The photosensitizer verteporfin has light-independent anti-leukemic activity for Ph-positive acute lymphoblastic leukemia and synergistically works with dasatinib
Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, particularly from the viewpoints of microenvironmental independence. Patient-derived xenografts (PDX) are established by the transfer of primary tumor cells directly from patients into immunodeficient mice and can provide primary-like tumor cells of the amount needed at the desired time. We developed a high-throughput drug screening system using PDX cells and performed drug screening using the PDX cells of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). We established four Ph+ ALL PDX mice and performed high-throughput screening of 3440 compounds using leukemia cells from the PDX mice (PDX-cell screening). The profiles of drugs selected by PDX-cell screening were markedly different from those by screening using the Ph+ ALL cell line. We found that verteporfin, an FDA-approved drug, exhibited strong PDX cell-specific cytotoxicity. In the validation assay, its GI50 was 228 nM, 395 nM, and 538 nM in three PDX cells and 3.93 µM, 2.11 µM, and 5.61 µM in three cell lines. Although verteporfin is a photosensitizer activated by photoirradiation, its cytotoxic effects were mediated by the light-independent production of reactive oxygen species; therefore, its anti-leukemic effects were also exerted in vivo without photoirradiation. Furthermore, it exhibited synergistic effects with dasatinib, an ABL kinase inhibitor. These results indicated the potential of verteporfin as a new anti-leukemic reagent.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
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| Enthalten in: |
Oncotarget - 7(2016), 35 vom: 30. Aug., Seite 56241-56252 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Morishita, Takanobu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.01.2018 Date Revised 02.12.2018 published: Print Citation Status MEDLINE |
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| doi: |
10.18632/oncotarget.11025 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM263159485 |
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| 245 | 1 | 4 | |a The photosensitizer verteporfin has light-independent anti-leukemic activity for Ph-positive acute lymphoblastic leukemia and synergistically works with dasatinib |
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| 520 | |a Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, particularly from the viewpoints of microenvironmental independence. Patient-derived xenografts (PDX) are established by the transfer of primary tumor cells directly from patients into immunodeficient mice and can provide primary-like tumor cells of the amount needed at the desired time. We developed a high-throughput drug screening system using PDX cells and performed drug screening using the PDX cells of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). We established four Ph+ ALL PDX mice and performed high-throughput screening of 3440 compounds using leukemia cells from the PDX mice (PDX-cell screening). The profiles of drugs selected by PDX-cell screening were markedly different from those by screening using the Ph+ ALL cell line. We found that verteporfin, an FDA-approved drug, exhibited strong PDX cell-specific cytotoxicity. In the validation assay, its GI50 was 228 nM, 395 nM, and 538 nM in three PDX cells and 3.93 µM, 2.11 µM, and 5.61 µM in three cell lines. Although verteporfin is a photosensitizer activated by photoirradiation, its cytotoxic effects were mediated by the light-independent production of reactive oxygen species; therefore, its anti-leukemic effects were also exerted in vivo without photoirradiation. Furthermore, it exhibited synergistic effects with dasatinib, an ABL kinase inhibitor. These results indicated the potential of verteporfin as a new anti-leukemic reagent | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Hayakawa, Fumihiko |e verfasserin |4 aut | |
| 700 | 1 | |a Sugimoto, Keiki |e verfasserin |4 aut | |
| 700 | 1 | |a Iwase, Mizuho |e verfasserin |4 aut | |
| 700 | 1 | |a Yamamoto, Hideyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Hirano, Daiki |e verfasserin |4 aut | |
| 700 | 1 | |a Kojima, Yuki |e verfasserin |4 aut | |
| 700 | 1 | |a Imoto, Naoto |e verfasserin |4 aut | |
| 700 | 1 | |a Naoe, Tomoki |e verfasserin |4 aut | |
| 700 | 1 | |a Kiyoi, Hitoshi |e verfasserin |4 aut | |
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