title: Radiosensitization by celastrol is mediated by modification of antioxidant thiol molecules.
abstract: The radiosensitizing effects of naturally occurring triterpenes were investigated in human lung cancer cells. Several quinone methide-containing triterpenes (QMTs) enhanced the cytotoxic effect of ionizing radiation (IR) and of these QMTs, celastrol (CE) had the greatest enhancing effect on IR-induced cell death in vitro. Additionally, the quinone methide moiety of CE was shown to be essential for CE-mediated radiosensitization; in contrast, dihydrocelastrol (DHCE), does not contain this moiety. Reactive oxygen species (ROS) production by IR was augmented in combination with CE, which was responsible for CE-mediated radiosensitization. CE induced the thiol reactivity and inhibited the activities of antioxidant molecules, such as thioredoxin reductase and glutathione. In vivo, nude mouse xenografting data also revealed that tumor growth delay was greater in mice treated with CE plus IR, compared with those treated with CE or IR alone. When DHCE, instead of CE, was combined with IR, tumor growth delay was similar to that in IR alone-treated mice. These results demonstrate that CE synergistically enhances the effects of IR and suggest the novel anticancer therapeutic use of CE in combination with radiation therapy.
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Haeng Ran
authors.initials: HR
authors.lastname: Seo
authors.forename: Woo Duck
authors.initials: WD
authors.lastname: Seo
authors.forename: Bo-Jeong
authors.initials: BJ
authors.lastname: Pyun
authors.forename: Byong Won
authors.initials: BW
authors.lastname: Lee
authors.forename: Yeung Bae
authors.initials: YB
authors.lastname: Jin
authors.forename: Ki Hun
authors.initials: KH
authors.lastname: Park
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Seo
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D053978:Pentacyclic Triterpenes; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D014183:Transplantation, Heterologous; D014315:Triterpenes / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D053978:Pentacyclic Triterpenes; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D014315:Triterpenes; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione; C050414:celastrol