TWI835370B - Ppar激動劑在製備治療急性髓細胞白血病的藥物中的應用 - Google Patents
Ppar激動劑在製備治療急性髓細胞白血病的藥物中的應用 Download PDFInfo
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- TWI835370B TWI835370B TW111140518A TW111140518A TWI835370B TW I835370 B TWI835370 B TW I835370B TW 111140518 A TW111140518 A TW 111140518A TW 111140518 A TW111140518 A TW 111140518A TW I835370 B TWI835370 B TW I835370B
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Abstract
本發明提供了PPAR激動劑在製備治療急性髓細胞白血病的藥物中的應用。通過急性髓細胞白血病(Acute Myeloid Leukemia,AML)細胞株和CDX模型,本發明研究得到PPAR激動劑抑制AML發生發展的作用機制為:以西格列他鈉為代表的PPAR激動劑與轉錄因子PPARα結合,抑制PPARα的泛素化降解,啟動AML細胞中PPARα的蛋白表達;PPARα啟動後進一步下調缺氧誘導因子HIF1α及其下游靶基因PGK1、Glut1、LDHA、PGM、MCT4、HK2的表達,抑制AML細胞的糖酵解過程,最終抑制了AML發生發展進程。因此,PPAR激動劑有望成為一種具有廣闊應用前景的治療急性髓細胞白血病的藥物。
Description
本發明屬於生物醫藥技術領域,具體涉及PPAR激動劑在製備治療急性髓細胞白血病的藥物中的應用。
急性髓細胞白血病(AML)是一種影響造血幹細胞和祖細胞的惡性克隆性造血疾病,一般是由非正常的基因突變或者表觀遺傳的改變導致,這種變異會增加細胞自我更新以及惡性增殖的可能性,在AML發展中期還會導致骨髓分化的某些關鍵基因發生突變(參見F.A.Lagunas-Rangel,V.Chávez-Valencia,M.A.Gómez-Guijosa,C.Cortes-Penagos,Acute myeloid Leukemia-genetic alterations and their clinical prognosis,Int.J.Hematol.Oncol.Stem Cell Res.11(4)(2017)328-339),AML的發展進程包含癌基因的突變、表觀遺傳修飾以及代謝紊亂。AML病人年齡中位數為68歲,近幾年,AML的發病率每年都在穩步上升並且預後很差。
AML的傳統治療選擇僅限於高劑量的細胞毒性化療,隨著對AML分子基礎的研究,越來越多的治療靶點被發現,分子靶向治療相比於傳統化療具有優越療效和較低毒性。自2017年以來,美國食品和藥物管理局批准了至少8種新藥,用於在不同環境下治療AML,其中包括小分子抑制劑、抗體藥物結合物和細胞毒性的藥物;常見的小分子抑制劑索拉非尼(sorafenib)是一種多激酶抑制劑,對多種受體酪氨酸激酶具有活性,包括VEGF、Ras、Raf和FLT3,在FLT3-ITD突變的AML中有較好的療效(參見Ravandi F,Alattar ML,Grunwald MR,et al.Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation.Blood.2013 Jun 6;121
(23):4655-4662),儘管如此,仍有患者出現耐藥或難以耐受治療。
