Δ9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo

Preet, Anju; Ganju, Ramesh K.; Groopman, Jerome E.

doi:10.1038/sj.onc.1210641

Cited by 156 publications

(131 citation statements)

References 40 publications

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“…Of these six proteins, inhibition of IkB-a and JNK were the most robust. The observed inhibition of JNK phosphorylation is consistent with a recent report that THC inhibited chemotaxis in EGFstimulated A549 (Preet et al, 2008). In that study, THC-dependent suppression of JNK phosphorylation was demonstrated in both in vitro and the in vivo models.…”

Section: Discussionsupporting

confidence: 92%

Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

Sarafian

Montes

Harui

et al. 2008

Toxicology and Applied Pharmacology

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Marijuana smoking is associated with a number of abnormal findings in the lungs of habitual smokers. Previous studies revealed that Δ 9 -tetrahydrocannabinol (THC) caused mitochondrial injury in primary lung epithelial cells and in the cell line, A549 (Sarafian et al., 2003;Sarafian et al., 2005). The role of cannabinoid receptors in this injury was unclear, as was the potential impact on cell function. In order to investigate these questions, A549 cells were engineered to over-express the type 2 cannabinoid receptor (CB2R) using a self-inactivating lentiviral vector. This transduction resulted in a 60-fold increase in CB2R mRNA relative to cells transduced with a control vector. Transduced cell lines were used to study the effects of THC on chemotactic activity and mitochondrial function. Chemotaxis in response to a 10 % serum gradient was suppressed in a concentration-dependent manner by exposure to THC. CB2R-transduced cells exhibited less intrinsic chemotactic activity (p < 0.05) and were 80-to 100-fold more sensitive to the inhibitory effects of THC. Studies using SR144528, a selective CB2R antagonist, verified that these effects were mediated by the CB2R. Marijuana smoke extract, but not smoke extracts from tobacco or placebo marijuana cigarettes, reproduced these effects (p < 0.05). THC decreased ATP level and mitochondrial membrane potential (Ψ m ) in both control and CB2R-transduced cells. However, these decreases did not play a significant role in chemotaxis inhibition since cyclosporine A, which protected against ATP loss, did not increase cell migration. Moreover, CB2R-transduced cells displayed higher Ψ m than did control cells. Since both Ψ m and chemotaxis are regulated by intracellular signaling, we investigated the effects of THC on the activation of multiple signaling pathways. Serum exposure activated several signaling events of which phosphorylation of IκB-α and JNK were regulated in a CB2R-and THC-dependent manner. We conclude that airway epithelial cells are sensitive to both CB2R-dependent and independent effects mediated by THC.

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Section: Discussionsupporting

confidence: 92%

Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

Sarafian

Montes

Harui

et al. 2008

Toxicology and Applied Pharmacology

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“…This was consistent with the defined role of ADM in the migration of osteosarcoma cells (3). Suppression of metastasis by THC was also reported in severe combined immunodeficient mice (29). The results implied that cannabinoid may enhance the antimetastastic effect of ADM for osteosarcoma, since the combined treatment with cannabinoid and ADM inhibited the migration and invasion of MG-63 cells to a significantly higher extent than the individual treatment with either of these two agents.…”

Section: Discussionsupporting

confidence: 86%

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

Niu

Zhao

et al. 2015

Oncology Letters

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Abstract. Osteosarcoma is the most frequent primary malignant bone tumor that occurs in children and adolescents. The present study aimed to identify novel therapeutic strategies for osteosarcoma, by assessing the antitumor activity of the cannabinoid WIN-55,212-2 and its combined effect with adriamycin (ADM) against the MG-63 human osteosarcoma cell line. To evaluate the antiproliferative action of these molecules, a Cell Counting kit-8 (CCK-8) assay was used. The ability of cannabinoid to inhibit the migration, invasion and angiogenic activity of MG-63 cells were assessed by scratch, Transwell ® chamber and angiogenesis assays, respectively, in vitro. To examine the alterations in expression of targeted genes, quantitative polymerase chain reaction and western blot analysis were used. The administration of cannabinoid combined with ADM was demonstrated to inhibit the growth of MG-63 cells, resulting in a cell viability of 32.12±3.13%, which was significantly lower (P<0.05) compared with the cell viability following treatment with cannabinoid (70.86±7.55%) and ADM (62.87±5.98%) alone. Greater antimetastasis and antiangiogenic activities were also observed following the coadministration of the two agents compared with individual treatments and controls. In addition, the expression levels of Notch-1, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in MG-63 cells were downregulated following the treatments with cannabinoid alone or in combination with ADM. In conclusion, the present findings demonstrated that cannabinoid WIN-55,212-2 may significantly potentiate the antiproliferative, antimetastasis and antiangiogenic effects of ADM against MG-63 cells via the downregulation of Notch-1, MMP-2 and VEGF. These findings may offer a novel strategy for the treatment of osteosarcoma.

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“…Treatment with ⌬ 9 -THC inhibits the growth of various types of tumor cell in vitro or tumor cell xenografts in vivo, including lung carcinoma (692), glioma (280), and lymphoma (553). The pro-apoptotic effect of ⌬ 9 -THC in tumor cells is complex and involves increased synthesis of the proapoptotic sphingolipid ceramide (280), in glioma cells; ceramide-dependent upregulation of the stress protein p8 resulting in upregulation of the endoplasmic reticulum (ER) stress-related genes ATF-4, CHOP, and TRB3 (121); p38 MAPK signaling, in human leukemia cells (343); downregulated Raf-1/mitogen-activated protein kinase/ERK kinase pathway leading to translocation of BAD to mitochondria, in leukemia T cells (400); inhibition of RAS-MAPK/ERK and PI3K-AKT survival signaling cascades, accompanied by activation of the pro-apoptotic BAD, in colorectal cancer cells (306); and rapid activation of ERK and c-Jun NH 2 -terminal kinase, in human U373MG astrocytoma cells (915).…”

Section: Cancermentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

380

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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Δ9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo

Cited by 156 publications

References 40 publications

Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

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