Xiang-Rong Ni1, Cheng-Cheng Guo1, Yan-Jiao Yu1, Zhi-Hui Yu1, Hai-Ping Cai1, Wei-Chi Wu1, Jun-Xiao Ma1, Fu-Rong Chen1, Jing Wang2, Zhong-Ping Chen3. 1. Department of Neurosurgery/Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Rd East, Guangdong, 510060, People's Republic of China. 2. Department of Neurosurgery/Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Rd East, Guangdong, 510060, People's Republic of China. wangj@sysucc.org.cn. 3. Department of Neurosurgery/Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Rd East, Guangdong, 510060, People's Republic of China. chenzhp@sysucc.org.cn.
Abstract
PURPOSE: Glioma, especially glioblastoma (GBM), is the most aggressive malignant brain tumor and its standard therapy is often ineffective because of temozolomide (TMZ) resistance. Reversal of the TMZ resistance might improve the prognosis of glioma patients. We previously found that interferon-α (IFN-α) and anti-epileptic drug levetiracetam (LEV) could sensitize glioma to TMZ, respectively. In this study, we further investigated the efficiency of combining of LEV and IFN-α for improving the efficacy of TMZ. METHODS: We evaluated whether LEV and IFN-α could increase TMZ efficacy using colony formation assay and cell viability assay with MGMT-positive and MGMT-negative glioma cell lines in vitro. Subcutaneous xenografts and orthotopic xenografts mice models were used in vivo to observe the tumor growth and mice survival upon treatments with TMZ, TMZ + IFN-α, TMZ + LEV, or TMZ + LEV + IFN-α. The expression levels of MGMT, markers of pro-apoptotic and anti-apoptotic in tumor samples were analyzed by Western blotting. RESULTS: The combinational use of IFN-α, LEV, and TMZ showed the best anti-tumor activity in MGMT-positive cell lines (U138, GSC-1, U118, and T98 G). TMZ + LEV + IFN-α further obviously increased TMZ + LEV or TMZ + IFN-α efficiency in MGMT-positive cell lines, while not in negative cell lines (SKMG-4, U87, U373, and U251) in vitro, which were also observed in subcutaneous mice models (U138, GSC-1 compared to SKMG-4, U87) and orthotopic models (GSC-1) in vivo. Strikingly, the combination of LEV and IFN-α together with TMZ significantly prolonged the survival of mice with orthotopic GSC-1 glioma. Furthermore, we confirmed that the combination of LEV and IFN-α enhanced the inhibition of MGMT and the activation of apoptosis in U138 tumor on the basis of TMZ treatment. CONCLUSIONS: The combination use of LEV and IFN-α could be an optimal method to overcome TMZ resistance through obvious MGMT inhibition in MGMT-positive glioma.
PURPOSE:Glioma, especially glioblastoma (GBM), is the most aggressive malignant brain tumor and its standard therapy is often ineffective because of temozolomide (TMZ) resistance. Reversal of the TMZ resistance might improve the prognosis of gliomapatients. We previously found that interferon-α (IFN-α) and anti-epileptic drug levetiracetam (LEV) could sensitize glioma to TMZ, respectively. In this study, we further investigated the efficiency of combining of LEV and IFN-α for improving the efficacy of TMZ. METHODS: We evaluated whether LEV and IFN-α could increase TMZ efficacy using colony formation assay and cell viability assay with MGMT-positive and MGMT-negative glioma cell lines in vitro. Subcutaneous xenografts and orthotopic xenografts mice models were used in vivo to observe the tumor growth and mice survival upon treatments with TMZ, TMZ + IFN-α, TMZ + LEV, or TMZ + LEV + IFN-α. The expression levels of MGMT, markers of pro-apoptotic and anti-apoptotic in tumor samples were analyzed by Western blotting. RESULTS: The combinational use of IFN-α, LEV, and TMZ showed the best anti-tumor activity in MGMT-positive cell lines (U138, GSC-1, U118, and T98 G). TMZ + LEV + IFN-α further obviously increased TMZ + LEV or TMZ + IFN-α efficiency in MGMT-positive cell lines, while not in negative cell lines (SKMG-4, U87, U373, and U251) in vitro, which were also observed in subcutaneous mice models (U138, GSC-1 compared to SKMG-4, U87) and orthotopic models (GSC-1) in vivo. Strikingly, the combination of LEV and IFN-α together with TMZ significantly prolonged the survival of mice with orthotopic GSC-1 glioma. Furthermore, we confirmed that the combination of LEV and IFN-α enhanced the inhibition of MGMT and the activation of apoptosis in U138 tumor on the basis of TMZ treatment. CONCLUSIONS: The combination use of LEV and IFN-α could be an optimal method to overcome TMZ resistance through obvious MGMT inhibition in MGMT-positive glioma.
Entities:
Keywords:
Combination chemotherapy; Drug resistance; Glioma; Interferon-α; Levetiracetam; Temozolomide