{"created":"2023-05-15T14:52:16.621874+00:00","id":71373,"links":{},"metadata":{"_buckets":{"deposit":"0d16f777-5925-4647-9187-b602d2804a29"},"_deposit":{"created_by":1,"id":"71373","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"71373"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00071373","sets":["10:28"]},"author_link":["701780","701788","701784","701778","701785","701786","701789","701781","701782","701783","701787","701779"],"item_10005_date_7":{"attribute_name":"発表年月日","attribute_value_mlt":[{"subitem_date_issued_datetime":"2013-09-25","subitem_date_issued_type":"Issued"}]},"item_10005_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Purpose/Objective (s): Radiation therapy for cancer often has severe side effects that limit its efficacy. Because these side effects are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to relieve the damage of normal tissues during treatment of p53-deficient tumors. On the other hand, it is known that dissociation of a zinc ion, which is coordinated to metal ion binding site of p53, could induce p53 denaturation, hence we evaluated some zinc chelators as radioprotective p53 inhibitor. As a result, we found 5-chloro-8-quinolinol (KH-3) as a radioprotector that can protect mice from a sublethal dose of 7.5 Gy total-body irradiation (TBI). In this study, we investigated the effects and mechanism of KH-3 comparatively to a known radioprotective p53 inhibitor, PFTm.\n \nMaterials /Methods: Imprinting control region (ICR) female mice, aged 8-week old, were total-body irradiated with an X-ray generator (Pantak-320S, Shimadzu) operated at 200 kV at a dose rate of 0.66 Gy/min. KH-3 (35 mg/kg) or vehicle was ip injected 30 minutes before 7.5 Gy TBI. In cell analysis, highly radiosensitive cell line MOLT-4, derived from human T-cell leukemia, was used and 10 Gy-irradiated. The suppressive effect of KH-3 and the reference compound PFTm on radiation-induced MOLT-4 apoptosis was evaluated using Annexin V-FITC or MitoTracker Red staining. To examine the specificity of KH-3 for p53-mediated apoptosis, we used MOLT-4 cells and their derivatives, namely, p53-knockdown transformant and p53 revertant which re-expressed p53 using shRNA-resistant FLAG-tagged p53-expressing plasmid. To elucidate the mechanism of action of KH-3 in p53-mediated apoptotic pathway, we mainly investigated the expression of p53 target-genes, p21 and PUMA, using quantitative real-time PCR and immunoblotting analyses.\n \nResults: For the 30-day survival study, half of the animals in the KH-3-treated group survived, whereas all the mice receiving only TBI died within 14 days (P < 0.01). Cell death analysis revealed that KH-3 had a higher inhibitory effect on cell death and lower toxicity than that of PFTm in the MOLT-4 cells. KH-3 was ineffective against the radiation-induced apoptosis of p53-knockdown transformant, but suppressed that of p53 revertant. Results indictated that suppression of radiation-induced apoptosis by KH-3 was specifically mediated through p53 signaling pathways. Furthermore, KH-3 modulated p53 target-gene expression without affecting p53 expression. In particular, p21, which has anti-apoptotic activity, was markedly up-regulated by KH-3.\n \nConclusion: KH-3 is a novel kind of radioprotector that modulates p53 transcription. The radioprotective effect of KH-3 may be associated with its ability to up-regulate p21 expression.","subitem_description_type":"Abstract"}]},"item_10005_description_6":{"attribute_name":"会議概要（会議名, 開催地, 会期, 主催者等）","attribute_value_mlt":[{"subitem_description":"American Society for Radiation Oncology (ASTRO) Annual Meeting","subitem_description_type":"Other"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"metadata only access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_14cb"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"高橋, 一平"}],"nameIdentifiers":[{"nameIdentifier":"701778","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"森田, 明典"}],"nameIdentifiers":[{"nameIdentifier":"701779","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"青木, 伸"}],"nameIdentifiers":[{"nameIdentifier":"701780","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"王, 冰"}],"nameIdentifiers":[{"nameIdentifier":"701781","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"細井, 義夫"}],"nameIdentifiers":[{"nameIdentifier":"701782","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"兼安, 祐子"}],"nameIdentifiers":[{"nameIdentifier":"701783","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"権丈, 雅浩"}],"nameIdentifiers":[{"nameIdentifier":"701784","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"木村, 智樹"}],"nameIdentifiers":[{"nameIdentifier":"701785","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"村上, 雄二"}],"nameIdentifiers":[{"nameIdentifier":"701786","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"永田, 靖"}],"nameIdentifiers":[{"nameIdentifier":"701787","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"王 冰","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"701788","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"細井 義夫","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"701789","nameIdentifierScheme":"WEKO"}]}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"conference object","resourceuri":"http://purl.org/coar/resource_type/c_c94f"}]},"item_title":"The mechanism of a novel radioprotector, 8-quinolinol derivative KH-3","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"The mechanism of a novel radioprotector, 8-quinolinol derivative KH-3"}]},"item_type_id":"10005","owner":"1","path":["28"],"pubdate":{"attribute_name":"公開日","attribute_value":"2013-11-18"},"publish_date":"2013-11-18","publish_status":"0","recid":"71373","relation_version_is_last":true,"title":["The mechanism of a novel radioprotector, 8-quinolinol derivative KH-3"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T19:52:00.551686+00:00"}