title: Miltirone exhibits antileukemic activity by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction pathways.
abstract: In this study, we investigated the effects of miltirone in human leukemia cell lines, primary leukemia cells, and nude mice U937 xenograft. Treatment of cells with miltirone resulted in apoptosis, mitochondria membrane potential (MMP) collapses, increase of Bax/Bcl-2 ratio, and cytochrome c release. Miltirone triggered the endoplasmic reticulum (ER) stress identified through several key molecules of the unfolded protein response, including phosphorylated PERK, eIF2a, GRP78, GRP94, and caspase-12. Miltrone treatment also resulted in the release of Ca(2+) from the ER stores and mitochondrial Ca(2+) loading in the cells. Further research revealed that miltirone resulted in dose-dependent decrease in complex III activity and elevated reactive oxygen species (ROS) production in these cells. Miltirone-induced apoptosis, dissipation of MMP and ER stress were dramatically blocked by pretreatment with antioxidant N-acetylcysteine (NAC). In contrast, treatment with ER stress inhibitor TUDCA significantly attenuated miltirone-induced ROS and apoptosis in leukemia cells. Moreover, our in vivo findings showed that administration of miltirone markedly inhibited tumor growth and induced apoptosis in U937 xenograft model with low systemic toxicity. Taken together, these findings indicate that miltirone may exert its antileukemic activity by inducing apoptosis through a ROS-dependent destructive cycle involving ER stress and mitochondrial dysfunction.
authors: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.|School of Pharmacy, Binzhou Medical University, Guanhai Road 346, Yantai, Shandong 264003, China.
authors: Ling
authors: L
authors: Zhou
authors: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors: Lifeng
authors: L
authors: Jiang
authors: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.|School of Pharmacy, Binzhou Medical University, Guanhai Road 346, Yantai, Shandong 264003, China.
authors: Maolei
authors: M
authors: Xu
authors: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors: Qun
authors: Q
authors: Liu
authors: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors: Ning
authors: N
authors: Gao
authors: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors: Ping
authors: P
authors: Li
authors: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors: E-Hu
authors: EH
authors: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; C068880:miltirone