CBD kills mutant cells that cause fibrosis and cancer.

CBD kills mutant cells that cause fibrosis and cancer.


Cannabidiol (CBD), a major non-psychoactive ingredient of some forms of cannabis has been shown to not only protect the liver, but to reverse liver fibrosis, the tenth leading cause of death in the US.  CBD and THC were shown in the lab to cause rogue cells, such as cancer cells and liver fibrosis cells to auto destruct, forming the basis of effective new treatments.


Liver fibrosis is the 10th leading cause of fatalities in the US, affecting over four hundred thousand patients.  The common wound-healing effect in the liver can result in a build up and tangling of fibrous material that impedes function, mitigating or exacerbating  many chronic liver-hepatic diseases, including viral and autoimmune hepatitis, alcoholic liver disease, and obesity-related liver-hepatic disease. The high incidence of cirrhosis and liver-hepatic failure that results directly from fibrosis motivated the identification of pharmacological treatments to halt the progression  even reverse, fibrosis.


Liver cells, hepatic (liver) stellate cells (HSC) job is to respond to insult and injury.  When the injury is great and prolonged, scar tissue can build up, and is the underlying cellular event of liver fibrogenesis.



"HSC (scar tissue) activation refers to the transdifferentiation of quiescent HSCells into proliferative and contractile myofibroblast-like cells. These activated Cells secrete excess extracellular matrix (ECM) proteins, predominantly collagen type I, leading to the accumulation of scar matrix, and ultimately liver fibrosis."


Because HS Cells have a fundamental and central role in fibrogenesis, the elimination of overly active  Cells through programmed cell death has been proposed as a mechanism to slow or reverse liver fibrosis. Phytocannabinoids, CBD and THC from medicinal marijuana varieties have been shown to possess the ability to modulate many bodily functions and induce programmed cell death in rodents and mammalian cancer cells in vitro.


Very few pharmacological agents have been found to date that are truly effective in reducing liver fibrosis, and the ones that do exist generally possess unacceptable side effects.  Cannabinoids on the other hand, have shown to be extremely safe with low side effects, and if they do occur, the duration of negative effects are only a few hours and possibly half a day in extreme examples.


The phytocannabinoid CBD has been found to lead to death of proliferative cells, such as cancer cells and rogue lymphocytes, through a variety of processes involving either cannabinoid receptors or perhaps other inner workings.  


Recently, it was revealed that the endocannabinoid system has been established as a critical mediator of HSC (scar tissue) activation and liver fibrosis, and studies with various cannabinoid ligand (bond with receptors) have demonstrated the therapeutic ability of this class of molecules. The rogue proliferative nature of activated Cells prompted us to examine the therapeutic effect of CBD on these cells.

The liver endoplasmic reticulum functions in lipid manufacture and metabolism and the production of steroid hormones, and detoxification. Smooth ER is especially abundant in mammalian liver and gonad cells. The endoplasmic reticulum (ER) forms an interconnected network of flattened, membrane-enclosed sacs or tube-like structures.

Amazingly, it was confirmed that CBD induced death of activated Cells through apoptosis - programmed cell death, an event that occurs independently of cannabinoid receptors. This led us to study alternative inner workings for the pro-apoptotic effect of CBD. Changes of ER morphology (formation), evidenced by modifications in calnexin distribution and ER dilation, suggested that Cannabidiol (CBD) induces ER stress. This was confirmed by activation of PERK, ATF6, and IRE1, the three major mediators of the ER stress effect, as well as their downstream signaling cascades.


Induction of CHOP, indicative of prolonged ER stress and pro-apoptotic signaling, further supported a Cannabidiol (CBD)-induced ER stress effect linked to apoptosis - programmed cell death. The downstream activation of the pro-apoptotic ASK1/JNK cascade, known to be activated upon severe ER stress, as well as our findings that expression of DN IRE1α and inhibition of JNK both markedly suppressed the apoptotic effect of Cannabidiol (CBD), provided evidence that Cannabidiol (CBD) mitigates ASK1/JNK-induced apoptosis - programmed cell death in activated Cells through an ER stress-mediated mechanism.

Importantly, the apoptotic effect of Cannabidiol (CBD) was specific to the activated Cells and could be seen in an activated HSC (scar tissue) line derived from ethanol-fed rats, in human LX-2 cells, as well as in central in vivo-activated Cells from mouse. In contrast, this effect was absent in primary rat hepatocytes and was detectable in control Cells only upon treatment with higher concentrations of Cannabidiol (CBD).

As Cells are the major fibrogenic cells in the liver, their production and secretion of excess ECM proteins is dependent upon the proper functioning of the ER. More so than in non-proliferative or non-fibrogenic cell types, the ER of activated Cells undergoes stress during excessive collagen production, and maintaining homeostasis is likely aided by an adaptive base ER stress effect. We find that activated Cells have a higher base level of ER stress, supported by the dialing up of ATF4, ATF6, and CHOP mRNA expression in activated Cells (responsive to Cannabidiol (CBD)) as compared with control Cells (not responsive to Cannabidiol (CBD)).