多項研究表明,腫瘤細胞對葡萄糖攝取和利用具有精細依賴性,糖代謝在腫瘤細胞生長中發揮重要作用,Chen等人證明增強糖酵解有助於降低抗AML藥物Ara-c的敏感性,而抑制糖酵解能進一步抑制AML細胞增殖和增強Ara-c的細胞毒性(參見Chen WL,Wang JH,Zhao AH,Xu X,Wang YH,Chen TL,Li JM,Mi JQ,Zhu YM,Liu YF,Wang YY,Chen Z,Chen SJ,Jia W.A distinct glucose metabolism signature of acute myeloid leukemia with prognostic value.Blood.2014 Sep 4;124(10):1645-54.doi:10.1182/blood-2014-02-554204.Epub 2014 Jul 8.Erratum in:Blood.2014 Oct 30;124(18):2893)。
西格列他鈉(Chiglitazar)是我國深圳微芯生物科技股份有限公司自主設計合成、並具有全新化學結構和全球智慧財產權保護的糖尿病治療藥物,具有PPARα、PPARδ和PPARγ全啟動作用,屬於新一代胰島素增敏劑,主要用於2型糖尿病的治療(參見Cheng HS,Tan WR,Low ZS,Marvalim C,Lee JYH,Tan NS.Exploration and Development of PPAR Modulators in Health and Disease:An Update of Clinical Evidence.Int J Mol Sci.2019 Oct 11;20(20):5055)。
但是,PPAR激動劑能否用於AML治療、其與AML相關細胞株的作用機制尚不清楚。
針對現有技術存在的不足,本發明的目的在於提供一種PPAR激動劑在製備治療急性髓細胞白血病的藥物中的應用,尤其是具有PPARα的激動活性的PPAR激動劑在製備預防和/或治療急性髓細胞白血病的藥物中的應用。
所述PPAR激動劑除了能夠與PPARα結合啟動PPARα,抑制PPARα的泛素化降解外,本發明證明了其在分子水準其能抑制AML細胞株的糖酵解過程,在細胞水準能夠抑制AML細胞株的增殖以及誘導其細胞凋亡水準,在動物實驗中通過CDX小鼠模型還證明了以西格列他鈉為代表的PPAR激動劑能夠抑制小鼠AML的成瘤進程。
為達此目的,本發明提供了以下技術方案:
第一方面,本發明提供一種PPAR激動劑在製備預防和/或治療急性髓細胞白血病的藥物中的應用。
本發明中,通過AML細胞株和CDX模型,證明PPAR激動劑,尤其是西格列他鈉(Chiglitazar),可以抑制AML細胞增殖以及誘導其發生凋亡,還能抑制NSG小鼠AML成瘤進程並且提高存活率,在機制方面,西格列他鈉能夠與PPARα結合並且抑制PPARα的泛素化降解,進而啟動AML細胞中PPARα的蛋白表達,PPARα啟動後進一步下調缺氧誘導因子HIF1α及其下游靶基因PGK1、Glut1、LDHA、PGM、MCT4、HK2的表達,抑制AML細胞的糖酵解過程,最終抑制了AML發生發展進程。
本發明中,還提供了PPAR激動劑在預防和/或治療急性髓細胞白血病中的應用。
在一些實施方案中,所述PPAR激動劑具有PPARα激動活性。
