title: Curcumin sensitizes glioblastoma to temozolomide by simultaneously generating ROS and disrupting AKT/mTOR signaling.
abstract: Temozolomide (TMZ), a DNA alkylating agent, represents the most important chemotherapeutic option for the treatment of glioblastoma in the clinic. Despite its frequent use, the therapeutic efficacy of TMZ remains very limited due to its frequent resistance in glioblastoma. Previous evidence suggested that curcumin (CUM), an ingredient of the Indian spice turmeric, is able to sensitize glioblastoma to TMZ treatment. However, the underlying molecular mechanism remains elusive. In the present study, we performed in vitro and in vivo experiments to evaluate the interaction of CUM and TMZ on the inhibition of glioblastoma and to investigate its potential mechanisms of action using U87MG cell lines and xenograft mouse models. We demonstrated that CUM enhanced the therapeutic response to TMZ in U87MG glioblastoma by enhancing apoptosis. We then proceeded to investigate the potential apoptotic signaling pathways that are involved. We observed a synergistic effect of the combination of CUM and TMZ in generating reactive oxygen species (ROS) production, suggesting that ROS may contribute to the impact of CUM on sensitizing TMZ treatment. We also showed that CUM and TMZ treatment alone significantly suppressed phosphorylated AKT and mTOR, whereas their combination achieved a more pronounced inhibitory effect. These data indicated that blockage of AKT/mTOR signaling appeared to contribute to the elevated apoptosis caused by the combination treatment with CUM and TMZ. In conclusion, this study provided molecular insights into the effects of CUM on the therapeutic response of glioblastoma to TMZ and opened new avenues for optimizing the therapeutic effects of TMZ-based therapies.
authors: Department of Radiotherapy, The Central Hospital of Xuzhou, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, P.R. China.
authors: Haitao
authors: H
authors: Yin
authors: Department of Radiotherapy, The Central Hospital of Xuzhou, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, P.R. China.
authors: Yun
authors: Y
authors: Zhou
authors: Department of Radiotherapy, The Central Hospital of Xuzhou, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, P.R. China.
authors: Cuixia
authors: C
authors: Wen
authors: Department of Radiotherapy, The Central Hospital of Xuzhou, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, P.R. China.
authors: Chong
authors: C
authors: Zhou
authors: Department of Radiotherapy, The Central Hospital of Xuzhou, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, P.R. China.
authors: Wei
authors: W
authors: Zhang
authors: Department of Radiotherapy, The Central Hospital of Xuzhou, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, P.R. China.
authors: Xiang
authors: X
authors: Hu
authors: Department of Oncology, Drum Tower Hospital Affiliated to Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, P.R. China.
authors: Lifeng
authors: L
authors: Wang
authors: Department of Oncology, Suqian People's Hospital, Suqian, Jiangsu, P.R. China.
authors: Chuanwen
authors: C
authors: You
authors: Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, P.R. China.
authors: Junfei
authors: J
authors: Shao
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; D003606:Dacarbazine; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D003474:Curcumin; D000077204:Temozolomide