Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia

• Type of Material: Article
• Authors: Zhengqi Wang, Emory University; Tian Mi, Emory University; Himalee L Bradley, Emory University; Jonathan Metts, Emory University; Himalee Sabnis, Emory University; Wandi Zhu, Emory University; Jack Arbiser, Emory University; Kevin Bunting, Emory University
• Language: English
• Date: 2021-06-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/antiox10060956
• Title of Journal or Parent Work: ANTIOXIDANTS
• Volume: 10
• Issue: 6
• Grant/Funding Information: Aflac Cancer and Blood Disorders Center Pilot Grant, NIHR01DK059380, Rally Childhood Cancer Foundation, Cure Childhood Cancer Foundation, Swim across America Foundation, Aflac Cancer & Blood Disorders Center of Children’s Healthcare of Atlanta.
• Keywords: COMBINATION; reactive oxygen species; Chemistry, Medicinal; SURVIVAL; BCL-2; mitoSox; RESISTANCE; BH3 mimetic; Life Sciences & Biomedicine; APOPTOSIS; ACTIVATION; mTOR inhibitor; N-DOMAIN; Food Science & Technology; PATHWAY; Science & Technology; Pharmacology & Pharmacy; MIMETIC ABT-737; acute myeloid leukemia; Biochemistry & Molecular Biology; Flt3-internal tandem duplication; CANCER; repurposed drugs
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

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.