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

“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/

 

Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1.

JNCI: Journal of the National Cancer Institute

“Cannabinoids, in addition to having palliative benefits in cancer therapy, have been associated with anticarcinogenic effects. Although the antiproliferative activities of cannabinoids have been intensively investigated, little is known about their effects on tumor invasion.”

“Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.”

“There is considerable evidence to suggest an important role for cannabinoids in conferring anticarcinogenic activities. In this study, we identified TIMP-1 as a mediator of the anti-invasive actions of MA, a hydrolysis-stable analog of the endocannabinoid anandamide, and THC, a plant-derived cannabinoid.”

“In conclusion, our results suggest that there exists a signaling pathway by which the binding of cannabinoids to specific receptors leads via intracellular MAPK activation to induction of TIMP-1 expression and subsequent inhibition of tumor cell invasion. To our knowledge, this is the first report of TIMP-1–dependent anti-invasive effects of cannabinoids.”

http://jnci.oxfordjournals.org/content/100/1/59.long

Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis.

  “Stimulation of cannabinoid CB1 receptors… inhibits the growth of a rat thyroid cancer cell-derived tumor…  also blocks the growth of tumors… the hypothesis that CB1 receptor stimulation interferes not only with angiogenesis but also with metastatic processes was tested in a widely used model of metastatic infiltration in vivo, the Lewis lung carcinoma… Our findings indicate that CB1 receptor agonists might be used therapeutically to retard tumor growth in vivo by inhibiting at once tumor growth, angiogenesis, and metastasis.”

http://www.ncbi.nlm.nih.gov/pubmed/12958205

Cannabinoid receptor agonists are mitochondrial inhibitors: a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death.

  “Time-lapse microscopy of human lung cancer (H460) cells showed that the endogenous cannabinoid anandamide (AEA), the phyto-cannabinoid Delta-9-tetrahydrocannabinol (THC) and a synthetic cannabinoid HU 210 all caused morphological changes characteristic of apoptosis… These data demonstrate that AEA, THC, and HU 210 are all able to cause changes in integrated mitochondrial function, directly, in the absence of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/17931597

Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy.

  “Endocannabinoids are now emerging as suppressors of key cell-signaling pathways involved in cancer cell growth, invasion, and metastasis. We have previously observed that the metabolically stable anandamide analog, 2-methyl-2′-F-anandamide (Met-F-AEA) can inhibit the growth of thyroid cancer in vivo. Our hypothesis was that the anti-tumor effect observed could be at least in part ascribed to inhibition of neo-angiogenesis… our results suggest that anandamide could be involved in the control of cancer growth targeting both tumor cell proliferation and the angiogenic stimulation of the vasculature.”

http://www.ncbi.nlm.nih.gov/pubmed/17192847

Media Ignored Expert’s Shocking Findings That Marijuana Helps Prevent Lung Cancer: Now It’s Med-School Material

  “You’d think it would have been very big news in the spring of 2005 when Donald Tashkin, a professor of pulmonology at UCLA’s David Geffin School of Medicine, revealed at a conference that components of marijuana smoke, although they damage cells in respiratory tissue, somehow prevent them from becoming malignant. But headlines announcing “Pot Doesn’t Cause Cancer” did not ensue. ”

“As to the highly promising implication of his own study — that something in marijuana stops damaged cells from becoming malignant — Tashkin noted that an anti-proliferative effect of THC has been observed in cell-culture systems and animal models of brain, breast, prostate, and lung cancer. THC has been shown to promote known apoptosis (damaged cells die instead of reproducing) and to counter angiogenesis (the process by which blood vessels are formed — a requirement of tumor growth). Other antioxidants in cannabis may also be involved in countering malignancy, Tashkin said.”

Read more: http://www.alternet.org/drugs/media-ignored-experts-shocking-findings-marijuana-helps-prevent-lung-cancer-now-its-med-school

Nabilone: an effective antiemetic in patients receiving cancer chemotherapy.

