Poly‐S‐nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide
Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short‐term therapeutic effects, whereas long‐term therapeutic benefits are rarely observed, probably due to hypoxia‐induced autophagy. Nitric oxide (NO) is an importa...
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| Veröffentlicht in: | Cancer science 2015-02, Vol.106 (2), p.194-200 |
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| creator | Ishima, Yu Inoue, Aki Fang, Jun Kinoshita, Ryo Ikeda, Mayumi Watanabe, Hiroshi Maeda, Hiroshi Otagiri, Masaki Maruyama, Toru |
| description | Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short‐term therapeutic effects, whereas long‐term therapeutic benefits are rarely observed, probably due to hypoxia‐induced autophagy. Nitric oxide (NO) is an important molecule with multiple functions, and it has recently been reported to function as a regulator of autophagy. Therefore, a reasonable therapeutic strategy for overcoming drug resistance by NO would involve it being directly delivered to the tumor. Here, we investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S‐nitrosated human serum albumin (SNO‐HSA) with a high degree of NO loading and tumor targeting potential. In colon 26 (C26) cells, SNO‐HSA significantly suppressed hypoxia‐induced autophagy by inhibiting the phosphorylation of JNK1 and the expression of its downstream molecule Beclin1. The effect of SNO‐HSA was also confirmed in vivo by combining it with Bev. In C26‐bearing mice, significant suppression of tumor growth as well as lung metastasis was achieved in the combination group compared to the SNO‐HSA or bevacizumab alone group. Similar to the in vitro experiments, the immunostaining of tumor tissues clearly showed that SNO‐HSA inhibited the autophagy of tumor cells induced by bevacizumab treatment. In addition to other known antitumor effects of SNO‐HSA, that is, the induction of apoptosis and the inhibition of multidrug efflux pumps, these data may open alternate strategies for cancer chemotherapy by taking advantage of the ability of SNO‐HSA to suppress autophagy‐mediated drug resistance and enhance the efficacy of chemotherapy.
Autophagy is one of the major causes of drug resistance. We investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S‐nitrosated human albumin (SNO‐HSA) with a high degree of NO loading and tumor targeting potential. As the result, the combination therapy of SNO‐HSA/bevacizumab resulted in a significant decrease in lung metastasis. |
| doi_str_mv | 10.1111/cas.12577 |
| format | Article |
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Autophagy is one of the major causes of drug resistance. We investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S‐nitrosated human albumin (SNO‐HSA) with a high degree of NO loading and tumor targeting potential. As the result, the combination therapy of SNO‐HSA/bevacizumab resulted in a significant decrease in lung metastasis.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.12577</identifier><identifier>PMID: 25457681</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Albumin ; Angiogenesis ; Angiogenesis inhibitors ; Animals ; Antibodies, Monoclonal, Humanized - pharmacology ; Antineoplastic Agents - pharmacology ; Antitumor activity ; Apoptosis ; Apoptosis - drug effects ; Apoptosis Regulatory Proteins - metabolism ; Autophagy ; Autophagy - drug effects ; Beclin-1 ; Bevacizumab ; Cancer therapies ; Cell Line, Tumor ; Chemotherapy ; Clinical trials ; Colon ; Colorectal cancer ; Drug resistance ; Glycoproteins ; Human serum albumin ; Humans ; Hypoxia ; Immunotherapy ; Macromolecules ; Membrane Proteins - metabolism ; Metastases ; Metastasis ; Mice ; Mitogen-Activated Protein Kinase 8 - metabolism ; Molecular weight ; Monoclonal antibodies ; Neoplasm Metastasis - drug therapy ; Nitric oxide ; Nitric Oxide - metabolism ; Nitroso Compounds - metabolism ; Original ; Phagocytosis ; Phosphorylation ; Phosphorylation - drug effects ; Serum Albumin - metabolism ; Serum Albumin, Human ; SNO‐HSA ; Studies ; Targeted cancer therapy ; Tumor cells ; Vascular endothelial growth factor</subject><ispartof>Cancer science, 2015-02, Vol.106 (2), p.194-200</ispartof><rights>2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.</rights><rights>2015. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4677-ff3419acc405bdc0730b9c2637e028a8ef71c7cdbfb41f794d9995d66de234e3</citedby><cites>FETCH-LOGICAL-c4677-ff3419acc405bdc0730b9c2637e028a8ef71c7cdbfb41f794d9995d66de234e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399024/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399024/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1416,11561,27923,27924,45573,45574,46051,46475,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25457681$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishima, Yu</creatorcontrib><creatorcontrib>Inoue, Aki</creatorcontrib><creatorcontrib>Fang, Jun</creatorcontrib><creatorcontrib>Kinoshita, Ryo</creatorcontrib><creatorcontrib>Ikeda, Mayumi</creatorcontrib><creatorcontrib>Watanabe, Hiroshi</creatorcontrib><creatorcontrib>Maeda, Hiroshi</creatorcontrib><creatorcontrib>Otagiri, Masaki</creatorcontrib><creatorcontrib>Maruyama, Toru</creatorcontrib><title>Poly‐S‐nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short‐term therapeutic effects, whereas long‐term therapeutic benefits are rarely observed, probably due to hypoxia‐induced autophagy. Nitric oxide (NO) is an important molecule with multiple functions, and it has recently been reported to function as a regulator of autophagy. Therefore, a reasonable therapeutic strategy for overcoming drug resistance by NO would involve it being directly delivered to the tumor. Here, we investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S‐nitrosated human serum albumin (SNO‐HSA) with a high degree of NO loading and tumor targeting potential. In colon 26 (C26) cells, SNO‐HSA significantly suppressed hypoxia‐induced autophagy by inhibiting the phosphorylation of JNK1 and the expression of its downstream molecule Beclin1. The effect of SNO‐HSA was also confirmed in vivo by combining it with Bev. In C26‐bearing mice, significant suppression of tumor growth as well as lung metastasis was achieved in the combination group compared to the SNO‐HSA or bevacizumab alone group. Similar to the in vitro experiments, the immunostaining of tumor tissues clearly showed that SNO‐HSA inhibited the autophagy of tumor cells induced by bevacizumab treatment. In addition to other known antitumor effects of SNO‐HSA, that is, the induction of apoptosis and the inhibition of multidrug efflux pumps, these data may open alternate strategies for cancer chemotherapy by taking advantage of the ability of SNO‐HSA to suppress autophagy‐mediated drug resistance and enhance the efficacy of chemotherapy.
