Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial Ca2+ Homeostasis |
| |
Authors: | Miguel Olivas-Aguirre Liliana Torres-Lpez Zeferino Gmez-Sandoval Kathya Villatoro-Gmez Igor Pottosin Oxana Dobrovinskaya |
| |
Affiliation: | 1.Laboratory of Immunobiology and Ionic Transport Regulation, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio 965, Villa de San Sebastián, Colima 28045, Mexico; (M.O.-A.); (L.T.-L.); (K.V.-G.);2.Facultad de Ciencias Químicas, Universidad de Colima, Carretera Colima-Coquimatlán, km. 9, Coquimatlán 28400, Mexico; |
| |
Abstract: | 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 (Ca2+]m) and protein-ligand docking analysis we determined that TAM targets cyclophilin D (CypD) to inhibit mPTP formation. This results in a sustained Ca2+]m overload upon the consequent CBD administration. Thus, TAM acting on CypD sensitizes T-ALL to mitocans such as CBD by altering the mitochondrial Ca2+ homeostasis. |
| |
Keywords: | acute lymphoblastic leukemia cannabidiol tamoxifen mitochondria calcium overload mitochondrial permeability transition pore cyclophilin D |
|
|