Naturally occurring and related synthetic cannabinoids and their potential therapeutic applications.

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Abstract

“Naturally occurring cannabinoids (phytocannabinoids) are biosynthetically related terpenophenolic compounds uniquely produced by the highly variable plant, Cannabis sativa L. Natural and synthetic cannabinoids have been extensively studied since the discovery that the psychotropic effects of cannabis are mainly due to Delta(9)-THC. However, cannabinoids exert pharmacological actions on other biological systems such as the cardiovascular, immune and endocrine systems. Most of these effects have been attributed to the ability of these compounds to interact with the cannabinoid CB1 and CB2 receptors. The FDA approval of Marinol, a product containing synthetic Delta(9)-THC (dronabinol), in 1985 for the control of nausea and vomiting in cancer patients receiving chemotherapy, and in 1992 as an appetite stimulant for AIDS patients, has further intensified the research interest in these compounds. This article reviews patents (2003-2007) that describe methods for isolation of cannabinoids from cannabis, chemical and chromatographic methods for their purification, synthesis, and potential therapeutic applications of these compounds.”

http://www.ncbi.nlm.nih.gov/pubmed/19519560

Fungal biotransformation of cannabinoids: potential for new effective drugs.

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Abstract

“Phytocannabinoids from the plant Cannabis sativa induce a variety of physiological and pharmacological responses in living systems, including anti-inflammatory, antinociceptive, anti-ulcer and antitumor activities. The discovery of the cannabinoid receptors CB1 and CB2 led to the development of agonists and antagonists of these receptors for the treatment of a variety of diseases. Nabilone, a synthetic derivative of Delta9-tetrahydrocannabinol (Delta9-THC), which is the main natural psychotropic constituent of C sativa, was approved by the US FDA for the treatment of nausea and as an anti-emetic for patients undergoing chemotherapy. Delta9-THC and related cannabinoids are involved in a variety of signal transduction pathways; thus, reducing or removing the psychotropic effects of these compounds would enhance their therapeutic spectra. Compound synthesis and qualitative SAR studies are time-consuming activities; however, microbes are effectively the most inventive synthetic chemists because of their metabolic plasticity. This review discusses the potential of C sativa mycoflora, which is pathogenic as well as endophytic, to remove the psychotropic effects of Delta9-THC and related cannabinoids, and describes the development of a model system for the rapid and cost-effective commercial production of cannabinoids through fermentation pathways.”

http://www.ncbi.nlm.nih.gov/pubmed/19333876

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