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Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia.

ABSTRACT: Anticancer properties of non-psychoactive cannabinoid cannabidiol (CBD) have been demonstrated on tumors of different histogenesis. Different molecular targets for CBD were proposed, including cannabinoid receptors and some plasma membrane ion channels. Here we have shown that cell lines derived from acute lymphoblastic leukemia of T lineage (T-ALL), but not resting healthy T cells, are highly sensitive to CBD treatment. CBD effect does not depend on cannabinoid receptors or plasma membrane Ca2+-permeable channels. Instead, CBD directly targets mitochondria and alters their capacity to handle Ca2+. At lethal concentrations, CBD causes mitochondrial Ca2+ overload, stable mitochondrial transition pore formation and cell death. Our results suggest that CBD is an attractive candidate to be included into chemotherapeutic protocols for T-ALL treatment.

SUBMITTER: Olivas-Aguirre M

PROVIDER: S-EPMC6791884 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia.

Olivas-Aguirre Miguel M Torres-López Liliana L Valle-Reyes Juan Salvador JS Hernández-Cruz Arturo A Pottosin Igor I Dobrovinskaya Oxana O

Cell death & disease 20191014 10

Anticancer properties of non-psychoactive cannabinoid cannabidiol (CBD) have been demonstrated on tumors of different histogenesis. Different molecular targets for CBD were proposed, including cannabinoid receptors and some plasma membrane ion channels. Here we have shown that cell lines derived from acute lymphoblastic leukemia of T lineage (T-ALL), but not resting healthy T cells, are highly sensitive to CBD treatment. CBD effect does not depend on cannabinoid receptors or plasma membrane Ca<s ...[more]

PMID: 31611561

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Project description:UNLABELLED:Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1-positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLLr B-ALLs. SIGNIFICANCE:We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR-ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survival of primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr.

Dataset Information

Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia.

Publications

Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia.

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