SMARCB1/INI1 de ciency is seen in several malignant tumors including malignant rhabdoid tumor (MRT), a highly aggressive pediatric malignancy. Loss of SMARCB1/INI1 function alters diverse oncogenic cellular signals, making it di cult to discover effective targeting therapy. By utilizing an in vitro drug screening system, effective therapeutic agents against SMARCB1/INI1-de cient tumors were explored in this study.In the in vitro drug sensitivity test, 80 agents with various actions were screened for their cytotoxicity in a panel of ve SMARCB1/INI1-de cient tumor cell lines. The combination effect was screened based on the Bliss independent model. The growth inhibitory effect was determined in both the conventional twodimensional culture and the collagen-embedded three-dimensional culture system. Survivin expression after agent exposure was determined by Western blot analysis.All ve cell lines were found to be sensitive to YM155, a selective survivin inhibitor. In the drug combination screening, YM155 showed additive to synergistic effects with various agents including chrysin. Chrysin enhanced YM155-induced apoptosis, but not mitochondrial depolarization upon exposure of SMARCB1/INI1-de cient tumor cells to the two agents for 6 hours. YM155 and chrysin synergistically suppressed survivin expression, especially in TTN45 cells in which such suppression was observed as early as 6 hours after exposure to the two agents.Survivin is suggested to be a therapeutic target in MRT and other SMARCB1/INI1-de cient tumors. Chrysin, a avone that is widely distributed in plants, cooperatively suppressed survivin expression and enhanced the cytotoxicity of YM155.
Approximately 20% of patients with transient abnormal myelopoiesis (TAM) die due to hepatic or multiorgan failure. To identify potential new treatments for TAM, we performed in vitro drug sensitivity testing (DST) using the peripheral blood samples of eight patients with TAM. DST screened 41 agents for cytotoxic properties against TAM blasts. Compared with the reference samples of healthy subjects, TAM blasts were more sensitive to glucocorticoids, the mitogen-activated protein kinase kinase (MAP2K) inhibitor trametinib, and cytarabine. Our present results support the therapeutic potential of glucocorticoids and the role of the RAS/ MAP2K signalling pathway in TAM pathogenesis.
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SMARCB1/INI1 deficiency is seen in several malignant tumors including malignant rhabdoid tumor (MRT), a highly aggressive pediatric malignancy. Loss of SMARCB1/INI1 function alters diverse oncogenic cellular signals, making it difficult to discover effective targeting therapy. By utilizing an in vitro drug screening system, effective therapeutic agents against SMARCB1/INI1-deficient tumors were explored in this study.In the in vitro drug sensitivity test, 80 agents with various actions were screened for their cytotoxicity in a panel of five SMARCB1/INI1-deficient tumor cell lines. The combination effect was screened based on the Bliss independent model. The growth inhibitory effect was determined in both the conventional two-dimensional culture and the collagen-embedded three-dimensional culture system. Survivin expression after agent exposure was determined by Western blot analysis.All five cell lines were found to be sensitive to YM155, a selective survivin inhibitor. In the drug combination screening, YM155 showed additive to synergistic effects with various agents including chrysin. Chrysin enhanced YM155-induced apoptosis, but not mitochondrial depolarization upon exposure of SMARCB1/INI1-deficient tumor cells to the two agents for 6 hours. YM155 and chrysin synergistically suppressed survivin expression, especially in TTN45 cells in which such suppression was observed as early as 6 hours after exposure to the two agents.Survivin is suggested to be a therapeutic target in MRT and other SMARCB1/INI1-deficient tumors. Chrysin, a flavone that is widely distributed in plants, cooperatively suppressed survivin expression and enhanced the cytotoxicity of YM155.
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