在一些實施方案中,所述PPAR激動劑選自下述藥物中的一種或至少兩種的組合:西格列羧(Chiglitazar)、非諾貝特(Fenofibrate)、吉非羅齊(Gemfibrozil)、非諾貝酸(Fenofibric acid)、氟芬那酸(Flufenamic acid)、布洛芬(Ibuprofen)、苯紮貝特(Bezafibrate)、吲哚美辛(Indomethacin)、羅格列酮(Rosiglitazone)、環丙貝特(Ciprofibrate)、丙戊酸(Valproic acid)、右旋布洛芬(Dexibuprofen)、胺碘酮(Amiodarone)、普拉睾酮(Prasterone)、α-月見草油酸(alpha-Linolenic acid)、PPM-204(Indeglitazar)、克利貝特(Clinofibrate)、沒藥(Myrrh)、棕櫚酸(Palmitic Acid)、非諾洛芬(Fenoprofen)、月桂酸(Lauric acid)、硬脂酸(Stearic acid)、氯貝丁酯(Clofibrate)、二十二碳六烯酸(Doconexent)、油酸(Oleic Acid)、曲格列酮(Troglitazone)、ω-3脂肪酸(Omega-3 fatty acids)、二十碳五烯酸(Icosapent)、肉豆蔻酸(Myristic acid)、花生四烯酸(Arachidonic Acid)、異黃酮(Isoflavone)、阿格列紮(Aleglitazar)、瑞格列紮(Reglitazar)、GFT505(Elafibranor)、莫格列紮(Muraglitazar)、厄羅他非(Ertiprotafib)、鄰苯二甲酸(Phthalic Acid)、拉格列紮(Ragaglitazar)、替格列紮(Tesaglitazar)、GW-590735、白細胞三烯B4(Leukotriene B4)、辛酸(Caprylic
acid)、GW501516(Cardarine)、白藜蘆醇(Resveratrol)、N,N-雙(3-(D-葡糖醯胺)丙基)去氧膽醯胺(N,N-Bis(3-(D-gluconamido)propyl)deoxycholamide)或其異構體、溶劑化物、代謝產物、晶型、無定形或藥學上可接受的鹽。
在一些實施方案中,所述PPAR激動劑選自西格列羧或其異構體、溶劑化物、代謝產物、晶型、無定形或藥學上可接受的鹽中的任意一種。
在一些實施方案中,所述藥學上可接受的鹽為鹼金屬鹽、鹼土金屬鹽、銨鹽或季銨鹽中的任意一種,優選為鹼金屬鹽,進一步優選為鈉鹽和鉀鹽。
在一些實施方案中,所述異構體為左旋體。
在一些實施方案中,所述PPAR激動劑為西格列他鈉、西格列他鉀或其左旋體。
第二方面,本發明提供一種預防和/或治療急性髓細胞白血病的藥物組合物,所述藥物組合物包括PPAR激動劑。
在一些實施方案中,所述藥物組合物還包括藥學上可接受的輔料。
在一些實施方案中,所述藥學上可接受的輔料包括載體、稀釋劑、賦形劑、填充劑、粘合劑、潤濕劑、崩解劑、乳化劑、助溶劑、增溶劑、滲透壓調節劑、表面活性劑、包衣材料、著色劑、pH調節劑、抗氧劑、抑菌劑或緩衝劑中的任意一種或至少兩種的組合。
在一些實施方案中,所述藥物組合物的劑型包括片劑、散劑、混懸劑、顆粒劑、膠囊劑、注射劑、噴霧劑、溶液劑、灌腸劑、乳劑、膜劑、栓劑、貼劑、滴鼻劑或滴丸劑中的任意一種。
在一些實施方案中,所述藥物組合物以PPAR激動劑為唯一活性成分。
在一些實施方案中,所述藥物組合物除PPAR激動劑外,還可以包括其他活性成分。該其他活性成分可以與PPAR激動劑產生協同作用,也可以二者產生相加作用,以不對PPAR激動劑產生拮抗作用為宜。
第三方面,本發明還提供PPAR激動劑在製備AML細胞株增殖抑制劑、AML細胞株凋亡促進劑或AML細胞株細胞週期阻滯劑中的應用。
本發明中,還提供了PPAR激動劑在抑制AML細胞株增殖、促進AML細胞株凋亡或阻滯AML細胞株細胞週期中的應用。
在一些實施方案中,所述AML細胞株為誘發急性髓細胞白血病的細胞株。
在一些實施方案中,所述AML細胞株包括KG-1α細胞和/或Kasumi細胞。
