1. Molecular targeting therapy against promyelocytic leukemia protein using arsenic acids in experimental intracranial medulloblastoma.
- Author
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Gu C, Yokota N, Gao Y, Amano S, Koizumi S, Tokuyama T, and Namba H
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Arsenates pharmacology, Arsenic Trioxide, Arsenicals therapeutic use, Cell Line, Tumor, Cerebellar Neoplasms metabolism, Cerebellar Neoplasms physiopathology, Cytarabine pharmacology, Cytarabine therapeutic use, Humans, Medulloblastoma metabolism, Medulloblastoma physiopathology, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Experimental metabolism, Neoplasms, Experimental physiopathology, Nuclear Proteins metabolism, Oxides therapeutic use, Promyelocytic Leukemia Protein, Transcription Factors metabolism, Tumor Suppressor Proteins metabolism, Arsenates therapeutic use, Arsenicals pharmacology, Cerebellar Neoplasms drug therapy, Medulloblastoma drug therapy, Molecular Targeted Therapy methods, Neoplasms, Experimental drug therapy, Nuclear Proteins antagonists & inhibitors, Oxides pharmacology, Transcription Factors antagonists & inhibitors, Tumor Suppressor Proteins antagonists & inhibitors
- Abstract
Our previous study using human Daoy medulloblastoma cells showed that the promyelocytic leukemia (PML) gene was significantly upregulated (2.5-fold) in cells positive to prominin-1 antigen (CD133), a possible marker for cancer initiating cells. Arsenic trioxide (As(2)O(3)) is known to degrade PML protein and has been used for the treatment of patients with acute PML. In the present study, the effect of PML targeting therapy with As(2)O(3) and cytarabine (Ara-C) on Daoy medulloblastoma cell proliferation was investigated. Daoy cells were pretreated with As(2)O(3) for 6 weeks. The As(2)O(3)-pretreated Daoy cells were cultured in medium containing Ara-C and cell viability was examined. Next, the As(2)O(3)-pretreated Daoy cells were inoculated into the nude mouse brain and the effect of Ara-C on the tumor size was evaluated. A significant increase in chemosensitivity to Ara-C was observed in the As(2)O(3)-pretreated Daoy cells in both in vitro and in vivo conditions. PML and CCND1 (cyclin D1) protein expression of Daoy medulloblastoma cells was downregulated by As(2)O(3) treatment. PML has been proposed as a novel therapeutic target to eradicate quiescent leukemia-initiating cells, and PML-expressing CD133-positive cells are similarly a potential therapeutic target of treatment for medulloblastoma.
- Published
- 2012
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