Oncotarget

Research Papers:

The photosensitizer verteporfin has light-independent anti-leukemic activity for Ph-positive acute lymphoblastic leukemia and synergistically works with dasatinib

Takanobu Morishita, Fumihiko Hayakawa _, Keiki Sugimoto, Mizuho Iwase, Hideyuki Yamamoto, Daiki Hirano, Yuki Kojima, Naoto Imoto, Tomoki Naoe and Hitoshi Kiyoi

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:56241-56252. https://doi.org/10.18632/oncotarget.11025

Metrics: PDF 746 views  |   HTML 1018 views  |   ?  


Abstract

Takanobu Morishita1, Fumihiko Hayakawa1, Keiki Sugimoto2, Mizuho Iwase3, Hideyuki Yamamoto1, Daiki Hirano1, Yuki Kojima1, Naoto Imoto1, Tomoki Naoe4 and Hitoshi Kiyoi1

1 Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2 Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan

3 Department of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan

4 National Hospital Organization Nagoya Medical Center, Nagoya, Japan

Correspondence to:

Fumihiko Hayakawa, email:

Keywords: drug screening, patient-derived xenograft, Ph+ ALL, verteporfin, drug repositioning

Received: July 10, 2016 Accepted: July 23, 2016 Published: August 02, 2016

Abstract

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 11025