本發明中,以西格列他鈉為研究物件,通過實驗在細胞水準證明PPAR激動劑能夠抑制AML細胞株的增殖以及誘導其細胞凋亡水準。
第四方面,本發明還提供PPAR激動劑在製備抑制AML細胞糖酵解、下調缺氧誘導因子HIF1α或降低糖酵解相關基因表達水準的藥物中的應用。
本發明中,還提供了PPAR激動劑在抑制AML細胞糖酵解、下調缺氧誘導因子HIF1α或降低糖酵解相關基因表達水準中的應用。
在一些實施方案中,所述糖酵解相關基因包括PGK1、MCT4、Glut1、PGM、LDHA或HK2中的任意一種或至少兩種的組合。
本發明中,以西格列他鈉為研究物件,通過Western blot、RT-PCR以及檢測葡萄糖消耗證明PPAR激動劑能夠抑制AML細胞株的糖酵解過程。
此外,本發明中還通過CDX小鼠模型證明PPAR激動劑西格列他鈉能夠抑制小鼠AML的成瘤進程。
第五方面,本發明提供了一種預防和/或治療急性髓細胞白血病的方法,所述方法包括向個體施用預防和/或治療有效量的所述的PPAR激動劑。
與現有技術相比,本發明的有益效果為:
本發明中,以西格列他鈉為研究物件,主要探索PPAR激動劑尤其是PPARα類型的激動劑對急性髓細胞白血病的抑制作用及其分子機制,首先根據Autodock分子對接建模與Co-IP實驗證明西格列他鈉能夠與轉錄因子PPARα結
合並能夠抑制PPARα的泛素化降解,進而啟動AML細胞中PPARα的蛋白表達;同時,在細胞水準證明西格列他鈉能夠抑制AML細胞株的增殖以及誘導其細胞凋亡;通過Western blot、RT-PCR、葡萄糖消耗以及乳糖生成的檢測證明西格列他鈉能夠抑制AML細胞株的糖酵解過程;通過CDX小鼠模型證明西格列他鈉能夠抑制小鼠AML的成瘤進程;根據實驗結果可知,西格列他鈉在啟動PPARα後,進一步下調缺氧誘導因子HIF1α及其下游靶基因PGK1、Glut1、LDHA、PGM、MCT4、HK2的表達,抑制AML細胞的糖酵解過程,最終抑制了AML發生發展進程;根據上述實驗結果,可將以西格列他鈉為代表的PPAR激動劑作為一種有效的治療急性髓細胞白血病的藥物。
G1,G2,S:週期
圖1A為實施例1中西格列他鈉處理KG-1α細胞48h和72h後的細胞增殖抑制率結果圖。
圖1B為實施例1中西格列他鈉處理Kasumi細胞48h和72h後的細胞增殖抑制率結果圖。
圖2A為實施例2中西格列他鈉處理KG-1α細胞48h以及72h後的細胞凋亡水準流式檢測結果圖。
圖2B為實施例2中KG-1α細胞的凋亡率統計結果圖。
圖2C為實施例2中西格列他鈉處理Kasumi細胞48h以及72h後的細胞凋亡水準流式檢測結果圖。
圖2D為實施例2中Kasumi細胞的凋亡率統計結果圖。
圖3A為實施例3中西格列他鈉處理Kasumi細胞後細胞週期在G1期、S期與G2期的細胞百分比統計結果圖。
圖3B為實施例3中西格列他鈉處理KG-1α細胞後細胞週期在G1期、S期與G2期的細胞百分比統計結果圖。
圖4A為實施例4中西格列他鈉與PPARα的分子對接模型圖。
圖4B為實施例4中不同濃度的西格列他鈉處理KG-1α細胞48h後的Western blot分析結果圖。
圖4C為實施例4中不同濃度的西格列他鈉處理Kasumi細胞48h後的Western blot分析結果圖。
圖5A為實施例5中不同濃度的西格列他鈉處理KG-1α細胞48h後缺氧誘導因子H1F1α和糖酵解相關基因LDHA、PGK1表達水準的Western blot結果圖。
圖5B為實施例5中不同濃度的西格列他鈉處理KG-1α細胞48h後糖酵解相關基因PGK1、MCT4、Glut1、PGM、LDHA和HK2的mRNA水準統計圖。
圖5C為實施例5中不同濃度的西格列他鈉處理KG-1α細胞48h後葡萄糖消耗水準的檢測結果統計圖。
