Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial Ca2+ Homeostasis

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.

Cyclophilin D: Guardian or Executioner for Tumor Cells?

“…As shown in Figure 6, most antitumor drugs can induce tumor cell necrosis by activating the CypD-mPTP axis (62)(63)(64)(65)(66)(67)(68)(69)(70). For example, icaritin could induce necrosis of colon tumor cells, but not apoptosis, which is dependent on activation of the JNK pathway (71).…”

Cannabidiol on the Path from the Lab to the Cancer Patient: Opportunities and Challenges

“…Tamoxifen (TAM) was shown to interact synergistically with CBD in the suppression of T-ALL cells and this synergism was higher when cells were pretreated with TAM or both drugs were added simultaneously compared to the case of TAM after CBD. This was explained by the fact that TAM pretreatment prevented the mitochondrial permeation transition pore formation by binding to cyclophilin D, so that a consequent CBD application resulted in a permanent mitochondrial Ca 2+ overload and more severe mitochondrial dysfunction [ 72 ].…”