Pimozide and imipramine blue exploit mitochondrial vulnerabilities and reactive oxygen species to cooperatively target high risk acute myeloid leukemia

Zhengqi Wang, Tian Mi, Heath L. Bradley, Jonathan Metts, Himalee Sabnis, Wandi Zhu, Jack Arbiser, Kevin D. Bunting

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number956
JournalAntioxidants
Volume10
Issue number6
DOIs
StatePublished - Jun 2021
Externally publishedYes

Keywords

  • Acute myeloid leukemia
  • BH3 mimetic
  • Flt3-internal tandem duplication
  • MTOR inhibitor
  • MitoSox
  • Reactive oxygen species
  • Repurposed drugs

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of 'Pimozide and imipramine blue exploit mitochondrial vulnerabilities and reactive oxygen species to cooperatively target high risk acute myeloid leukemia'. Together they form a unique fingerprint.

Cite this