圖5D為實施例5中不同濃度的西格列他鈉處理KG-1α細胞48h後乳糖生成水準的檢測結果統計圖。
圖5E為實施例5中不同濃度的西格列他鈉處理Kasumi細胞48h後缺氧誘導因子H1F1α和糖酵解相關基因LDHA、PGK1表達水準的Western blot結果圖。
圖5F為實施例5中不同濃度的西格列他鈉處理Kasumi細胞48h後糖酵解相關基因PGK1、MCT4、Glut1、PGM、LDHA和HK2的mRNA水準統計圖。
圖5G為實施例5中不同濃度的西格列他鈉處理Kasumi細胞48h後葡萄糖消耗水準的檢測結果統計圖。
圖5H為實施例5中不同濃度的西格列他鈉處理Kasumi細胞48h後乳糖生成水準的檢測結果統計圖。
圖6A為實施例6中將西格列他鈉注射到CDX小鼠模型後在第0天、第7天和第14天時的活體成像圖。
圖6B為實施例6中將西格列他鈉注射到CDX小鼠模型後小鼠的生存率統計圖。
圖7為本發明中研究得到的西格列他鈉抑制AML發生發展的作用機制示意圖。
下面結合圖式並通過具體實施方式來進一步說明本發明的技術方案,但下述的實例僅僅是本發明的簡易例子,並不代表或限制本發明的權利保護範圍,本發明的保護範圍以申請專利範圍為準。
以下實施例中,若無特殊說明,所用試劑及耗材均購自本領域常規試劑廠商;若無特殊說明,所用實驗方法和技術手段均為本領域常規的方法和手段。
實施例1 西格列他鈉抑制AML細胞株增殖水準
取1×104對數生長期AML細胞株KG-1α與Kasumi分別接種於96孔細胞培養板中,其中KG-1α與Kasumi細胞株由廈門大學醫學院血液學研究所提供;
對照組用DMSO處理細胞,實驗組的西格列他鈉濃度梯度設置為5μM、10μM、15μM、20μM和25μM;
分別在處理48h以及72h後用CCK8試劑盒檢測細胞增殖水準。
所得細胞增殖水準結果如圖1A和圖1B所示;
使用西格列他鈉分別處理KG-1α與Kasumi細胞48h和72h後,檢測得到的西格列他鈉的IC50值如下表1所示:
結合上述結果可知,西格列他鈉能夠抑制AML細胞的增殖水準,並且表現出時間與濃度的依賴性;隨著處理濃度和處理時間的增加,其抑制率逐漸上升。
實施例2 西格列他鈉誘導AML細胞株發生凋亡
取1×105對數生長期AML細胞株KG-1α與Kasumi分別接種於24孔細胞培養板中;
對照組用DMSO處理細胞,實驗組的西格列他鈉濃度梯度設置為5μM、
10μM、15μM、20μM和25μM;
處理48h和72h後用Annexin V/PI流式染色法檢測細胞凋亡水準並統計細胞凋亡率。
圖2A和圖2B為使用不同濃度的西格列他鈉處理KG-1α細胞,在48h和72h後的細胞凋亡水準流式檢測結果以及凋亡率統計結果;
圖2C和圖2D為使用不同濃度的西格列他鈉處理Kasumi細胞,在48h和72h後的細胞凋亡水準流式檢測結果以及凋亡率統計結果;
由上述結果可知,西格列他鈉誘導AML細胞發生凋亡,提高AML細胞的凋亡水準,且呈現濃度依賴性。
實施例3 西格列他鈉阻滯AML細胞株的細胞週期
取1×105 AML細胞株KG-1α與Kasumi分別接種於24孔細胞培養板中;
對照組用DMSO處理細胞,西格列他鈉濃度為10μM;
處理48h後,300g離心5min收集細胞,PBS洗一次,75%酒精4℃固定4h,用PI染色15min後流式檢測分析細胞週期的阻滯情況。
所得結果如圖3A和圖3B所示,由圖可知,使用西格列他鈉處理AML細胞株之後,相比對照組,其S期與G2期細胞數量明顯上升,G1期細胞數量明顯下降,說明西格列他鈉能夠阻滯AML細胞週期進程。
實施例4 西格列他鈉對PPARα泛素化水準的影響
首先,建立西格列他鈉與PPARα分子對接模型。
