Abstract
Cannabidiol (CBD), the major non-psychoactive compound found in cannabis, is frequently used both as a nutraceutical and therapeutic. Despite anecdotal evidence as an anticancer agent, little is known about the effect CBD has on cancer cells. Given the intractability and poor prognoses of brain cancers in human and veterinary medicine, we sought to characterize the in vitro cytotoxicity of CBD on human and canine gliomas. Glioma cells treated with CBD showed a range of cytotoxicity from 4.9 to 8.2 μg/ml; canine cells appeared to be more sensitive than human. Treatment with >5 μg/ml CBD invariably produced large cytosolic vesicles. The mode of cell death was then interrogated using pharmacologic inhibitors. Inhibition of apoptosis was sufficient to rescue CBD-mediated cytotoxicity. Inhibition of RIPK3, a classical necroptosis kinase, also rescued cells from death and prevented the formation of the large cytosolic vesicles. Next, cellular mitochondrial activity in the presence of CBD was assessed and within 2 hours of treatment CBD reduced oxygen consumption in a dose dependent manner with almost complete ablation of activity at 10 μg/ml CBD. Fluorescent imaging with a mitochondrial-specific dye revealed that the large cytosolic vesicles were, in fact, swollen mitochondria. Lastly, calcium channels were pharmacologically inhibited and the effect on cell death was determined. Inhibition of mitochondrial channel VDAC1, but not the TRPV1 channel, rescued cells from CBD-mediated cytotoxicity. These results demonstrate the cytotoxic nature of CBD in human and canine glioma cells and suggest a mechanism of action involving dysregulation of calcium homeostasis and mitochondrial activity.
Highlights
The prognosis following a glioma diagnosis is notoriously grave, no matter the species
While the exact mechanism of action underlying this cytotoxicity has not been fully elucidated, it has been hypothesized that mitochondrial dysfunction precipitated by altering Voltage Dependent Anion Channel 1 (VDAC1) channel activity is central to the observed antiproliferative, apoptotic, and other antineoplastic signaling pathways (Rimmerman et al, 2013; Magrì et al, 2018; Olivas-Aguirre et al, 2019)
We demonstrate that highly purified CBD isolate reduced proliferation and induced caspase-mediated cell death, suggestive of apoptosis, in both canine glioma cell lines SDT3G and J3TBG as well as the human glioma cell lines U87MG and U373MG Uppsala
Summary
The prognosis following a glioma diagnosis is notoriously grave, no matter the species. High grade gliomas portend a median survival rate of 14–16 months in human (Stupp et al, 2009) and 2–4 months in canine patients (Rossmeisl et al, 2012). Tumor cell resistance to the currently available multimodal treatments underlies these dismal prognoses. Improvements in patient outcome have not paralleled the medical advances in glioma treatment regimens (Hadziahmetovic et al, 2011; Uhm and Porter, 2017). This highlights the crucial need for further brain cancer treatment research. The cannabinoid family, a group of pharmacologically active compounds that primarily interact with specific cannabinoid G-protein coupled receptors (GPCR) (Hermanson and Marnett, 2011), are being rigorously studied for their putative anti-tumorigenic and therapeutically relevant
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