Interferon-α/β enhances temozolomide activity against MGMT-positive glioma stem-like cells.
Glioma is one of the most common primary tumors of the central nervous system in adults. Glioblastoma (GBM) is the most lethal type of glioma, whose 5-year survival is 9.8% at best. Glioma stem-like cells (GSCs) play an important role in recurrence and treatment resistance. MGMT is a DNA repair protein that removes DNA adducts and therefore attenuates treatment efficiency. It has been reported that interferon-α/β (IFN-α/β) downregulates the level of MGMT and sensitizes glioma cells to temozolomide. In the present study, we assessed whether IFN-α/β is able to sensitize GSCs to temozolomide by modulating MGMT expression. Upon the treatment of IFN-α/β, the efficacy of temozolomide against MGMT‑positive GSCs was markedly enhanced by combination treatment with IFN-α/β when compared with the temozolomide single agent group, and MGMT expression was markedly decreased at the same time. Further mechanistic study showed that IFN-α/β suppressed the NF-κB activity, which further mediated the sensitization of MGMT‑positive GSCs to temozolomide. Our data therefore demonstrated that the application of IFN-α/β is a promising agent with which to enhance temozolomide efficiency and reduce drug resistance, and our findings shed light on improving clinical outcomes and prolonging the survival of patients with malignant gliomas.
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Dong
D
Shen
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Cheng-Cheng
CC
Guo
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Jing
J
Wang
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Zhi-Kun
ZK
Qiu
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Ke
K
Sai
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Qun-Ying
QY
Yang
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Yin-Sheng
YS
Chen
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Fu-Rong
FR
Chen
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Jie
J
Wang
Department of Oncology, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
Lawrence
L
Panasci
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Zhong-Ping
ZP
Chen
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007370:Interferon Type I; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide