGGjnY7-viHLcgujdtd32NEmu6DQxaimy06GuI2dOEl-_xiQ_F-THmi4zyM5QM59KYv-PG5npCfl19vNt_Z1fW3H5vzK2ZlU09M2Kpqbdd447xXTopa8Kb1WBnvPHZKOeQSpHVg1sI3qpVG1K1TXccNGlfLE_J5nzvm9GvGMum7NOe4nNSCr9sKJK_ahRJ7yuZUSkavxxyG5TnNQT9p13vtetGu_2nXaln69Bw9dwO6_ysvnhdA7oGyjOIt5tfbb8T-BaPMkfc</recordid><startdate>20190301</startdate><enddate>20190301</enddate><creator>Di Giacomo, Silvia</creator><creator>Briz, Oscar</creator><creator>Monte, Maria J.</creator><creator>Sanchez-Vicente, Laura</creator><creator>Abete, Lorena</creator><creator>Lozano, Elisa</creator><creator>Mazzanti, Gabriela</creator><creator>Di Sotto, Antonella</creator><creator>Marin, Jose J. 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G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-2c448cb7fadff9d3252178fe4afdfeb99de1303cd0a62f7983a258d9bb1aead53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Accumulation</topic><topic>Animals</topic><topic>Antineoplastic Agents - toxicity</topic><topic>ATP-Binding Cassette Transporters - metabolism</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Calcein</topic><topic>Cancer</topic><topic>Carcinoma, Hepatocellular</topic><topic>Caryophyllene</topic><topic>Caryophyllene oxide</topic><topic>Cell Line, Tumor</topic><topic>Chemosensitization</topic><topic>Chemotherapy</topic><topic>Cytotoxicity</topic><topic>Diclofenac</topic><topic>Drug Resistance, Multiple</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Efflux</topic><topic>Environmental Health</topic><topic>Essential oils</topic><topic>Exports</topic><topic>Flow cytometry</topic><topic>Fluorescein</topic><topic>Fluorescence</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatocytes</topic><topic>Hepatoma</topic><topic>High-performance liquid chromatography</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Inhibitor drugs</topic><topic>Intracellular</topic><topic>Liquid chromatography</topic><topic>Liver</topic><topic>Liver cancer</topic><topic>Liver Neoplasms</topic><topic>MDR1 protein</topic><topic>Mice</topic><topic>Molecular Toxicology</topic><topic>mRNA</topic><topic>Multidrug resistance</topic><topic>Multidrug resistant organisms</topic><topic>Neoplasm Proteins</topic><topic>Occupational Medicine/Industrial Medicine</topic><topic>P-Glycoprotein</topic><topic>Pharmacology/Toxicology</topic><topic>Phenotypes</topic><topic>Polycyclic Sesquiterpenes - metabolism</topic><topic>Proteins</topic><topic>Pumps</topic><topic>Rhodamine</topic><topic>Sesquiterpenes</topic><topic>Sorafenib - toxicity</topic><topic>Substrates</topic><topic>Targeted cancer therapy</topic><topic>Toxicity</topic><topic>Tumors</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Di Giacomo, Silvia</creatorcontrib><creatorcontrib>Briz, Oscar</creatorcontrib><creatorcontrib>Monte, Maria J.</creatorcontrib><creatorcontrib>Sanchez-Vicente, Laura</creatorcontrib><creatorcontrib>Abete, Lorena</creatorcontrib><creatorcontrib>Lozano, Elisa</creatorcontrib><creatorcontrib>Mazzanti, Gabriela</creatorcontrib><creatorcontrib>Di Sotto, Antonella</creatorcontrib><creatorcontrib>Marin, Jose J. 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G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chemosensitization of hepatocellular carcinoma cells to sorafenib by β-caryophyllene oxide-induced inhibition of ABC export pumps</atitle><jtitle>Archives of toxicology</jtitle><stitle>Arch Toxicol</stitle><addtitle>Arch Toxicol</addtitle><date>2019-03-01</date><risdate>2019</risdate><volume>93</volume><issue>3</issue><spage>623</spage><epage>634</epage><pages>623-634</pages><issn>0340-5761</issn><eissn>1432-0738</eissn><abstract>Several ATP-binding cassette (ABC) proteins reduce intracellular concentrations of antitumor drugs and hence weaken the response of cancer cells to chemotherapy. Accordingly, the inhibition of these export pumps constitutes a promising strategy to chemosensitize highly chemoresistant tumors, such as hepatocellular carcinoma (HCC). Here, we have investigated the ability of β-caryophyllene oxide (CRYO), a naturally occurring sesquiterpene component of many essential oils, to inhibit, at non-toxic doses, ABC pumps and improve the response of HCC cells to sorafenib. First, we have obtained a clonal subline (Alexander/R) derived from human hepatoma cells with enhanced multidrug resistance (MDR) associated to up-regulation (mRNA and protein) of MRP1 and MRP2. Analysis of fluorescent substrates export (flow cytometry) revealed that CRYO did not affect the efflux of fluorescein (MRP3, MRP4 and MRP5) but inhibited that of rhodamine 123 (MDR1) and calcein (MRP1 and MRP2). This ability was higher for CRYO than for other sesquiterpenes assayed. CRYO also inhibited sorafenib efflux, increased its intracellular accumulation (HPLC–MS/MS) and enhanced its cytotoxic response (MTT). For comparison, the effect of known ABC pumps inhibitors was also determined. They induced strong (diclofenac on MRPs), modest (verapamil on MDR1) or null (fumitremorgin C on BCRP) effect on sorafenib efflux and cytotoxicity. In the mouse xenograft model, the response to sorafenib treatment of subcutaneous tumors generated by mouse hepatoma Hepa 1–6/R cells, with marked MDR phenotype, was significantly enhanced by CRYO co-administration. In conclusion, at non-toxic dose, CRYO is able to chemosensitizating liver cancer cells to sorafenib by favoring its intracellular accumulation.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>30659321</pmid><doi>10.1007/s00204-019-02395-9</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-1186-6849</orcidid></addata></record> |
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| subjects | Accumulation Animals Antineoplastic Agents - toxicity ATP-Binding Cassette Transporters - metabolism Biomedical and Life Sciences Biomedicine Calcein Cancer Carcinoma, Hepatocellular Caryophyllene Caryophyllene oxide Cell Line, Tumor Chemosensitization Chemotherapy Cytotoxicity Diclofenac Drug Resistance, Multiple Drug Resistance, Neoplasm - drug effects Efflux Environmental Health Essential oils Exports Flow cytometry Fluorescein Fluorescence Hepatocellular carcinoma Hepatocytes Hepatoma High-performance liquid chromatography Humans Inhibition Inhibitor drugs Intracellular Liquid chromatography Liver Liver cancer Liver Neoplasms MDR1 protein Mice Molecular Toxicology mRNA Multidrug resistance Multidrug resistant organisms Neoplasm Proteins Occupational Medicine/Industrial Medicine P-Glycoprotein Pharmacology/Toxicology Phenotypes Polycyclic Sesquiterpenes - metabolism Proteins Pumps Rhodamine Sesquiterpenes Sorafenib - toxicity Substrates Targeted cancer therapy Toxicity Tumors Xenografts Xenotransplantation |
| title | Chemosensitization of hepatocellular carcinoma cells to sorafenib by β-caryophyllene oxide-induced inhibition of ABC export pumps |
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