title: Ursolic acid attenuates temozolomide resistance in glioblastoma cells by downregulating O(6)-methylguanine-DNA methyltransferase (MGMT) expression.
abstract: The DNA-alkylating agent temozolomide (TMZ) is an effective chemotherapeutic agent against malignant glioma, including glioblastoma multiforme (GBM). However, the clinical efficacy of TMZ is limited in many patients because of O(6)-methylguanine-DNA methyltransferase (MGMT)-driven resistance. Thus, new strategies to overcome TMZ resistance are urgently needed. Ursolic acid (UA) is a naturally derived pentacyclic triterpene acid that exerts broad anticancer effects, and shows capability to cross the blood-brain barrier. In this study, we evaluated the possible synergistic effect of TMZ and UA in resistant GBM cell lines. The results showed that UA prevented the proliferation of resistant GBM cells in a concentration-dependent manner. Compared with TMZ or UA treatment alone, the combination treatment of TMZ and UA synergistically enhanced cytotoxicity and senescence in TMZ-resistant GBM cells. This effect was correlated with the downregulation of MGMT. Moreover, experimental results with an in vivo mouse xenograft model showed that the combination treatment of UA and TMZ reduced tumor volumes by depleting MGMT. Therefore, UA as both a monotherapy and a resensitizer, might be a candidate agent for patients with refractory malignant gliomas.
authors: Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and HospitalTianjin 300060, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and TherapyTianjin 300060, China.
authors: Zhongling
authors: Z
authors: Zhu
authors: Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and HospitalTianjin 300060, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and TherapyTianjin 300060, China.
authors: Shuangshuang
authors: S
authors: Du
authors: Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and HospitalTianjin 300060, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and TherapyTianjin 300060, China.
authors: Fengxia
authors: F
authors: Ding
authors: Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and HospitalTianjin 300060, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and TherapyTianjin 300060, China.
authors: Shanshan
authors: S
authors: Guo
authors: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and TherapyTianjin 300060, China; Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and HospitalTianjin 300060, China.
authors: Guoguang
authors: G
authors: Ying
authors: Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and HospitalTianjin 300060, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and TherapyTianjin 300060, China.
authors: Zhao
authors: Z
authors: Yan
keywords: O6-methylguanine-DNA methyltransferase; Ursolic acid; glioblastoma; senescence; temozolomide