“The effect of anandamide on human osteoblasts is unclear. This study examined the effect of anandamide on viability, apoptosis, mitogen-activated protein kinases (MAPKs) and Ca2+ levels in MG63 osteosarcoma cells. Anandamide at 50-200 microM decreased cell viability via apoptosis as demonstrated by propidium iodide staining and activation of caspase-3. Immunoblotting suggested that anandamide induced expression of ERK, JNK and p38 MAPK. Anandamide-induced cell death and apoptosis were reversed by SB203580, but not by PD98059 and SP600125, suggesting that anandamide’s action was via p38 MAPK, but not via ERK and JNK. Anandamide at 1-100 microM induced [Ca2+]i increases. Removal of extracellular Ca2+ decreased the anandamide response, indicating that anandamide induced Ca2+ influx and Ca2+ release. Chelation of intracellular Ca2+ with BAPTA reversed anandamide-induced cell death and p38 MAPK phosphorylation. Collectively, in MG63 cells, anandamide induced [Ca2+]i increases which evoked p38 MAPK phosphorylation. This p38 MAPK phosphorylation subsequently activated caspase-3 leading to apoptosis.”
Category Archives: Osteosarcoma
Involvement of PAR-4 in cannabinoid-dependent sensitization of osteosarcoma cells to TRAIL-induced apoptosis.
“Osteosarcoma is the most common malignant bone tumor in childhood and adolescence.
Cannabinoids (CBs), the active constituents of Cannabis sativa, are known to exert a wide range of central and peripheral effects.
Recently, numerous studies evidenced the role of cannabinoids in the regulation of cell death and survival, focusing the anti-proliferative effects of these compounds in various tumours… cannabinoids can also activate autophagic process…
The aim of the present study was to investigate the effects induced by cannabinoids in osteosarcoma cells and the molecular pathway…
The synthetic cannabinoid WIN 55,212-2 is a potent cannabinoid receptor agonist with anticancer potential.
Moreover, we indicate that a key role in WIN action is played by the tumor suppressor protein PAR-4.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007360/
Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2
“Osteosarcoma is the most frequent primary malignant bone tumor that occurs in children and adolescents. Osteosarcoma is a bone malignancy that predominantly affects children and adolescents, and exhibits high invasion and metastasis rates.
Although adriamycin (ADM) is an effective benchmark agent for the management of osteosarcoma, it also results in harmful side-effects including toxicity and chemoresistance that substantially affect the quality of life of patients. Therefore, novel therapeutic approaches and drugs must be sought for the treatment of osteosarcoma.
Natural products which have potential antitumor activities have become a focus of attention for study in previous years. Cannabinoids, the active components naturally derived from the marijuana plant Cannabis sativa L., have been reported as potential antitumor drugs based on their ability to limit inflammation, cell proliferation and cell survival.
To date, several cannabinoids have been identified and characterized, including Δ(9)-tetrahydrocannabinol (THC), cannabidiol, cannabinol (CBN) and anandamide, as well as synthetic cannabinoids, including WIN-55,212-2, JWH-133 and (R)-methanandamide.
In the early 1970s, THC and CBN were shown to inhibit tumor growth in Lewis lung carcinoma. Subsequently, cannabinoids were found to induce apoptosis and inhibit the proliferation of various cancer cells, including those of glioma and lymphoma, and prostate, breast, skin and pancreatic cancer…
In conclusion, the present study indicated that cannabinoid WIN-55,212-2 is antiproliferative, antimetastatic and antiangiogenic against MG-63 cells in vitro, and presented evidence that cannabinoid WIN-55,212-2 may result in synergistic antitumor action in combination with ADM against osteosarcoma.
These findings may offer a novel strategy for the treatment of osteosarcoma.”
Bone cell-autonomous contribution of type 2 cannabinoid receptor to breast cancer induced osteolysis.
“The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumour growth, bone remodelling and bone pain.
However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here, we found that the CB2 selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micro-molar concentrations…
When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands, depending upon cell type and concentration used.
We therefore conclude that both, CB2 selective activation and antagonism have potential efficacy in cancer associated bone disease but further studies are warranted and ongoing.”
A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts.
“The bone remodeling process is influenced by various factors, including estrogens and transmitters of the endocannabinoid system. In osteoblasts, cannabinoid receptors 2 (CB-2) are expressed at a much higher level compared to CB-1 receptors. Previous studies have shown that estrogens could influence CB-2 receptor expression.
