Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V

Abstract

Mutated receptor tyrosine kinases (MT-RTKs) such as internal tandem duplication of FMSlike tyrosine kinase 3 (FLT3 ITD) and a point mutation KIT D816V are driver mutations for acute myeloid leukemia (AML). Clathrin assembly lymphoid myeloid leukemia protein (CALM) regulates intracellular transport of RTKs, however, the precise role for MT-RTKs remains elusive. We here show that CALM knock down leads to severely impaired FLT3 ITDor KIT D814V-dependent cell growth compared to marginal influence on wild-type FLT3-or KIT-mediated cell growth. An antipsychotic drug chlorpromazine (CPZ) suppresses the growth of primary AML samples, and human CD34 + CD38-AML cells including AML initiating cells with MT-RTKs in vitro and in vivo. Mechanistically, CPZ reduces CALM protein at post transcriptional level and perturbs the intracellular localization of MT-RTKs, thereby blocking their signaling. Our study presents a therapeutic strategy for AML with MT-RTKs by altering the intracellular localization of MT-RTKs using CPZ.

Potent efficacy of chlorpromazine in acute myeloid leukemia harboring KIT-D816V mutation

“…2 b, c ). Next, we tested anti-leukemic activities of CPZ in a xenograft mouse model using her AML cells at the same CPZ concentrations utilized in our previous study [5] . For the first few days after transplantation, the CPZ treated mice slept for half a day, and slight weight loss was observed compared to the control mice, however, the side effect of weight loss was transient.…”

“…CPZ is a phenothiazine drug that has been utilized for many years to treat several psychiatric disorders. Pharmacologically, CPZ acts as an antagonist on different postsynaptic and presynaptic receptors, including dopamine, serotonin, and histamine 1 receptor, which accounts for its versatility and clinical utility in various disorders [ 5 , 6 ]. In addition, preclinical studies have reported that CPZ has antitumor activities in several cellular systems [ 5 , 7 , 8 ].…”

“…In vitro and in vivo experiments were performed as described before [5] . The sample was obtained after written informed consent following institutional guidelines of Kindai University Faculty of Medicine (Authorization Number: 24–017, −018) per Declaration of Helsinki principles.…”

“…We recently showed that Chlorpromazine (CPZ), which is a widely used as an antipsychotic drug, interferes with the intracellular localization of KIT-D816V, leading to cell death in AML cells with KIT-D816V in vitro and in vivo [5] . We herein report that daily administration of CPZ, prescribed for controlling anxiety disorder in an AML patient with RUNX1-RUNX1T1 harboring KIT-D816V , led to a dramatic reduction in AML cells.…”

Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

“…However, there are few mechanistic studies about the cytotoxicity of phenothiazines in leukemia. Chlorpromazine suppressed the growth of primary AML cells and AML cells with mutated tyrosine kinase receptor [ 11 ]. Yet, in AML cells, TR induced cell death promoting cytoskeletal remodeling of blast cells selectively in variant t (6;11) AML cells involving Ca 2+ overload, ROS production, and mitochondrial dysfunction [ 12 ].…”