Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial Ca 2+ Homeostasis

Cytotoxic effects of cannabidiol (CBD) and tamoxifen (TAM) have been observed in several cancer types. We have recently shown that CBD primarily targets mitochondria, inducing a stable mitochondrial permeability transition pore (mPTP) and, consequently, the death of acute lymphoblastic leukemia (T-A...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-08, Vol.22 (16)
Main Authors: Olivas-Aguirre, Miguel, Torres-López, Liliana, Gómez-Sandoval, Zeferino, Villatoro-Gómez, Kathya, Pottosin, Igor, Dobrovinskaya, Oxana
Format: Article
Language:English
Subjects:
Calcium - metabolism
Cannabidiol - pharmacology
Cell Line, Tumor
Drug Synergism
Homeostasis - drug effects
Humans
Jurkat Cells
Membrane Potential, Mitochondrial - drug effects
Mitochondrial Permeability Transition Pore - metabolism
Models, Molecular
Molecular Docking Simulation
Peptidyl-Prolyl Isomerase F - chemistry
Peptidyl-Prolyl Isomerase F - metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Protein Conformation
Tamoxifen - pharmacology
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Summary:Cytotoxic effects of cannabidiol (CBD) and tamoxifen (TAM) have been observed in several cancer types. We have recently shown that CBD primarily targets mitochondria, inducing a stable mitochondrial permeability transition pore (mPTP) and, consequently, the death of acute lymphoblastic leukemia (T-ALL) cells. Mitochondria have also been documented among cellular targets for the TAM action. In the present study we have demonstrated a synergistic cytotoxic effect of TAM and CBD against T-ALL cells. By measuring the mitochondrial membrane potential (ΔΨm), mitochondrial calcium ([Ca ] ) and protein-ligand docking analysis we determined that TAM targets cyclophilin D (CypD) to inhibit mPTP formation. This results in a sustained [Ca ] overload upon the consequent CBD administration. Thus, TAM acting on CypD sensitizes T-ALL to mitocans such as CBD by altering the mitochondrial Ca homeostasis.
ISSN:1422-0067