Pristimerin induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation by blocking NF-kappaB signaling and depleting Bcr-Abl.
Pristimerin induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation by blocking NF-kappaB signaling and depleting Bcr-Abl.
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DOI：
10.1186/1476-4598-9-112
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发表时间：
2010-05-19
期刊：
影响因子：
37.3
通讯作者：
Pan J
中科院分区：
文献类型：
--
作者：
Lu Z;Jin Y;Chen C;Li J;Cao Q;Pan J
慢性粒细胞性白血病（CML）是以嵌合酪氨酸激酶Bcr-Abl为特征的，Bcr-Abl-T315 I是众所周知的点突变，该点突变导致伊马替尼和第二代酪氨酸激酶抑制剂耐药，导致预后不良。CML原始细胞具有组成性p65（RelA NF-κB）转录活性，NF-κB可能是CML分子治疗的潜在靶点，也可能对Bcr-Abl-T315 I的CML细胞有效。在本研究中，我们发现从卫矛科和希波克拉底科中分离的醌甲基三萜类化合物pristimerin抑制CML细胞的生长并诱导其凋亡，包括携带Bcr-Abl-T315 I突变的细胞。此外，pristimerin抑制裸鼠中伊马替尼耐药Bcr-Abl-T315 I异种移植物的生长。Pristimerin阻断了TNFα诱导的IκBα磷酸化、p65易位和NF-κ B调节基因的表达。Pristimerin抑制NF-κB信号通路中的两个步骤：TAK 1 →IKK和IKK→IκBα。Pristimerin有效抑制两对CML细胞系（KBM 5与KBM 5-T315 I，32 D-Bcr-Abl与32 D-Bcr-Abl-T315 I）和来自伊马替尼获得性耐药CML患者的原代细胞。伊马替尼敏感（KBM 5）和伊马替尼耐药（KBM 5-T315 I）CML细胞经pristimerin处理后Bcr-Abl的mRNA和蛋白水平均降低。此外，通过伊马替尼预处理灭活Bcr-Abl并没有消除TNFα诱导的NF-κB活化，而通过siRNA沉默p65并没有影响Bcr-Abl的水平，这两个结果共同表明NF-κB灭活和Bcr-Abl抑制可能是平行的独立途径。据我们所知，这是第一份报告表明，pristimerin是有效的，在体外和体内对CML细胞，包括那些与T315 I突变。其机制可能与抑制NF-κB和Bcr-Abl有关。我们认为，pristimerin可能成为克服CML患者伊马替尼耐药的先导化合物。
Chronic myelogenous leukemia (CML) is characterized by the chimeric tyrosine kinase Bcr-Abl. Bcr-Abl-T315I is the notorious point mutation that causes resistance to imatinib and the second generation tyrosine kinase inhibitors, leading to poor prognosis. CML blasts have constitutive p65 (RelA NF-κB) transcriptional activity, and NF-κB may be a potential target for molecular therapies in CML that may also be effective against CML cells with Bcr-Abl-T315I. In this report, we discovered that pristimerin, a quinonemethide triterpenoid isolated from Celastraceae and Hippocrateaceae, inhibited growth and induced apoptosis in CML cells, including the cells harboring Bcr-Abl-T315I mutation. Additionally, pristimerin inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Pristimerin blocked the TNFα-induced IκBα phosphorylation, translocation of p65, and expression of NF-κB-regulated genes. Pristimerin inhibited two steps in NF-κB signaling: TAK1→IKK and IKK→IκBα. Pristimerin potently inhibited two pairs of CML cell lines (KBM5 versus KBM5-T315I, 32D-Bcr-Abl versus 32D-Bcr-Abl-T315I) and primary cells from a CML patient with acquired resistance to imatinib. The mRNA and protein levels of Bcr-Abl in imatinib-sensitive (KBM5) or imatinib-resistant (KBM5-T315I) CML cells were reduced after pristimerin treatment. Further, inactivation of Bcr-Abl by imatinib pretreatment did not abrogate the TNFα-induced NF-κB activation while silencing p65 by siRNA did not affect the levels of Bcr-Abl, both results together indicating that NF-κB inactivation and Bcr-Abl inhibition may be parallel independent pathways. To our knowledge, this is the first report to show that pristimerin is effective in vitro and in vivo against CML cells, including those with the T315I mutation. The mechanisms may involve inhibition of NF-κB and Bcr-Abl. We concluded that pristimerin could be a lead compound for further drug development to overcome imatinib resistance in CML patients.
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