Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia.
Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia.
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DOI：
10.3390/antiox10060956
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发表时间：
2021-06-15
期刊：
影响因子：
--
通讯作者：
Bunting KD
中科院分区：
文献类型：
--
作者：
Wang Z;Mi T;Bradley HL;Metts J;Sabnis H;Zhu W;Arbiser J;Bunting KD
急性髓系白血病（AML）是一种异质性疾病，复发率高.细胞因子受体靶向疗法在治疗上是有吸引力的，但易发生耐药突变。同样，针对下游信号通路也很困难。最近在开发协同组合方面的成功为难治性AML患者提供了新的希望。虽然作为单一疗法通常无效，但BH 3模拟物与化疗剂组合非常有效。考虑到这一点，我们进一步探索了新的BH 3模拟药物组合，并表明匹莫齐特与AML细胞中的mTOR抑制剂和BH 3模拟物合作。三种药物的组合能够到达对单一或双重药物组合没有反应的细胞。在Flt 3-内部串联重复（ITD）-阳性细胞中，我们先前表明匹莫齐特与丙咪嗪蓝（IB）联合使用时非常有效。在这里，我们表明Flt 3-ITD+细胞对IB诱导的动力蛋白1样（Drp 1）-p38-ROS通路敏感。匹莫齐特在线粒体氧化代谢中发挥重要的钙通道阻滞剂活性，与IB汇合。总的来说，这些数据支持抗氧化剂是一把双刃剑的概念。合理设计的联合治疗对进一步的临床前开发具有重要的前景，并可能最终导致改善的反应。
Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to resistance-conferring mutations. Likewise, targeting downstream signaling pathways has been difficult. Recent success in the development of synergistic combinations has provided new hope for refractory AML patients. While generally not efficacious as monotherapy, BH3 mimetics are very effective in combination with chemotherapy agents. With this in mind, we further explored novel BH3 mimetic drug combinations and showed that pimozide cooperates with mTOR inhibitors and BH3 mimetics in AML cells. The three-drug combination was able to reach cells that were not as responsive to single or double drug combinations. In Flt3-internal tandem duplication (ITD)-positive cells, we previously showed pimozide to be highly effective when combined with imipramine blue (IB). Here, we show that Flt3-ITD+ cells are sensitive to an IB-induced dynamin 1-like (Drp1)-p38-ROS pathway. Pimozide contributes important calcium channel blocker activity converging with IB on mitochondrial oxidative metabolism. Overall, these data support the concept that antioxidants are a double-edged sword. Rationally designed combination therapies have significant promise for further pre-clinical development and may ultimately lead to improved responses.
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影响因子：
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作者：
Iacovelli S;Ricciardi MR;Allegretti M;Mirabilii S;Licchetta R;Bergamo P;Rinaldo C;Zeuner A;Foà R;Milella M;McCubrey JA;Martelli AM;Tafuri A
通讯作者：
Tafuri A
影响因子：
20.3
作者：
Chen, Wen-Lian;Wang, Jing-Han;Jia, Wei
通讯作者：
Jia, Wei
影响因子：
--
作者：
Nogami A;Oshikawa G;Okada K;Fukutake S;Umezawa Y;Nagao T;Kurosu T;Miura O
通讯作者：
Miura O
影响因子：
--
作者：
Pallis M;Burrows F;Ryan J;Grundy M;Seedhouse C;Abdul-Aziz A;Montero J;Letai A;Russell N
通讯作者：
Russell N
在急性髓样白血病的临床前模型中，将BH3摄影作用靶向Bcl-2和Mcl1具有有效的活性。
影响因子：
11.4
作者：
Moujalled DM;Pomilio G;Ghiurau C;Ivey A;Salmon J;Rijal S;Macraild S;Zhang L;Teh TC;Tiong IS;Lan P;Chanrion M;Claperon A;Rocchetti F;Zichi A;Kraus-Berthier L;Wang Y;Halilovic E;Morris E;Colland F;Segal D;Huang D;Roberts AW;Maragno AL;Lessene G;Geneste O;Wei AH
通讯作者：
Wei AH