A molecular basis of the therapeutic and psychoactive properties of cannabis (delta9-tetrahydrocannabinol).

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Abstract

“All of the therapeutic properties of marihuana (analgesic, antiemetic, appetite stimulant, antiglaucoma) have been duplicated by the tetrahydrocannabinol (THC) molecule or its synthetic derivatives. Today, the molecular mechanisms of action of these compounds have led to a general understanding of the pharmacological effects of marihuana and of its therapeutic properties. These mechanisms involve the specific binding of THC to the 7-transmembrane (7TM) domain G protein-linked receptor, a molecular switch which regulates signal transduction in the cell membrane. The natural ligand of the 7TM receptor is an eicosanoid, arachidonylethanolamide (AEA), generated in the membrane and derived from arachidonic acid. THC acts as a substitute ligand to the 7TM receptor site of AEA. THC would deregulate the physiological function of the 7TM receptor and of its ligand AEA. As a result, the therapeutic effects of the drug may not be separated from its adverse psychoactive and cardiovascular effects. The binding of THC to the 7TM receptor site of AEA induces allosteric changes in the receptor sites of neurotransmitter and opiates resulting in variable interactions and pharmacological responses. The pharmacokinetics of THC with its prolonged storage in fat and its slow release result in variable and delayed pharmacological response, which precludes precise dosing to achieve timely therapeutic effects. The experimental use of THC and of its synthetic analogues, agonists, and antagonists has provided novel information in the nature of molecular signaling in the cell membrane. As a result, the relationships between allosteric receptor responsiveness, molecular configuration of proteins, and physiological regulation of cellular and organ function may be further investigated.”

http://www.ncbi.nlm.nih.gov/pubmed/12188105

Marijuana May Fight Lung Tumors – FoxNews

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   “…the active ingredient in marijuana may help combat lung cancer, new research suggests.

In lab and mouse studies, the compound, known as THC, cut lung tumor growth in half and helped prevent the cancer from spreading, says Anju Preet, PhD, a Harvard University researcher in Boston who tested the chemical. 

While a lot more work needs to be done, “the results suggest THC has therapeutic potential,” she tells WebMD. 

Moreover, other early research suggests the cannabis compound could help fight brain, prostate, and skin cancers as well, Preet says.”

Read more: http://www.foxnews.com/story/0,2933,266715,00.html

Read more: http://www.foxnews.com/story/0,2933,266715,00.html#ixzz2C1POR7Ap

Antineoplastic activity of cannabinoids.

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   “Lewis lung adenocarcinoma growth was retarded by the oral administration of delta9-tetrahydrocannabinol (delta9-THC), delta8-tetrahydrocannabinol (delta8-THC), and cannabinol (CBN), but not cannabidiol (CBD)… CBD was active only in high concentrations.”

http://www.ncbi.nlm.nih.gov/pubmed/1159836

In vivo effects of cannabinoids on macromolecular biosynthesis in Lewis lung carcinomas.

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Abstract

“Cannabinoids represent a novel class of drugs active in increasing the life span mice carrying Lewis lung tumors and decreasing primary tumor size. In the present studies, the effects of delta9-THC, delta8-THC, and cannabidiol on tumor macromolecular biosynthesis were studied. These drugs inhibit thymidine-3H incorporation into DNA acutely, but did not inhibit leucine uptake into tumor protein. At 24 h after treatment, cannabinoids did not inhibit thymidine-3H incorporation into DNA, leucine-3H uptake into protein or cytidine-3H into RNA.”

http://www.ncbi.nlm.nih.gov/pubmed/616322

Decrease of plasminogen activator inhibitor-1 may contribute to the anti-invasive action of cannabidiol on human lung cancer cells

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“PURPOSE:

Using human lung cancer cells, we evaluated the involvement of plasminogen activator inhibitor-1 (PAI-1) in the anti-invasive action of cannabidiol, a non-psychoactive cannabinoid.”

“RESULTS:

Cannabidiol caused a profound inhibition of A549 cell invasion, accompanied by a decreased expression and secretion of PAI-1… Key data were confirmed in two other human lung cancer cell lines (H460, H358). In vivo, a significant downregulation of PAI-1 protein by cannabidiol was demonstrated in A549 xenografts.”

“CONCLUSION:

Our data provide evidence for a hitherto unknown mechanism underlying the anti-invasive action of cannabidiol on human lung cancer cells.”

http://www.ncbi.nlm.nih.gov/pubmed/20668920

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1.

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Cover image

“Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects. Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using Matrigel invasion assays we found a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1 expression by siRNA led to a reversal of the cannabidiol-elicited decrease in tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated protein kinases were identified as upstream targets conferring TIMP-1 induction and subsequent decreased invasiveness. Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of A549 lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls.

Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.”  http://www.ncbi.nlm.nih.gov/pubmed/19914218

http://www.sciencedirect.com/science/article/pii/S000629520900971X

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.

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   “Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460.. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.”

http://www.ncbi.nlm.nih.gov/pubmed/22198381

Anti-proliferative and anti-angiogenic effects of CB2R agonist (JWH-133) in non-small lung cancer cells (A549) and human umbilical vein endothelial cells: an in vitro investigation.

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“Non-small cell lung cancer has one of the highest mortality rates among cancer-suffering patients. It is well known that the unwanted psychotropic effects of cannabinoids (CBs) are mediated via the CB(1) receptor (R), and selective targeting of the CB(2)R would thus avoid side effects in cancer treatment…

the aim of our study was to evaluate the effect of selective CB(2)R agonist, JWH-133, on A549 cells (non-small lung cancer) and human umbilical vein endothelial cells (HUVECs)…

The present study demonstrates the in vitro anti-proliferative and anti-angiogenic potential of CB(2)R agonist, JWH-133, in nonsmall lung cancer cells and HUVECs.

Our results generate a rationale for further in vivo efficacy studies with this compound in preclinical cancer models.”

http://www.ncbi.nlm.nih.gov/pubmed/22578958

Cannabinoid Receptors, CB1 and CB2, as Novel Targets for Inhibition of Non-Small Cell Lung Cancer Growth and Metastasis

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“Cannabinoid receptors are expressed in human lung cancers”

 

  “Recently, CB1 and CB2 have been shown to be overexpressed on tumor cells compared to normal cells in various types of cancers, such as breast and liver, and therefore could be used as novel targets for cancer. In addition, several cannabinoids, including THC and cannabidiol, synthetic cannabinoid-agonists JWH-133, Win55,212-2, were shown to inhibit tumor growth and progression of several types of cancers, including glioma, glioblastoma multiforme, breast, prostate, colon carcinomas, leukemia and lymphoid tumors.”

“There are three general types of cannabinoids: phytocannabinoids, THC and cannabidiol, are derived from plants; endogenous cannabinoids, 2AG and AEA, which are produced inside the body; and synthetic cannabinoids, JWH-133/JWH-015, CP-55 and Win55,212-2.”

“Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide; however, only limited therapeutic treatments are available. Hence, we investigated the role of cannabinoid receptors, CB1 and CB2, as novel therapeutic targets against NSCLC…”

“These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025486/