Autophagy is one of the major causes of drug resistance. We investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S‐nitrosated human albumin (SNO‐HSA) with a high degree of NO loading and tumor targeting potential. As the result, the combination therapy of SNO‐HSA/bevacizumab resulted in a significant decrease in lung metastasis.</description><subject>Albumin</subject><subject>Angiogenesis</subject><subject>Angiogenesis inhibitors</subject><subject>Animals</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Beclin-1</subject><subject>Bevacizumab</subject><subject>Cancer therapies</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Colon</subject><subject>Colorectal cancer</subject><subject>Drug resistance</subject><subject>Glycoproteins</subject><subject>Human serum albumin</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Immunotherapy</subject><subject>Macromolecules</subject><subject>Membrane Proteins - metabolism</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinase 8 - metabolism</subject><subject>Molecular weight</subject><subject>Monoclonal antibodies</subject><subject>Neoplasm Metastasis - drug therapy</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitroso Compounds - metabolism</subject><subject>Original</subject><subject>Phagocytosis</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Serum Albumin - metabolism</subject><subject>Serum Albumin, Human</subject><subject>SNO‐HSA</subject><subject>Studies</subject><subject>Targeted cancer therapy</subject><subject>Tumor cells</subject><subject>Vascular endothelial growth factor</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kt1qFDEUgAdRbK1e-AIS8EbBbZOZTDK5KZSl_kBBob0PmczJTMpMsiaZ6njVR_A5fCyfxOxuLSoYEs4J-fg44ZyieE7wMcnrRKt4TMqa8wfFIamoWHGM2cNdzlcCV-VB8STGa4wrRgV9XByUNa05a8hh8eOTH5eft98v83E2BR9Vgg4N86QcUmM7T9YhcINyGiJKAyDlkk3z5EPOut1tgqRi3jYiMAZ0Qt6gFm6Utt-yp32DNiqkcUHtgqwbbGuTdT1Sc_KbQfVL1gY_98NO34ODoJL1bmvZlmQ18l9tB0-LR0aNEZ7dxaPi6u351fr96uLjuw_rs4uVpozzlTEVJUJpTXHddhrzCrdCl6zigMtGNWA40Vx3rWkpMVzQTghRd4x1UFYUqqPidK_dzO0EnQaXghrlJthJhUV6ZeXfL84Osvc3klZC4JJmwas7QfCfZ4hJTjZqGEflwM9RElY3lDSc44y-_Ae99nNw-XeyLBvBWM0rlqnXe0rn9sQA5r4YguV2AGQeALkbgMy--LP6e_J3xzNwsge-2BGW_5vk-uxyr_wFAPnB8g</recordid><startdate>201502</startdate><enddate>201502</enddate><creator>Ishima, Yu</creator><creator>Inoue, Aki</creator><creator>Fang, Jun</creator><creator>Kinoshita, Ryo</creator><creator>Ikeda, Mayumi</creator><creator>Watanabe, Hiroshi</creator><creator>Maeda, Hiroshi</creator><creator>Otagiri, Masaki</creator><creator>Maruyama, Toru</creator><general>John Wiley & Sons, Inc</general><general>BlackWell Publishing Ltd</general><scope>24P</scope><scope>WIN</scope><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>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201502</creationdate><title>Poly‐S‐nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide</title><author>Ishima, Yu ; Inoue, Aki ; Fang, Jun ; Kinoshita, Ryo ; Ikeda, Mayumi ; Watanabe, Hiroshi ; Maeda, Hiroshi ; Otagiri, Masaki ; Maruyama, Toru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4677-ff3419acc405bdc0730b9c2637e028a8ef71c7cdbfb41f794d9995d66de234e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Albumin</topic><topic>Angiogenesis</topic><topic>Angiogenesis inhibitors</topic><topic>Animals</topic><topic>Antibodies, Monoclonal, Humanized - pharmacology</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Beclin-1</topic><topic>Bevacizumab</topic><topic>Cancer therapies</topic><topic>Cell Line, Tumor</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Colon</topic><topic>Colorectal cancer</topic><topic>Drug resistance</topic><topic>Glycoproteins</topic><topic>Human serum albumin</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Immunotherapy</topic><topic>Macromolecules</topic><topic>Membrane Proteins - metabolism</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinase 8 - metabolism</topic><topic>Molecular weight</topic><topic>Monoclonal antibodies</topic><topic>Neoplasm Metastasis - drug therapy</topic><topic>Nitric oxide</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitroso Compounds - metabolism</topic><topic>Original</topic><topic>Phagocytosis</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Serum