西格列他鈉分子結構模型用ChemDraw軟體建立,PPARα結構來自PDB資料庫,PDB ID為3KDT,對接模型用AUTODOCK軟體建立並進一步用Pymol軟體進行修飾;
所得模型如圖4A所示,由圖可知,PPARα上LYS-266和ALA-256兩個氨基酸殘基與西格列他鈉分子相接;說明西格列他鈉與PPARα分子之間存在相互作用。
其次,研究西格列他鈉對PPARα泛素化(Ubiquitylation)水準的影響。
取1×107對數生長期的AML細胞株KG-1α與Kasumi分別接種於10cm細胞培養皿中;
對照組用DMSO處理細胞,實驗組的西格列他鈉濃度設置為10μM和20μM(並標記為Chi 10μM和Chi 20μM);
處理48h後,300g離心5min收集細胞,加500μL RIPA裂解液冰置30min後,加入Protein A/G beads、Anti-PPARα抗體,4℃孵育過夜進行共免疫沉澱(Co-Immunoprecipitation,CO-IP),進一步通過Western blot分析結果,一抗分別用Anti-PPARα以及Anti-Ubiquitylation抗體。
所得結果如圖4B和圖4C所示,不同濃度的西格列他鈉處理KG-1α細胞與Kasumi細胞48h後,PPARα表達上調,同時CO-IP實驗結果表明,PPARα的泛素化降解水準明顯抑制。
該結果表明,西格列他鈉結合轉錄因子PPARα並且能夠抑制PPARα的泛素化降解水準,進而啟動PPARα的蛋白表達。
實施例5 西格列他鈉對AML細胞株HIF1α及其下游靶基因表達的影響
取1×106對數生長期AML細胞株KG-1α與Kasumi分別接種於6cm細胞培養皿中;
對照組用DMSO處理細胞,西格列他鈉濃度分別為10μM和20μM;
處理48h後300g離心5min收集細胞,取一半細胞用200μL RIPA裂解液冰置裂解1h,提取總蛋白進行Western blot,檢測HIF1α及其下游靶基因蛋白水準表達;
另一半細胞加500μL Trizol試劑,用RNA提取試劑盒提取得到總RNA,進一步用反轉錄試劑盒進行反轉錄實驗得到總cDNA,最後設計引物進行RT-PCR檢測HIF1α及其下游靶基因在mRNA水準的表達情況。
收集細胞上清並通過葡萄糖檢測試劑盒以及乳糖生成檢測試劑盒用於檢測葡萄糖消耗以及乳糖生成水準。
KG-1α細胞所得結果如圖5A、圖5B、圖5C以及圖5D所示,不
同濃度的西格列他鈉處理後蛋白表達水準的Western blot結果顯示,HIF1α及其下游靶基因LDHA和PGK1的表達量明顯下降;同時通過反轉錄實驗可知,糖酵解相關基因PGK1、MCT4、Glut1、PGM、LDHA和HK2的mRNA水準表達明顯下調;最後通過對葡萄糖以及乳糖的檢測發現,葡萄糖的消耗以及乳糖的生成水準明顯下降。
同樣的,Kasumi細胞所得結果如圖5E、圖5F、圖5G和圖5H所示,不同濃度的西格列他鈉處理後蛋白表達水準的Western blot結果顯示,HIF1α及其下游靶基因LDHA和PGK1的表達量明顯下降;同時通過反轉錄實驗可知,糖酵解相關基因PGK1、MCT4、Glut1、PGM、LDHA和HK2的mRNA水準表達明顯下調;葡萄糖的消耗以及乳糖的生成水準明顯下降。
實施例6 西格列他鈉抑制AML細胞移植瘤的成瘤進程
將PLV-luciferase-GFP質粒通過慢病毒法穩定轉染到KG-1α細胞株中,構建穩定表達螢光素酶luciferase的AML細胞株,其中PLV-luciferase-GFP質粒由廈門大學醫學院血液學研究所提供。收集3×106對數生長期AML細胞株luciferase-GFP-KG-1α通過尾靜脈注射到NOD-Prkdc-/-IL2rg-/-(NSG)小鼠體內進行成瘤,其中NSG小鼠購自廈門大學實驗動物中心,並且由實驗動物中心飼養。
