Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of Kv1.3 potassium channels, AKT and ERK1/2 signaling

BACKGROUND: Treatment of acute leukemia is challenging and long-lasting remissions are difficult to induce. Innovative therapy approaches aim to complement standard chemotherapy to improve drug efficacy and decrease toxicity. Promising new therapeutic targets in cancer therapy include voltage-gated Kv1.3 potassium channels, but their role in acute leukemia is unclear. We reported that Kv1.3 channels of lymphocytes are blocked by memantine, which is known as an antagonist of neuronal N-methyl-D-aspartate type glutamate receptors and clinically applied in therapy of advanced Alzheimer disease. Here we evaluated whether pharmacological targeting of Kv1.3 channels by memantine promotes cell death of acute leukemia cells induced by chemotherapeutic cytarabine.

METHODS: We analyzed acute lymphoid (Jurkat, CEM) and myeloid (HL-60, Molm-13, OCI-AML-3) leukemia cell lines and patients' acute leukemic blasts after treatment with either drug alone or the combination of cytarabine and memantine. Patch-clamp analysis was performed to evaluate inhibition of Kv1.3 channels and membrane depolarization by memantine. Cell death was determined with propidium iodide, Annexin V and SYTOX staining and cytochrome C release assay. Molecular effects of memantine co-treatment on activation of Caspases, AKT, ERK1/2, and JNK signaling were analysed by Western blot. Kv1.3 channel expression in Jurkat cells was downregulated by shRNA.

RESULTS: Our study demonstrates that memantine inhibits Kv1.3 channels of acute leukemia cells and in combination with cytarabine potentiates cell death of acute lymphoid and myeloid leukemia cell lines as well as primary leukemic blasts from acute leukemia patients. At molecular level, memantine co-application fosters concurrent inhibition of AKT, S6 and ERK1/2 and reinforces nuclear down-regulation of MYC, a common target of AKT and ERK1/2 signaling. In addition, it augments mitochondrial dysfunction resulting in enhanced cytochrome C release and activation of Caspase-9 and Caspase-3 leading to amplified apoptosis.

CONCLUSIONS: Our study underlines inhibition of Kv1.3 channels as a therapeutic strategy in acute leukemia and proposes co-treatment with memantine, a licensed and safe drug, as a potential approach to promote cytarabine-based cell death of various subtypes of acute leukemia.

Medienart:

E-Artikel

Erscheinungsjahr:

2019

Erschienen:

2019

Enthalten in:

Zur Gesamtaufnahme - volume:17

Enthalten in:

Cell communication and signaling : CCS - 17(2019), 1 vom: 16. Jan., Seite 5

Sprache:

Englisch

Beteiligte Personen:

Lowinus, Theresa [VerfasserIn]
Heidel, Florian H [VerfasserIn]
Bose, Tanima [VerfasserIn]
Nimmagadda, Subbaiah Chary [VerfasserIn]
Schnöder, Tina [VerfasserIn]
Cammann, Clemens [VerfasserIn]
Schmitz, Ingo [VerfasserIn]
Seifert, Ulrike [VerfasserIn]
Fischer, Thomas [VerfasserIn]
Schraven, Burkhart [VerfasserIn]
Bommhardt, Ursula [VerfasserIn]

Links:

Volltext

Themen:

04079A1RDZ
8L70Q75FXE
9007-43-6
Acute leukemia
Adenosine Triphosphate
Caspase 3
Cell death
Cytarabine
Cytochromes c
EC 2.7.11.1
EC 3.4.22.-
Journal Article
Kv1.3 Potassium Channel
Memantine
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-myc
Research Support, Non-U.S. Gov't
Signaling
W8O17SJF3T

Anmerkungen:

Date Completed 12.06.2019

Date Revised 09.03.2020

published: Electronic

Citation Status MEDLINE

doi:

10.1186/s12964-018-0317-z

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM292790090