In the present study, the possible interactions of a specific CB-2 agonist and a specific CB-2 antagonist/inverse agonist with 17-β-estradiol were investigated in primary human osteoblasts (HOB)…
In conclusion, for the first time a synergistic interaction between 17-β-estradiol and specific CB-2 antagonist/inverse agonist was observed in HOB.
Understanding the molecular pathways of this interaction would be of great importance in developing more efficient and safer drugs for treating or preventing bone diseases.”
The use of cannabinoids as anticancer agents.
“It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumour growth in animal models of cancer.
Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death.
In addition, cannabinoids inhibit tumour angiogenesis and decrease cancer cell migration.
The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored.
In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.” http://www.ncbi.nlm.nih.gov/pubmed/26071989
“… cannabinoids have been shown to alleviate nausea and vomit induced by chemotherapy and several cannabinoid-based medicines [Marinol (THC) and Cesamet (nabilone, a synthetic analogue of THC)] are approved for this purpose. Cannabinoids also inhibit pain, and Sativex (a standardized cannabis extract) has been approved in Canada for the treatment of cancer-associated pain. Other potential palliative effects of cannabinoids in oncology include appetite stimulation and attenuation of wasting. In addition to these palliative actions of cannabinoids in cancer patients, THC and other cannabinoids exhibit antitumour effects in animal models of cancer… a large body of scientific evidences strongly support THC and other cannabinoid agonists exert anticancer actions in preclinical models of cancer… In conclusion there exist solid scientific evidences supporting that cannabinoids exhibit a remarkable anticancer activity in preclinical models of cancer. Since these agents also show an acceptable safety profile, clinical studies aimed at testing them as single agents or in combinational therapies are urgently needed.” http://www.sciencedirect.com/science/article/pii/S0278584615001190
Intrathecal Injection of JWH-015 Attenuates Bone Cancer Pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord.
“Cannabinoid receptor type 2 (CB2) agonists display potential analgesic effects in acute and neuropathic pain.
Overall, our results provided evidences for the persistent participation of inflammation reaction in the progression of bone cancer pain, and demonstrated that JWH-015 reduced the expression of IL-1β, IL-6, IL-18, and TNF-α and inhibited astrocytes activation in a time-dependent manner, thereby displaying an analgesic effect.”
Cannabidiol, a Major Non-Psychotrophic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts.
“Cannabinoid ligands regulate bone mass, but skeletal effects of cannabis (marijuana and hashish) have not been reported. Bone fractures are highly prevalent, involving prolonged immobilization and discomfort.
Here we report that the major non-psychoactive cannabis constituent, cannabidiol (CBD), enhances the biomechanical properties of healing rat mid-femoral fractures.
Using Fourier Transform Infrared Spectroscopy we confirmed the increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus.
Taken together, these data show that CBD leads to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes.”
Cannabinoid Receptor CB2 Is Involved in Tetrahydrocannabinol-Induced Anti-Inflammation against Lipopolysaccharide in MG-63 Cells.
“Cannabinoid Δ9-tetrahydrocannabinol (THC) is effective in treating osteoarthritis (OA)…
Activation of cannabinoid receptor CB2 reduces inflammation; whether the activation CB2 is involved in THC-induced therapeutic action for OA is still unknown.
We hypothesized that the activation of CB2 is involved in THC-induced anti-inflammation in the MG-63 cells exposed to LPS, and the anti-inflammation is mediated by cofilin-1…
We found that THC suppressed the release of proinflammatory factors, including tumor necrosis factor α (TNF-α), interleukin- (IL-) 1β, IL-6, and IL-8, decreased nuclear factor-κB (NF-κB) expression, and inhibited the upregulation of cofilin-1 protein in the LPS-stimulated MG-63 cells.
These results suggested that CB2 is involved in the THC-induced anti-inflammation in LPS-stimulated MG-63 cells, and the anti-inflammation may be mediated by cofilin-1.”
http://www.ncbi.nlm.nih.gov/pubmed/25653478
Endocannabinoid system in cancer cachexia.
“More than 60% of advanced cancer patients suffer from anorexia and cachexia.
This review focuses on the possible mechanisms by which the endocannabinoid system antagonizes cachexia-anorexia processes in cancer patients and how it can be tapped for therapeutic applications.
Cannabinoids stimulate appetite and food intake…
Cannabinoid type 1 receptor activation stimulates appetite and promotes lipogenesis and energy storage.
Further study of cancer-cachexia pathophysiology and the role of endocannabinoids will help us to develop cannabinoids without psychotropic properties, which will help cancer patients suffering from cachexia and improve outcomes of clinical antitumor therapy.”