The effect of iron ion on the specificity of photodynamic therapy with 5-aminolevulinic acid
Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells,...
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| description | Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. Using SFC as a source of iron might thus increase the specificity of ALA-PDT effects. |
| doi_str_mv | 10.1371/journal.pone.0122351 |
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ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. 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This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Hayashi et al 2015 Hayashi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c736t-fd3b55c0144fc1bcfbc8eec224622f02118af1137c11b749b8964c308dd96a073</citedby><cites>FETCH-LOGICAL-c736t-fd3b55c0144fc1bcfbc8eec224622f02118af1137c11b749b8964c308dd96a073</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/PMC4379089/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379089/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25822972$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hayashi, Maiko</creatorcontrib><creatorcontrib>Fukuhara, Hideo</creatorcontrib><creatorcontrib>Inoue, Keiji</creatorcontrib><creatorcontrib>Shuin, Taro</creatorcontrib><creatorcontrib>Hagiya, Yuichiro</creatorcontrib><creatorcontrib>Nakajima, Motowo</creatorcontrib><creatorcontrib>Tanaka, Tohru</creatorcontrib><creatorcontrib>Ogura, Shun-ichiro</creatorcontrib><title>The effect of iron ion on the specificity of photodynamic therapy with 5-aminolevulinic acid</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. Using SFC as a source of iron might thus increase the specificity of ALA-PDT effects.</description><subject>Accumulation</subject><subject>Acids</subject><subject>Aminolevulinic acid</subject><subject>Aminolevulinic Acid - pharmacology</subject><subject>Biosynthesis</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cation Transport Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Citric acid</subject><subject>Glucose</subject><subject>Health aspects</subject><subject>Heme</subject><subject>Heme - metabolism</subject><subject>Humans</subject><subject>Iron</subject><subject>Iron - metabolism</subject><subject>MCF-7 Cells</subject><subject>Medical schools</subject><subject>Metabolism</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial DNA</subject><subject>Photochemotherapy</subject><subject>Photochemotherapy - methods</subject><subject>Photodynamic therapy</subject><subject>Photosensitizing Agents - pharmacology</subject><subject>Physiological aspects</subject><subject>Protoporphyrin</subject><subject>Protoporphyrin IX</subject><subject>Protoporphyrins - metabolism</subject><subject>Sensitivity and Specificity</subject><subject>Side effects</subject><subject>Sodium</subject><subject>Substrates</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Urology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1uL1DAUx4so7kW_gWhBEH2YMbemzYuwLF4GFhZ09UkIaZpMM2SabpKuO9_edKe7TGUfpG1azvmdf3pOzsmyVxAsIS7hx40bfCfssnedWgKIEC7gk-wYMowWFAH89OD7KDsJYQNAgStKn2dHqKgQYiU6zn5ftSpXWisZc6dz412Xm_SkOyZP6JU02kgTd6O7b110za4TWyNHvxf9Lv9jYpsXi2TrnFU3gzVd8gppmhfZMy1sUC-n92n288vnq_Nvi4vLr6vzs4uFLDGNC93guigkgIRoCWupa1kpJREiFCENEISV0DAlLSGsS8LqilEiMaiahlEBSnyavdnr9tYFPhUmcEhpSSkkJU3Eak80Tmx4781W-B13wvA7g_NrLnw00iqu61pjREuMtCAkLUoQhkpIICxFxeqk9Wnabai3qpGqi17Ymejc05mWr90NJ7hkoGJJ4P0k4N31oELkWxOkslZ0yg13_10hTBkgCX37D_p4dhO1FikB02mX9pWjKD8jkAFMUTVqLR-h0tWodJypi7RJ9lnAh1lAYqK6jWsxhMBXP77_P3v5a86-O2BbJWxsg7NDTI0X5iDZg9K7ELzSD0WGgI9DcF8NPg4Bn4Yghb0-PKCHoPuux38Ba1cBHQ</recordid><startdate>20150330</startdate><enddate>20150330</enddate><creator>Hayashi, Maiko</creator><creator>Fukuhara, Hideo</creator><creator>Inoue, Keiji</creator><creator>Shuin, Taro</creator><creator>Hagiya, Yuichiro</creator><creator>Nakajima, Motowo</creator><creator>Tanaka, Tohru</creator><creator>Ogura, Shun-ichiro</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150330</creationdate><title>The effect of iron ion on the specificity of photodynamic therapy with 5-aminolevulinic acid</title><author>Hayashi, Maiko ; Fukuhara, Hideo ; Inoue, Keiji ; Shuin, Taro ; Hagiya, Yuichiro ; Nakajima, Motowo ; Tanaka, Tohru ; Ogura, Shun-ichiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c736t-fd3b55c0144fc1bcfbc8eec224622f02118af1137c11b749b8964c308dd96a073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Accumulation</topic><topic>Acids</topic><topic>Aminolevulinic acid</topic><topic>Aminolevulinic Acid - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hayashi, Maiko</au><au>Fukuhara, Hideo</au><au>Inoue, Keiji</au><au>Shuin, Taro</au><au>Hagiya, Yuichiro</au><au>Nakajima, Motowo</au><au>Tanaka, Tohru</au><au>Ogura, Shun-ichiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The effect of iron ion on the specificity of photodynamic therapy with 5-aminolevulinic acid</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-03-30</date><risdate>2015</risdate><volume>10</volume><issue>3</issue><spage>e0122351</spage><epage>e0122351</epage><pages>e0122351-e0122351</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. Using SFC as a source of iron might thus increase the specificity of ALA-PDT effects.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25822972</pmid><doi>10.1371/journal.pone.0122351</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Accumulation Acids Aminolevulinic acid Aminolevulinic Acid - pharmacology Biosynthesis Biotechnology Cancer Cancer therapies Cation Transport Proteins - metabolism Cell Line, Tumor Citric acid Glucose Health aspects Heme Heme - metabolism Humans Iron Iron - metabolism MCF-7 Cells Medical schools Metabolism Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondrial DNA Photochemotherapy Photochemotherapy - methods Photodynamic therapy Photosensitizing Agents - pharmacology Physiological aspects Protoporphyrin Protoporphyrin IX Protoporphyrins - metabolism Sensitivity and Specificity Side effects Sodium Substrates Tumor cells Tumors Urology |
| title | The effect of iron ion on the specificity of photodynamic therapy with 5-aminolevulinic acid |
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