Combination treatment with arsenic trioxide and irradiation enhances autophagic effects in U118-MG cells through increased mitotic arrest and regulation of PI3K/Akt and ERK1/2 signaling pathways.
Malignant gliomas are resistant to many kinds of treatments including chemotherapy, radiotherapy and other adjuvant therapies. Autophagy is a novel response of cancer cells to ionizing radiation (IR) or chemotherapy, but its significance and underlying mechanism remains largely elusive. Induction of autophagy in glioma cells using irradiation and arsenic trioxide (ATO) has been reported separately. However, the combined effects of ATO and IR on the cell death processes of malignant glioma cells have not been thoroughly studied, especially in U118-MG cells. In the present study, we investigated the anticancer effect of IR combined with ATO and the underlying mechanisms on U118-MG human malignant glioma cells in vitro. We found that the enhanced cytotoxic effect of IR combined with ATO was through induction of more autophagy in U118-MG cells, which were characterized by the presence of acidic vascular organelle formation, determined by electron microscopic observation and immunoblotting of LC3. Combined treatment could induce more mitotic arrest compared to ATO or IR alone. In addition, we also found that the combined treatment-induced autophagy occurred through inhibition of PI3K/Akt and activation of ERK1/2 signaling pathways. These findings suggest a potential therapeutic strategy for malignant gliomas, which are resistant to various proapoptotic therapies.
Chiu
Hui-Wen
HW
Department of Environmental and Occupational Health, National Cheng Kung University, Medical College, 138 Sheng-Li Road, Tainan, Taiwan.
Ho
Sheng-Yow
SY
Guo
How-Ran
HR
Wang
Ying-Jan
YJ
D000165:Acridine Orange; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects* / Q000528:radiation effects*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000528:radiation effects / Q000648:ultrastructure; D004307:Dose-Response Relationship, Radiation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000528:radiation effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D008940:Mitotic Index; D010087:Oxides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011839:Radiation, Ionizing; D013997:Time Factors
D000165:Acridine Orange; D000077237:Arsenic Trioxide; D001152:Arsenicals; D048049:Extracellular Signal-Regulated MAP Kinases; D008869:Microtubule-Associated Proteins; D010087:Oxides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C477012:MAP1LC3A protein, human