Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia
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 develo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/6/956 |
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| author | Zhengqi Wang Tian Mi Heath L. Bradley Jonathan Metts Himalee Sabnis Wandi Zhu Jack Arbiser Kevin D. Bunting |
| author_facet | Zhengqi Wang Tian Mi Heath L. Bradley Jonathan Metts Himalee Sabnis Wandi Zhu Jack Arbiser Kevin D. Bunting |
| author_sort | Zhengqi Wang |
| collection | DOAJ |
| description | 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<sup>+</sup> 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. |
| first_indexed | 2024-03-10T10:24:20Z |
| format | Article |
| id | doaj.art-55cef3b857214f6c9597debf32e669f4 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T10:24:20Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-55cef3b857214f6c9597debf32e669f42023-11-22T00:08:07ZengMDPI AGAntioxidants2076-39212021-06-0110695610.3390/antiox10060956Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid LeukemiaZhengqi Wang0Tian Mi1Heath L. Bradley2Jonathan Metts3Himalee Sabnis4Wandi Zhu5Jack Arbiser6Kevin D. Bunting7Division of Hem/Onc/BMT, Department of Pediatrics, Emory University, Atlanta, GA 30322, USADivision of Hem/Onc/BMT, Department of Pediatrics, Emory University, Atlanta, GA 30322, USADivision of Hem/Onc/BMT, Department of Pediatrics, Emory University, Atlanta, GA 30322, USADivision of Hem/Onc/BMT, Department of Pediatrics, Emory University, Atlanta, GA 30322, USADivision of Hem/Onc/BMT, Department of Pediatrics, Emory University, Atlanta, GA 30322, USADivision of Hem/Onc/BMT, Department of Pediatrics, Emory University, Atlanta, GA 30322, USADepartment of Dermatology, Emory University, Atlanta, GA 30322, USADivision of Hem/Onc/BMT, Department of Pediatrics, Emory University, Atlanta, GA 30322, USAAcute 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<sup>+</sup> 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.https://www.mdpi.com/2076-3921/10/6/956acute myeloid leukemiaFlt3-internal tandem duplicationreactive oxygen speciesmitoSoxBH3 mimeticmTOR inhibitor |
| spellingShingle | Zhengqi Wang Tian Mi Heath L. Bradley Jonathan Metts Himalee Sabnis Wandi Zhu Jack Arbiser Kevin D. Bunting Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia Antioxidants acute myeloid leukemia Flt3-internal tandem duplication reactive oxygen species mitoSox BH3 mimetic mTOR inhibitor |
| title | Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia |
| title_full | Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia |
| title_fullStr | Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia |
| title_full_unstemmed | Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia |
| title_short | Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia |
| title_sort | pimozide and imipramine blue exploit mitochondrial vulnerabilities and reactive oxygen species to cooperatively target high risk acute myeloid leukemia |
| topic | acute myeloid leukemia Flt3-internal tandem duplication reactive oxygen species mitoSox BH3 mimetic mTOR inhibitor |
| url | https://www.mdpi.com/2076-3921/10/6/956 |
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