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The chlorin <jats:styled-content style=\"fixed-case\">NP<\/jats:styled-content>e6 and the benzoporphyrin derivative (<jats:styled-content style=\"fixed-case\">BPD<\/jats:styled-content>) were used to separately target lysosomes and mitochondria, respectively, in murine hepatoma cells. Lyso\u2010<jats:styled-content style=\"fixed-case\">PDT<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content><jats:sub>5<\/jats:sub> conditions) followed by mito\u2010<jats:styled-content style=\"fixed-case\">PDT<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content><jats:sub>15<\/jats:sub> conditions) enhanced the loss of the mitochondrial membrane potential, activation of procaspases\u20103\/7 and photokilling. Reversing the sequence was less effective. The optimal sequence did not enhance reactive oxygen species formation above that obtained with low\u2010dose mito\u2010<jats:styled-content style=\"fixed-case\">PDT<\/jats:styled-content>. In contrast, alkalinization of lysosomes with bafilomycin also enhanced low\u2010dose mito\u2010<jats:styled-content style=\"fixed-case\">PDT<\/jats:styled-content> photokilling, but via a different pathway. This involves redistribution of iron from lysosomes to mitochondria leading to enhanced hydroxyl radical formation, effects not observed after the sequential procedure. Moreover, Ru360, an inhibitor of mitochondrial calcium and iron uptake, partially suppressed the ability of bafilomycin to enhance mito\u2010<jats:styled-content style=\"fixed-case\">PDT<\/jats:styled-content> photokilling without affecting the enhanced efficacy of the sequential protocol. We conclude that sequential <jats:styled-content style=\"fixed-case\">PDT<\/jats:styled-content> protocol promotes <jats:styled-content style=\"fixed-case\">PDT<\/jats:styled-content> efficacy by a process not involving iron translocation, but via promotion of the pro\u2010apoptotic signal that derives from mitochondrial photodamage.<\/jats:p>","DOI":"10.1111\/php.12270","type":"journal-article","created":{"date-parts":[[2014,3,12]],"date-time":"2014-03-12T08:27:26Z","timestamp":1394612846000},"page":"889-895","source":"Crossref","is-referenced-by-count":56,"title":["Enhanced Efficacy of Photodynamic Therapy via a Sequential Targeting Protocol"],"prefix":"10.1111","volume":"90","author":[{"given":"David","family":"Kessel","sequence":"first","affiliation":[{"name":"Department of Pharmacology Wayne State University Detroit MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr","given":"John J.","family":"Reiners","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Wayne State University Detroit MI"},{"name":"Institute of Environmental Health Sciences Wayne State University Detroit MI"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,4]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/90.12.889"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.20114"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1562\/0031-8655(2000)0710634QAOPLI2.0.CO2"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107678200"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.2007.00088.x"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1562\/0031-8655(2003)0780001ABTPLO2.0.CO2"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1338.035"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-697-9_3"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.2012.01081.x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.422667"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401048"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2010.11.006"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008944200"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400783"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/c0pp00276c"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.2012.01106.x"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1039\/c2sc21649c"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.9.15865"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.2009.00555.x"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijch.201100059"},{"key":"e_1_2_6_22_1","first-page":"6985","article-title":"Potentiation of photodynamic therapy by ursodeoxycholic acid","volume":"60","author":"Kessel D.","year":"2000","journal-title":"Cancer Res."},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1562\/0031-8655(2000)0710196DOTART2.0.CO2"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/php.12027"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.21.7972"},{"key":"e_1_2_6_26_1","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.2174\/0929867306666220401184707","article-title":"Chemistry and structure activity relationships of bafiomycin A1, a potent and selective inhibitor of the vacuolar H+\u2010ATPase","volume":"6","author":"Gagliardi S.","year":"1999","journal-title":"Curr. 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