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
inductionof
cell death, inhibition of cell growth, and inhibition of tumor
angiogenesis invasion and
metastasis.[
9-
12] Two reviews summarize the molecular mechanisms of action of cannabinoids as antitumor agents.[
13,
14] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. For example, these compounds have been shown to induce
apoptosis in
gliomacells in
culture and induce
regression of glioma tumors in mice and rats, while they protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1
receptor.[
9]
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] Other studies have also shown the antitumor effect of cannabinoids (i.e., CBD and THC) in preclinical models of breast cancer.[
19,
20]
CBD has also been demonstrated to exert a
chemopreventive effect in a
mouse modelof
colon cancer.[
21] In this
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. In a subsequent study, the investigators found that the antiproliferative effect of CBD was counteracted by selective CB1 but not CB2 receptor
antagonists, suggesting an involvement of CB1 receptors.[
22]
Another investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1).[
12] ICAM-1 expression in tumor cells 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.[
23] 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.[
24,
25]
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.[
26] As a result, a
hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of
colorectal cancer has been developed.[
27-
30]
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. [
31] One study showed that coadministration of THC and CBD over single-agent usage had greater antiproliferative activity in an
in vitrostudy with multiple human glioblastoma multiforme cell lines.[
32] 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. Also, CBD together with THC may enhance the antitumor activity of classic chemotherapeutic drugs such as
temozolomide in some mouse models of cancer.[
13,
33] A
meta-analysis of 34
in vitro and
in vivo studies of cannabinoids in glioma reported that all but one study confirmed that cannabinoids selectively kill tumor cells.[
34]
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