This could account for the selectivity of the pro-apoptotic effect of Cannabidiol (CBD) in activated Cells, wherein Cannabidiol (CBD) exacerbates the pre-existing ER stress effect, thereby switching signaling from adaptive to apoptotic. In line with this, inducing ER stress in control Cells with tunicamycin led to a sensitization of these cells to Cannabidiol (CBD).


Moreover, downregulation of ATF4 in untreated activated HAVells led to decreased CHOP expression and apoptosis - programmed cell death, suggesting that blocking the base level PERK-mediated ER stress effect lowers sensitivity to Cannabidiol (CBD), and that ER stress determines susceptibility to the pro-apoptotic effect of Cannabidiol (CBD). These observations offer insight into ER stress as a new intracellular pathway that could be selected to achieve antifibrotic effects through selective elimination of activated Cells.

Although ER stress has been linked to many pathophysiological processes,15 our studies show for the first time that it might be involved in the activated HSC (scar tissue) phenotype, and that ER stress can be exploited in the context of liver fibrosis to kill specifically the Cells that promote fibrosis. Our finding that Cannabidiol (CBD) leads to activated HSC (scar tissue) death independently of cannabinoid receptors further underscores the novelty of the mechanism proposed herein, in contrast to a conventional cannabinoid ligand (bond with receptors) that mediate antifibrotic effects through their cognate receptors.


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Interestingly, another cannabinoid ligand (bond with receptors) such as d9THC have been shown to induce apoptosis - programmed cell death in different cancer models such as glioma cells and pancreatic tumor cells through a mechanism involving ER stress,32, 33 dependent on cannabinoid receptor activation. This is reminiscent of the pro-apoptotic effect of the CB2R-dependent CP55940-induced HSC (scar tissue) death that we observed, and suggests that Cannabidiol (CBD) promotes ER stress-induced apoptosis - programmed cell death in activated Cells through a mechanism distinct from that of cannabinoid receptor agonists.

In this study, we find that Cannabidiol (CBD) selectively kills activated Cells through the previously unexplored mechanism of ER stress. We provide a biochemical molecular basis of action for Cannabidiol (CBD) and identify Cannabidiol (CBD) as a novel  therapeutic agent for liver fibrosis. These promising findings warrant further investigation - the evaluating the antifibrotic effect of Cannabidiol (CBD) in vivo. The prospect of Cannabidiol (CBD) as a new antifibrotic compound is rendered more appealing by the fact that Cannabidiol (CBD) is a non-psychoactive small drug-like molecule already approved for clinical use in many countries.


The major cellular event in the development and progression of liver fibrosis is the activation of liver stellate cells (HES Cells). Activated Cells proliferate and produce excess collagen, leading to accumulation of scar matrix and fibrotic liver. Therefore, the induction of activated HSC (scar tissue) death has been proposed as a means to achieve resolution of liver fibrosis. Here we demonstrate that cannabidiol, a major non-psychoactive component of the plant Cannabis sativa, induces apoptosis - programmed cell death in activated Cells through a cannabinoid receptor-independent mechanism.


Cannabidiol (CBD) elicits an endoplasmic reticulum (ER) stress effect, defined by modifications in ER morphology (formation) and the initiation of RNA-dependent protein kinase-like ER kinase-, activating transcription factor-6-, and inositol-requiring ER-to-nucleus signal kinase-1 (IRE1)-mediated signaling cascades.


Furthermore, Cannabidiol (CBD) induces downstream activation of the pro-apoptotic kinase pathway, leading to HSC (scar tissue) (scar tissue) death. Importantly, we show that this mechanism of Cannabidiol (CBD)-induced ER stress-mediated apoptosis - programmed cell death is specific to activate Cells, as it occurs in activated human and rat HSC (scar tissue) lines, and in primary in vivo-activated mouse Cells, but not in quiescent Cells or primary hepatocytes from rat.


Finally, we provide evidence that the elevated base level of ER stress in activated Cells has a role in their susceptibility to the pro-apoptotic effect of Cannabidiol (CBD).  We propose that Cannabidiol (CBD), by selectively inducing death of activated Cells, serves as a possible therapeutic agent for the treatment of liver fibrosis.


To study the possibilities of Cannabidiol (CBD) and other cannabinoid ligand (bond with receptors) to induce activated HSC (scar tissue) death, we treated grew activated Cells, isolated from livers of rats that were fed an 8-month ethanol diet , with increasing concentrations of different cannabinoids for 8 h, and measured cell viability using an acid phosphatase assay.


In order to define the mechanism through which Cannabidiol (CBD) mitigates apoptosis - programmed cell death, we first studied whether Cannabidiol (CBD) was acting through cannabinoid receptors


Cannabidiol (CBD) mitigates a modification in morphology (formation) of the ER in activated Cells through induction of ER stress  During the course of our experiments, we noticed marked modifications in the morphology (formation) of Cannabidiol (CBD)-treated activated Cells. The presence of distinct structures surrounding the nucleus suggested an effect of Cannabidiol (CBD) on the ER.


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Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis


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