Elimination of stem-like cancer cell side-population by auranofin through modulation of ROS and glycolysis.
Elimination of stem-like cancer cell side-population by auranofin through modulation of ROS and glycolysis.
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金诺芬通过调节 ROS 和糖酵解消除干细胞样癌细胞副群。
DOI：
10.1038/s41419-017-0159-4
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发表时间：
2018-01-24
影响因子：
9
通讯作者：
Huang P
中科院分区：
文献类型：
--
作者：
Hou GX;Liu PP;Zhang S;Yang M;Liao J;Yang J;Hu Y;Jiang WQ;Wen S;Huang P
Cancer side-population （SP）是干细胞样癌细胞的一个亚群，由于其参与药物输出的atp结合盒转运体ABCG2的高表达，在耐药性中起着重要作用。金嘌呤（AF）是一种用于治疗类风湿性关节炎的金络合物的临床药物，已被报道具有抗肿瘤增殖的作用。然而，AF是否能影响SP细胞尚不清楚。我们的研究表明，AF引起SP细胞的耗竭和干细胞标记物的下调，损害了SP细胞在体外形成肿瘤集落的能力和肺癌细胞在体内发生肿瘤的发生率。活性氧（Reactive oxygen species， ROS）在af诱导的SP细胞衰竭中起重要作用，而抗氧化剂NAC可以逆转这一过程。进一步研究表明，AF还可通过抑制糖酵解引起ATP耗竭。细胞ATP的耗竭可能损害ABCG2泵的功能，导致细胞内药物蓄积增加，从而增强阿霉素等化疗药物的抗癌活性。体外和体内实验均证实了AF与阿霉素的协同作用。同时增加活性氧和抑制糖酵解是一种消除干细胞样癌细胞的新策略。房颤联合阿霉素似乎有望提高治疗效果。
Cancer side-population (SP) represents a sub-population of stem-like cancer cells that have an important role in drug resistance due to their high expression of the ATP-binding cassette transporter ABCG2 involved in drug export. Auranofin (AF), a clinical drug of gold complex that is used in treatment of rheumatoid arthritis, has been reported inducing tumor antiproliferation. However, whether AF can impact SP cells remains unclear. Our study showed that AF caused a depletion of SP cells and a downregulation of stem cell markers, and impaired their ability to form tumor colonies in vitro and incidence to develop tumors in vivo of lung cancer cells. Reactive oxygen species (ROS) had an important role in mediating AF-induced depletion of SP cells, which could be reversed by antioxidant NAC. Further study revealed that AF could also cause ATP depletion by inhibition of glycolysis. The depletion of cellular ATP might impair the function of ABCG2 pump, leading to increased drug accumulation within the cells and thus enhancing anticancer activity of chemotherapeutic agents such as adriamycin. Synergistic effect of AF and adriamycin was demonstrated both in vitro and in vivo. Simultaneous increase of ROS and inhibition of glycolysis is a novel strategy to eliminate stem-like cancer cells. Combination of AF with adriamycin seems to be promising to enhance therapeutic effectiveness.
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影响因子：
37.3
作者：
Gasch C;Ffrench B;O'Leary JJ;Gallagher MF
通讯作者：
Gallagher MF
DOI：
10.2174/1871520615666150716104152
发表时间：
2016-01-01
影响因子：
2.8
作者：
Kuhlmann, Jan Dominik;Kurth, Linda Hein Ina;Dubrovska, Anna
通讯作者：
Dubrovska, Anna
影响因子：
5.2
作者：
Dayem AA;Choi HY;Kim JH;Cho SG
通讯作者：
Cho SG
Auranofin诱导致命的氧化和内质网应激，并针对慢性淋巴细胞性白血病发挥有效的临床前活性。
影响因子：
11.2
作者：
Fiskus W;Saba N;Shen M;Ghias M;Liu J;Gupta SD;Chauhan L;Rao R;Gunewardena S;Schorno K;Austin CP;Maddocks K;Byrd J;Melnick A;Huang P;Wiestner A;Bhalla KN
通讯作者：
Bhalla KN
影响因子：
11.2
作者：
Li, Chenwei;Heidt, David G.;Simeone, Diane M.
通讯作者：
Simeone, Diane M.