Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1.
Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1.
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DOI：
10.1371/journal.pone.0055509
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Plattner R
中科院分区：
文献类型：
--
作者：
Sims JT;Ganguly SS;Bennett H;Friend JW;Tepe J;Plattner R
尽管在癌症检测和预防方面取得了进展，但由于许多癌症对化疗（常规或靶向）具有抗性或在治疗期间产生抗性，并且残留的化疗抗性细胞具有高度转移性，因此转移性疾病的诊断仍然是死刑。转移性癌细胞通过上调药物转运蛋白（其流出药物）以及通过激活增殖和存活信号传导途径来抵抗化疗剂的作用。以前，我们发现c-Abl和Arg非受体酪氨酸激酶在乳腺癌、黑色素瘤和胶质母细胞瘤细胞中被激活，并促进癌症进展。在这份报告中，我们证明，c-Abl/精氨酸抑制剂，伊马替尼（伊马替尼甲磺酸盐，STI 571，格列卫），逆转内在和获得性耐药性的蒽环类药物，阿霉素，诱导G2/M期阻滞和促进细胞凋亡的癌细胞表达高活性的c-Abl和精氨酸。重要的是，伊马替尼通过促进阿霉素介导的NF-κB/p65核定位和以STAT 3依赖性方式抑制NF-κB靶点，以及通过阻止新的STAT 3/HSP 27/p38/Akt存活途径的激活来防止内在耐药。相比之下，伊马替尼通过抑制ABC药物转运蛋白ABCB 1的上调，直接抑制ABCB 1功能和消除生存信号传导来预防获得性耐药。因此，伊马替尼抑制多种新的化学耐药途径，这表明它可能有效逆转含有高活性c-Abl和Arg的癌症的内在和获得性耐药，这是有效治疗转移性疾病的关键步骤。此外，由于伊马替尼将主存活调节因子NF-κB从促存活因子转化为促凋亡因子，我们的数据表明NF-κB抑制剂可能在使含有活化的c-Abl/Arg的肿瘤对蒽环类药物敏感方面无效，而是可能拮抗蒽环类药物诱导的细胞凋亡。
Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
16
作者：
Campbell, KJ;Rocha, S;Perkins, ND
通讯作者：
Perkins, ND
影响因子：
11.5
作者：
Deininger, Michael W.
通讯作者：
Deininger, Michael W.
影响因子：
4
作者：
Gangadharan, Charitha;Thoh, Maikho;Manna, Sunil K.
通讯作者：
Manna, Sunil K.
影响因子：
15.9
作者：
Balint, K;Xiao, M;Liu, ZJ
通讯作者：
Liu, ZJ