Oncology Medical News about Ewing sarcoma;adtinomycin D;mitogen-activaterd protein kinase;phosphatidylinositol 3-kinase

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Simultaneous inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways augment the sensitivity to actinomycin D in Ewing sarcoma
Journal of Cancer Research & Clinical Oncology, 02/17/09

Yamamoto T et al. - In a trial to determine the role of EWS/Fli-1 fusion and its downstream targets regarding the cells’ resistance against actinomycin D (ActD), it was demonstrated that combination U0126 and LY294002 can augment cytotoxicity of ActD against Ewing sarcoma cells in vitro and in vivo.

Methods

Cytotoxicity was measured by WST-8 assay.
Caspase-dependent and -independent cell death was examined by fluorescence microscope; protein expression was analyzed by western blotting.
Caspase activity was determined by Caspase-Glo assay.

Results

ActD induced caspase-dependent apoptotic cell death to Ewing sarcoma TC-135 cells in a dose- and time- dependent manner.
Knockdown of EWS/Fli-1 fusion by siRNA resulted in enhancement of ActD-induced apoptosis.
ActD treatment activated both mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways although in a distinctive manner.
Combined administration of U0126 and LY294002 significantly enhanced ActD-induced apoptosis in vitro and suppressed xenograft tumor growth in vivo.

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