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Wen-Jian Liu,1,* Yi-Bo Yin,1,* Jing-Yi Sun,2,* Sai Feng,3 Jin-Kui Ma,4 Xiao-Yan Fu,5 Ya-Jun Hou,5 Ming-Feng Yang,5 Bao-Liang Sun,1,5 Cun-Dong Fan5 1Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, People’s Republic of China; 2Department of Orthopaedics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Gangwon, Korea; 3Guangzhou New BenFu Technology Co., Ltd, Guangzhou, Guangdong, People’s Republic of China; 4Faculty of Bioresource Sciences, Akita Prefectural University, Shimoshinjo-Nakano, Akita-shi, Akita, Japan; 5Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, People’s Republic of China *These authors contributed equally to this work Background: Temozolomide (TMZ)-based chemotherapy represents an effective way for treating human glioma. However, its clinical application is limited because of its side effects and resistance to standard chemotherapy. Hence, the search for novel chemosensitizers to augment their anticancer efficiency has attracted much attention. Natural borneol (NB) has been identified as a potential chemosensitizer in treating human cancers. However, the synergistic effect and mechanism of NB and TMZ in human glioma have not been investigated yet. Materials and methods: U251 human glioma cells were cultured, and the cytotoxicity and apoptosis of NB and/or TMZ were examined by MTT assay, flow cytometric analysis and Western blot. Nude mice tumor model was also employed to evaluate the in vivo anticancer effect and mechanism. Results: The results showed that the combined treatment of NB and TMZ more effectively inhibited human glioma growth via triggering mitochondria-mediated apoptosis in vitro, accompanied by the caspase activation. Combined treatment of NB and TMZ also caused mitochondrial dysfunction through disturbing Bcl-2 family expression. Further investigation revealed that NB enhanced TMZ-induced DNA damage through inducing reactive oxide species (ROS) overproduction. Moreover, glioma tumor xenograft growth in vivo was more effectively inhibited by the combined treatment with NB and TMZ through triggering apoptosis and anti-angiogenesis. Conclusion: Taken together, our findings validated that the strategy of using NB and TMZ could be a highly efficient way to achieve anticancer synergism. Keywords: glioma, borneol, temozolomide, DNA damage, apoptosis |
