Sorafenib Induces Apoptosis Specifically in Cells Expressing BCR/ABL by Inhibiting Its Kinase Activity to Activate the Intrinsic Mitochondrial Pathway
Sorafenib Induces Apoptosis Specifically in Cells Expressing BCR/ABL by Inhibiting Its Kinase Activity to Activate the Intrinsic Mitochondrial Pathway
复制标题
DOI：
10.1158/0008-5472.can-08-2978
复制
发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Miura, Osamu
中科院分区：
文献类型：
--
作者：
Kurosu, Tetsuya;Ohki, Manabu;Miura, Osamu
尽管BCR/ABL酪氨酸激酶抑制剂伊马替尼对慢性粒细胞白血病和费城染色体阳性（Ph+）急性淋巴细胞白血病的治疗非常有效，但BCR/ABL激酶结构域中出现伊马替尼耐药突变的复发构成了一个重大问题。在这里，我们发现，多激酶抑制剂索拉非尼抑制增殖，并诱导细胞凋亡在低得多的浓度时，由诱导表达的BCR/ABL比由白细胞介素-3驱动时，在Ton.B210细胞。在诱导表达具有伊马替尼耐药E255 K或T3151突变的BCR/ABL的细胞中也观察到对索拉非尼的敏感性增加。在这些细胞和Ph+白血病细胞中，索拉非尼诱导的细胞凋亡被rottlerin、硼替佐米或ABT-737协同增强，并被泛半胱天冬酶抑制剂BOC-d-favor或Bcl-XL的过表达抑制。进一步揭示，索拉非尼激活Bax和半胱天冬酶-3，并降低线粒体膜电位，特别是在BCR/ABL驱动的细胞。索拉非尼还抑制BCR/ABL诱导的其细胞底物的酪氨酸磷酸化及其在Ton.B210中的自磷酸化。最后显示索拉非尼在体外激酶测定中抑制BCR/ABL及其E255 K和T3151突变体的激酶活性。这些结果表明，索拉非尼诱导BCR/ABL表达细胞的凋亡，至少部分，通过抑制BCR/ABL，激活BCR介导的凋亡途径。因此，索拉非尼可能提供一种有效的治疗措施，以治疗Ph+白血病，特别是那些表达T3151突变体，这是完全耐伊马替尼和第二代BCR/ABL抑制剂。[Cancer Res 2009;69（9）：3927-36]
Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, relapse with emerging imatinib resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we show that the multikinase inhibitor sorafenib inhibits proliferation and induces apoptosis at much lower concentrations in Ton.B210 cells when driven by inducibly expressed BCR/ABL than when driven by interleukin-3. The increased sensitivity to sorafenib was also observed in cells inducibly expressing BCR/ABL with the imatinib-resistant E255K or T3151 mutation. Sorafenib-induced apoptosis in these cells and Ph+ leukemic cells was synergistically enhanced by rottlerin, bortezomib, or ABT-737 and inhibited by the pan-caspase inhibitor BOC-d-fmk or the overexpression of Bcl-XL. It was further revealed that sorafenib activates Bax and caspase-3 and reduces mitochondrial membrane potential specifically in BCR/ABL-driven cells. Sorafenib also inhibited BCR/ABL-induced tyrosine phosphorylation of its cellular substrates and its autophosphorylation in Ton.B210. It was finally shown that sorafenib inhibits the kinase activity of BCR/ABL as well as its E255K and T3151 mutants in in vitro kinase assays. These results indicate that sorafenib induces apoptosis of BCR/ABL-expressing cells, at least partly, by inhibiting BCR/ABL to activate the mitochondria-mediated apoptotic pathway. Thus, sorafenib may provide an effective therapeutic measure to treat Ph+ leukemias, particularly those expressing the T3151 mutant, which is totally resistant to imatinib and the second generation BCR/ABL inhibitors. [Cancer Res 2009;69(9):3927-36]