Nutlin-3 plus tanshinone IIA exhibits synergetic anti-leukemia effect with imatinib by reactivating p53 and inhibiting the AKT/mTOR pathway in Ph plus ALL
Nutlin-3 plus tanshinone IIA exhibits synergetic anti-leukemia effect with imatinib by reactivating p53 and inhibiting the AKT/mTOR pathway in Ph plus ALL
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DOI：
10.1042/bcj20170386
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发表时间：
2017-12-15
影响因子：
4.1
通讯作者：
Gong, Yu-Ping
中科院分区：
文献类型：
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作者：
Guo, Yong;Li, Yi;Gong, Yu-Ping
费城染色体阳性的急性淋巴细胞白血病(Ph+ALL)是由bcr/abl激酶引发的。最近的努力集中在开发更有效的酪氨酸激酶抑制剂(TKI)，它也可以抑制突变的酪氨酸激酶，如尼洛替尼和达沙替尼。虽然在治疗这种侵袭性疾病方面取得了重大进展，但由于耐药，缓解期患者经常因耐药而复发，至少部分原因可能是TKI治疗后白血病细胞生长信号通路和保护性反馈信号的补偿性激活。AKT/mTOR信号通路的持续激活和p53通路的失活是TKI耐药的两种机制。在此，我们报道了Nutlin-3和丹参酮IIA通过下调AKT/mTOR通路和重新激活Ph+ALL细胞系中的P53通路，显著增强了伊马替尼的细胞毒性和诱导凋亡的作用。在Ph+ALL患者的原始样本中，Nutlin-3和丹参酮IIA也显示出与伊马替尼的协同细胞毒作用。值得注意的是，携带T315I突变的Ph+ALL患者的三个样本也显示出对伊马替尼、Nutlin-3和丹参酮IIA联合治疗的敏感性。在Ph+ALL小鼠模型中，伊马替尼联合Nutlin-3+丹参酮IIA也显示出减轻白血病负担的协同作用。这些结果表明，Nutlin-3联合丹参酮IIA联合TKI治疗Ph+ALL可能是一种有前途的治疗策略。
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL kinase. Recent efforts focused on the development of more potent tyrosine kinase inhibitors (TKIs) that also inhibit mutant tyrosine kinases such as nilotinib and dasatinib. Although major advances in the treatment of this aggressive disease with potent inhibitors of the BCR/ABL kinases, patients in remission frequently relapse due to drug resistance possibly mediated, at least in part, by compensatory activation of growth-signaling pathways and protective feedback signaling of leukemia cells in response to TKI treatment. Continuous activation of AKT/mTOR signaling and inactivation of p53 pathway were two mechanisms of TKI resistance. Here, we reported that nutlin-3 plus tanshinone IIA significantly potentiated the cytotoxic and apoptotic induction effects of imatinib by down-regulation of the AKT/mTOR pathway and reactivating the p53 pathway deeply in Ph+ ALL cell line. In primary samples from Ph+ ALL patients, nutlin-3 plus tanshinone IIA also exhibited synergetic cytotoxic effects with imatinib. Of note, three samples from Ph+ ALL patients harboring T315I mutation also showed sensitivity to the combined treatment of imatinib, nutlin-3 plus tanshinone IIA. In Ph+ ALL mouse models, imatinib combined with nutlin-3 plus tanshinone IIA also exhibited synergetic effects on reduction in leukemia burden. These results demonstrated that nutlin-3 plus tanshinone IIA combined TKI might be a promising treatment strategy for Ph+ ALL patients.