Abstract

“Eighty evaluable patients receiving chemotherapy were entered on a random prospective double-blind study to evaluate the effectiveness of nabilone, a synthetic cannabinoid, compared to prochlorperazine. Most of these patients received cisplatin, a drug that universally produces severe nausea and vomiting, as part of a combination chemotherapy regimen. The patients served as their own controls, receiving either nabilone or prochlorperazine during two consecutive treatment courses with the identical chemotherapy. Side effects consisting of hypotension and lethargy were more pronounced with nabilone. Toxicity, in general, did not preclude antiemetic treatment and in no way interfered with chemotherapy. Sixty patients (75 per cent) reported nabilone to be more effective than prochlorperazine for relief of nausea and vomiting. Of these 60 patients, 46 required further chemotherapy and continued taking nabilone as the antiemetic of choice.”

http://www.ncbi.nlm.nih.gov/pubmed/6271844

Nabilone. A preliminary review of its pharmacological properties and therapeutic use.

Abstract

“Nabilone is a new orally active cannabinoid for the treatment of severe gastrointestinal toxicity associated with cancer chemotherapy. The pharmacological profile of nabilone suggests that it acts primarily by preventing emesis controlled by the medulla oblongata, although its secondary mild anxiolytic activity may contribute to the overall efficacy. Nabilone 2mg twice daily starting 12 hours prior to, and continued for the duration of, chemotherapy produces significant reduction in the severity and duration of nausea and the frequency of vomiting in about 50 to 70% of patients with severe symptoms refractory to conventional therapy. Nabilone has proven to be more effective in controlling symptoms and preferred by more patients than prochlorperazine 10mg 2 to 4 times daily in a limited number of studies, despite a higher incidence of side effects. Comparative trials against other new antiemetic agents, such as high dose metoclopramide, and use of nabilone in combination with other antiemetics remain to be undertaken. The incidence of side effects is high with nabilone; drowsiness, dizziness and/or vertigo occur in 60 to 70% of patients, but rarely lead to drug withdrawal, although more troublesome effects, such as postural hypotension, ataxia, vision disturbance and toxic psychoses, may cause discontinuation of therapy. Thus, nabilone offers an effective alternative to the treatment options available in a difficult therapeutic area – those patients with severe gastrointestinal side effects from cancer chemotherapy who are refractory to conventional therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/2863127

Recent advantages in cannabinoid research.

Abstract

“Although the active component of cannabis Delta9-THC was isolated by our group 35 years ago, until recently its mode of action remained obscure. In the last decade it was established that Delta9-THC acts through specific receptors – CB1 and CB2 – and mimics the physiological activity of endogenous cannabinoids of two types, the best known representatives being arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG). THC is officially used against vomiting caused by cancer chemotherapy and for enhancing appetite, particularly in AIDS patients. Illegally, usually by smoking marijuana, it is used for ameliorating the symptoms of multiple sclerosis, against pain, and in a variety of other diseases. A synthetic cannabinoid, HU-211, is in advanced clinical tests against brain damage caused by closed head injury. It may prove to be valuable against stroke and other neurological diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/10575284

Marijuana as antiemetic medicine: a survey of oncologists’ experiences and attitudes.

Abstract

“A random-sample, anonymous survey of the members of the American Society of Clinical Oncology (ASCO) was conducted in spring 1990 measuring the attitudes and experiences of American oncologists concerning the antiemetic use of marijuana in cancer chemotherapy patients. The survey was mailed to about one third (N = 2,430) of all United States-based ASCO members and yielded a response rate of 43% (1,035). More than 44% of the respondents report recommending the (illegal) use of marijuana for the control of emesis to at least one cancer chemotherapy patient. Almost one half (48%) would prescribe marijuana to some of their patients if it were legal. As a group, respondents considered smoked marijuana to be somewhat more effective than the legally available oral synthetic dronabinol ([THC] Marinol; Unimed, Somerville, NJ) and roughly as safe. Of the respondents who expressed an opinion, a majority (54%) thought marijuana should be available by prescription. These results bear on the question of whether marijuana has a “currently accepted medical use,” at issue in an ongoing administrative and legal dispute concerning whether marijuana in smoked form should be available by prescription along with synthetic THC in oral form. This survey demonstrates that oncologists’ experience with the medical use of marijuana is more extensive, and their opinions of it are more favorable, than the regulatory authorities appear to have believed.”

http://www.ncbi.nlm.nih.gov/pubmed/2045870