Sensitization of U937 leukemia cells to doxorubicin by the MG132 proteasome inhibitor induces an increase in apoptosis by suppressing NF-kappa B and mitochondrial membrane potential loss.
Sensitization of U937 leukemia cells to doxorubicin by the MG132 proteasome inhibitor induces an increase in apoptosis by suppressing NF-kappa B and mitochondrial membrane potential loss.
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DOI：
10.1186/1475-2867-14-13
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发表时间：
2014-02-04
影响因子：
5.8
通讯作者：
Hernández-Flores G
中科院分区：
文献类型：
--
作者：
Ortiz-Lazareno PC;Bravo-Cuellar A;Lerma-Díaz JM;Jave-Suárez LF;Aguilar-Lemarroy A;Domínguez-Rodríguez JR;González-Ramella O;De Célis R;Gómez-Lomelí P;Hernández-Flores G
癌细胞对化疗的耐药性仍然是目前癌症治疗的主要限制。多柔比星（DOX）是一种有效的抗肿瘤药物，其激活泛素-蛋白酶体系统，但不幸的是，它也激活核因子κ B（NF-κ B）途径，导致促进肿瘤细胞存活。MG 132是一种通过蛋白酶体避免NF-κ B活化来抑制I κ B降解的药物。本工作研究了MG 132蛋白酶体抑制剂对阿霉素抗肿瘤活性的增敏作用。用MG 132、DOX或两种药物处理U937人白血病细胞。我们评估了增殖、活力、凋亡、半胱天冬酶-3、-8和-9活性和裂解、细胞色素c释放、线粒体膜电位、Bcl-2和Bcl-XL抗凋亡蛋白、衰老、p65磷酸化以及促凋亡和抗凋亡基因。MG 132 + DOX联合用药组U937细胞凋亡率最高。同样地，使用这两种药物，我们观察到肿瘤细胞增殖和重要的caspase-3激活减少，以及线粒体膜电位丧失。因此，MG 132降低衰老、p65磷酸化和DOX诱导的Bcl-2抗凋亡蛋白。MG 132 + DOX处理诱导促凋亡基因BAX、DIABLO、NOXA、DR 4和FAS的上调。它还诱导了抗凋亡基因BCL-XL和SURVIVIN的下调。MG 132使U937白血病细胞对DOX诱导的细胞凋亡敏感，从而增加其抗白血病效力。
The resistance of cancerous cells to chemotherapy remains the main limitation for cancer treatment at present. Doxorubicin (DOX) is a potent antitumor drug that activates the ubiquitin-proteasome system, but unfortunately it also activates the Nuclear factor kappa B (NF-кB) pathway leading to the promotion of tumor cell survival. MG132 is a drug that inhibits I kappa B degradation by the proteasome-avoiding activation of NF-кB. In this work, we studied the sensitizing effect of the MG132 proteasome inhibitor on the antitumor activity of DOX. U937 human leukemia cells were treated with MG132, DOX, or both drugs. We evaluated proliferation, viability, apoptosis, caspase-3, -8, and −9 activity and cleavage, cytochrome c release, mitochondrial membrane potential, the Bcl-2 and Bcl-XL antiapoptotic proteins, senescence, p65 phosphorylation, and pro- and antiapoptotic genes. The greatest apoptosis percentage in U937 cells was obtained with a combination of MG132 + DOX. Likewise, employing both drugs, we observed a decrease in tumor cell proliferation and important caspase-3 activation, as well as mitochondrial membrane potential loss. Therefore, MG132 decreases senescence, p65 phosphorylation, and the DOX-induced Bcl-2 antiapoptotic protein. The MG132 + DOX treatment induced upregulation of proapoptotic genes BAX, DIABLO, NOXA, DR4, and FAS. It also induced downregulation of the antiapoptotic genes BCL-XL and SURVIVIN. MG132 sensitizes U937 leukemia cells to DOX-induced apoptosis, increasing its anti-leukemic effectiveness.
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影响因子：
5.8
作者：
Fournier MJ;Gareau C;Mazroui R
通讯作者：
Mazroui R
影响因子：
7.7
作者：
Denard B;Lee C;Ye J
通讯作者：
Ye J
影响因子：
2.8
作者：
Chen D;Dou QP
通讯作者：
Dou QP
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
3.9
作者：
Bagriacik, E. Umit;Uslu, Kadriye;Karasu, Cimen
通讯作者：
Karasu, Cimen