One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors.[3] During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma (HCC) was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas)
were also noted in the rats. In another study, delta-9-THC,
delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo .[4] In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5-8]
Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis invasion and metastasis.[9-12] One review summarizes the molecular mechanisms of action of cannabinoids as antitumor agents.[13]
Cannabinoids appear to kill tumor cells but do not affect their
nontransformed counterparts and may even protect them from cell death.
These compounds have been shown to induce apoptosis in glioma cells in culture and induce regression
of glioma tumors in mice and rats. Cannabinoids protect normal glial
cells of astroglial and oligodendroglial lineages from apoptosis
mediated by the CB1 receptor.[14]
The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in HCC.[15] Both agents reduced the viability of HCC cells in vitro
and demonstrated antitumor effects in HCC subcutaneous xenografts in
nude mice. The investigations documented that the anti-HCC effects are
mediated by way of the CB2 receptor. Similar to findings in glioma
cells, the cannabinoids were shown to trigger cell death through
stimulation of an endoplasmic reticulum stress pathway that activates
autophagy and promotes apoptosis. Other investigations have confirmed
that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma [16] and breast cancer.[17]
An in vitro
study of the effect of CBD on programmed cell death in breast cancer
cell lines found that CBD induced programmed cell death, independent of
the CB1, CB2, or vanilloid receptors. CBD inhibited the survival of both
estrogen receptor–positive and estrogen receptor–negative breast cancer cell lines, inducing apoptosis in a concentration-dependent manner while having little effect on nontumorigenic, mammary cells.[18]
CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer.[19] In the experimental system, azoxymethane increased premalignant and malignant lesions
in the mouse colon. Animals treated with azoxymethane and CBD
concurrently were protected from developing premalignant and malignant
lesions. In in vitro experiments involving colorectal cancer cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation.
Another investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1).[12] ICAM-1 expression has been reported to be negatively correlated with cancer metastasis. In lung cancer cell lines, CBD upregulated ICAM-1, leading to decreased cancer cell invasiveness.
In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[20]
Tumor growth was inhibited by 60% in THC-treated mice compared with
vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic
and antiproliferative effects. However, research with immunocompetent
murine tumor models has demonstrated immunosuppression and enhanced
tumor growth in mice treated with THC.[21,22]
In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory
effects. A mouse study demonstrated that endogenous cannabinoid system
signaling is likely to provide intrinsic protection against colonic inflammation.[23] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[24-27]
CBD
may also enhance uptake of cytotoxic drugs into malignant cells.
Activation of the transient receptor potential vanilloid type 2 (TRPV2)
has been shown to inhibit proliferation of human glioblastoma multiforme
cells and overcome resistance to the chemotherapy agent carmustine.[28] In an in vitro
model, CBD increased TRPV2 activation and increased uptake of cytotoxic
drugs, leading to apoptosis of glioma cells without affecting normal
human astrocytes. This suggests that coadministration of CBD with
cytotoxic agents may increase drug uptake and potentiate cell death in
human glioma cells.
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