Albumin - metabolism</topic><topic>Serum Albumin, Human</topic><topic>SNO‐HSA</topic><topic>Studies</topic><topic>Targeted cancer therapy</topic><topic>Tumor cells</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ishima, Yu</creatorcontrib><creatorcontrib>Inoue, Aki</creatorcontrib><creatorcontrib>Fang, Jun</creatorcontrib><creatorcontrib>Kinoshita, Ryo</creatorcontrib><creatorcontrib>Ikeda, Mayumi</creatorcontrib><creatorcontrib>Watanabe, Hiroshi</creatorcontrib><creatorcontrib>Maeda, Hiroshi</creatorcontrib><creatorcontrib>Otagiri, Masaki</creatorcontrib><creatorcontrib>Maruyama, Toru</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ishima, Yu</au><au>Inoue, Aki</au><au>Fang, Jun</au><au>Kinoshita, Ryo</au><au>Ikeda, Mayumi</au><au>Watanabe, Hiroshi</au><au>Maeda, Hiroshi</au><au>Otagiri, Masaki</au><au>Maruyama, Toru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Poly‐S‐nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2015-02</date><risdate>2015</risdate><volume>106</volume><issue>2</issue><spage>194</spage><epage>200</epage><pages>194-200</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short‐term therapeutic effects, whereas long‐term therapeutic benefits are rarely observed, probably due to hypoxia‐induced autophagy. Nitric oxide (NO) is an important molecule with multiple functions, and it has recently been reported to function as a regulator of autophagy. Therefore, a reasonable therapeutic strategy for overcoming drug resistance by NO would involve it being directly delivered to the tumor. Here, we investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S‐nitrosated human serum albumin (SNO‐HSA) with a high degree of NO loading and tumor targeting potential. In colon 26 (C26) cells, SNO‐HSA significantly suppressed hypoxia‐induced autophagy by inhibiting the phosphorylation of JNK1 and the expression of its downstream molecule Beclin1. The effect of SNO‐HSA was also confirmed in vivo by combining it with Bev. In C26‐bearing mice, significant suppression of tumor growth as well as lung metastasis was achieved in the combination group compared to the SNO‐HSA or bevacizumab alone group. Similar to the in vitro experiments, the immunostaining of tumor tissues clearly showed that SNO‐HSA inhibited the autophagy of tumor cells induced by bevacizumab treatment. In addition to other known antitumor effects of SNO‐HSA, that is, the induction of apoptosis and the inhibition of multidrug efflux pumps, these data may open alternate strategies for cancer chemotherapy by taking advantage of the ability of SNO‐HSA to suppress autophagy‐mediated drug resistance and enhance the efficacy of chemotherapy.
Autophagy is one of the major causes of drug resistance. We investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S‐nitrosated human albumin (SNO‐HSA) with a high degree of NO loading and tumor targeting potential. As the result, the combination therapy of SNO‐HSA/bevacizumab resulted in a significant decrease in lung metastasis.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>25457681</pmid><doi>10.1111/cas.12577</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Albumin Angiogenesis Angiogenesis inhibitors Animals Antibodies, Monoclonal, Humanized - pharmacology Antineoplastic Agents - pharmacology Antitumor activity Apoptosis Apoptosis - drug effects Apoptosis Regulatory Proteins - metabolism Autophagy Autophagy - drug effects Beclin-1 Bevacizumab Cancer therapies Cell Line, Tumor Chemotherapy Clinical trials Colon Colorectal cancer Drug resistance Glycoproteins Human serum albumin Humans Hypoxia Immunotherapy Macromolecules Membrane Proteins - metabolism Metastases Metastasis Mice Mitogen-Activated Protein Kinase 8 - metabolism Molecular weight Monoclonal antibodies Neoplasm Metastasis - drug therapy Nitric oxide Nitric Oxide - metabolism Nitroso Compounds - metabolism Original Phagocytosis Phosphorylation Phosphorylation - drug effects Serum Albumin - metabolism Serum Albumin, Human SNO‐HSA Studies Targeted cancer therapy Tumor cells Vascular endothelial growth factor |
| title | Poly‐S‐nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide |
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