通過活體成像系統檢測小鼠成瘤進展,小鼠總螢光強度達到1×106-1×107後(約14 days)按15mg/kg/day劑量給藥14 days,並且以給藥起始日記為0天,統計實驗結果及小鼠存活率。
所得結果如圖6A和圖6B所示,西格列他鈉能夠明顯抑制CDX模型的成瘤進程,通過生存率曲線可知,西格列他鈉能夠顯著改善CDX模型的生存率。
結合上述實施例能夠分析概括出西格列他鈉抑制AML發生發展的作用機制,具體如圖7所示:
以西格列他鈉為代表的PPAR激動劑能夠與轉錄因子PPARα結合並且抑制PPARα的泛素化降解,進而啟動AML細胞中PPARα的蛋白表達,PPARα啟動
後進一步下調缺氧誘導因子HIF1α及其下游靶基因PGK1、Glut1、LDHA、PGM、MCT4、HK2的表達,抑制AML細胞的糖酵解過程,最終抑制了AML發生發展進程。
申請人聲明,以上所述僅為本發明的具體實施方式,但本發明的保護範圍並不局限於此,所屬技術領域的技術人員應該明瞭,任何屬於本技術領域的技術人員在本發明揭露的技術範圍內,可輕易想到的變化或替換,均落在本發明的保護範圍和公開範圍之內。
Claims (10)
- 一種PPARα激動劑在製備預防和/或治療急性髓細胞白血病的藥物中的應用,其中所述PPARα激動劑選自西格列羧或其藥學上可接受的鹽。
- 如請求項1所述的應用,其中所述藥學上可接受的鹽為鹼金屬鹽、鹼土金屬鹽、銨鹽或季銨鹽中的任意一種。
- 如請求項1所述的應用,其中所述藥學上可接受的鹽為鹼金屬鹽。
- 如請求項2所述的應用,其中所述藥學上可接受的鹽為鈉鹽或鉀鹽。
- 如請求項1所述的應用,其中所述PPARα激動劑為西格列他鈉或西格列他鉀。
- 一種PPARα激動劑在製備AML細胞株增殖抑制劑、AML細胞株凋亡促進劑或AML細胞株細胞週期阻滯劑中的應用,其中所述PPARα激動劑選自西格列羧或其藥學上可接受的鹽。
- 如請求項6所述的應用,其中,所述AML細胞株為誘發急性髓細胞白血病的細胞株。
- 如請求項6所述的應用,其中所述AML細胞株包括KG-1α細胞和/或Kasumi細胞。
- 一種PPARα激動劑在製備抑制AML細胞糖酵解、下調缺氧誘導因子HIF1α或降低糖酵解相關基因表達水準的藥物中的應用,其中所述PPARα激動劑選自西格列羧或其藥學上可接受的鹽。
- 如請求項9所述的應用,其中,所述糖酵解相關基因包括PGK1、MCT4、Glut1、PGM、LDHA或HK2中的任意一種或至少兩種的組合。
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期刊 Tatiana M. Garcia-Bates et al., Role of Peroxisome Proliferator-Activated Receptor Gamma and Its Ligands in the Treatment of Hematological Malignancies, PPAR Res. 2008 ;2008:834612. doi:10.1155/2008/834612;期刊 曾明月,郭鹏翔,王季石, 苯扎貝特聯合醋酸甲羥孕酮治療急性髓系白血病療效觀察分析, 重慶醫學, 2014年2月第43卷第6期, 第666-670頁 * |
期刊 曾明月,郭鹏翔,王季石, 苯扎貝特聯合醋酸甲羥孕酮治療急性髓系白血病療效觀察分析, 重慶醫學, 2014年2月第43卷第6期, 第666-670頁。 |
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