2016年7月21日，英國(guó)《自然》旗下《細(xì)胞死亡與疾病》在線發(fā)表加拿大曼尼托巴大學(xué)、中國(guó)吉林大學(xué)的研究報(bào)告，發(fā)現(xiàn)西拉美新和拉帕替尼可誘發(fā)乳腺癌細(xì)胞鐵死亡。
細(xì)胞死亡是一個(gè)重要的生命過程，是一切細(xì)胞的宿命，在整個(gè)機(jī)體的生長(zhǎng)和發(fā)育中起到了基礎(chǔ)性作用。細(xì)胞死亡的方式也是生物醫(yī)學(xué)領(lǐng)域的重大問題，過去曾經(jīng)認(rèn)為細(xì)胞死亡都是非程序性的，或是意外發(fā)生的。現(xiàn)在發(fā)現(xiàn)細(xì)胞死亡不僅存在程序或調(diào)節(jié)，而且存在許多不同類型的細(xì)胞死亡類型。這方面現(xiàn)在已經(jīng)比較成熟的研究包括凋亡、自噬、壞死，其中壞死是最新的研究熱點(diǎn)。
鐵死亡（程序性鐵壞死）是一種新發(fā)現(xiàn)的鐵依賴性氧化損傷所致細(xì)胞死亡模式，從形態(tài)學(xué)、生物化學(xué)和遺傳學(xué)等角度，與凋亡、壞死和自噬有較大差別。
該研究證實(shí)西拉美新（溶酶體破壞試劑）和拉帕替尼（酪氨酸激酶抑制劑）聯(lián)合作用超過24小時(shí)可協(xié)同誘發(fā)MDA MB 231、MCF-7、ZR-75和SKBr3乳腺癌細(xì)胞產(chǎn)生活性氧類（氧自由基）和細(xì)胞死亡。此外，去鐵胺（鐵螯合劑）可顯著減少西拉美新和拉帕替尼治療后的活性氧類（氧自由基）和細(xì)胞死亡。
該研究還發(fā)現(xiàn)，經(jīng)西拉美新和拉帕替尼治療后，細(xì)胞三氯化鐵水平升高提示鐵依賴性細(xì)胞死亡。為了證實(shí)這點(diǎn)，該研究在西拉美新和拉帕替尼治療細(xì)胞后，使用高鐵膽固醇合成酶抑制劑-1（鐵死亡潛在抑制劑）可有效地抑制細(xì)胞死亡。鐵轉(zhuǎn)運(yùn)變化可能引起鐵水平增加。該研究發(fā)現(xiàn)，拉帕替尼單藥或與西拉美新聯(lián)合治療后，負(fù)責(zé)把鐵轉(zhuǎn)運(yùn)到細(xì)胞中的轉(zhuǎn)鐵蛋白表達(dá)水平增加。敲落（敲低）轉(zhuǎn)鐵蛋白基因可減少治療后的細(xì)胞死亡和活性氧類（氧自由基）。此外，鐵轉(zhuǎn)運(yùn)蛋白-1是一種跨膜鐵轉(zhuǎn)運(yùn)蛋白，負(fù)責(zé)從細(xì)胞中移除鐵。該研究發(fā)現(xiàn)，西拉美新單藥或與拉帕替尼聯(lián)合治療后，鐵轉(zhuǎn)運(yùn)蛋白-1表達(dá)降低。鐵轉(zhuǎn)運(yùn)蛋白-1過表達(dá)可減少活性氧類（氧自由基）和細(xì)胞死亡，而敲落（敲低）鐵轉(zhuǎn)運(yùn)蛋白-1可增加西拉美新和拉帕替尼治療后的細(xì)胞死亡。
因此，該研究發(fā)現(xiàn)了一種使用溶酶體破壞劑和酪氨酸激酶抑制劑治療乳腺癌、調(diào)控鐵變化、誘發(fā)鐵死亡的新機(jī)制。
Cell Death Dis. 2016 Jul 21;7:e2307.
Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells.
Ma S, Henson ES, Chen Y, Gibson SB.
University of Manitoba, Winnipeg, MB, Canada; Jilin University, Changchun 130021, Jilin, China.
Ferroptosis is an iron-dependent, oxidative cell death, and is distinct from apoptosis, necrosis and autophagy. In this study, we demonstrated that lysosome disrupting agent, siramesine and a tyrosine kinase inhibitor, lapatinib synergistically induced cell death and reactive oxygen species (ROS) in MDA MB 231, MCF-7, ZR-75 and SKBr3 breast cancer cells over a 24h time course. Furthermore, the iron chelator deferoxamine (DFO) significantly reduced cytosolic ROS and cell death following treatment with siramesine and lapatinib. Furthermore, we determined that FeCl3 levels were elevated in cells treated with siramesine and lapatinib indicating an iron-dependent cell death, ferroptosis. To confirm this, we treated cells with a potent inhibitor of ferroptosis, ferrastatin-1 that effectively inhibited cell death following siramesine and lapatinib treatment. The increase levels of iron could be due to changes in iron transport. We found that the expression of transferrin, which is responsible for the transport of iron into cells, is increased following treatment with lapatinib alone or in combination with siramesine. Knocking down of transferrin resulted in decreased cell death and ROS after treatment. In addition, ferroportin-1 (FPN) is an iron transport protein, responsible for removal of iron from cells. We found its expression is decreased after treatment with siramesine alone or in combination with lapatinib. Overexpression FPN resulted in decreased ROS and cell death whereas knockdown of FPN increased cell death after siramesine and lapatinib treatment. This indicates a novel induction of ferroptosis through altered iron regulation by treating breast cancer cells with a lysosome disruptor and a tyrosine kinase inhibitor.
PMID: 27441659
DOI: 10.1038/cddis.2016.208
聯(lián)系客服
