cannabidiol and Neoplasm-Metastasis

AF1q has a precise oncogenic function. The purpose of this study is to investigate whether CBD has an effect on the AF1q/ICAM-1 regulatory axis in Burkitt's lymphoma (BL), and thus has potential to enhance immunotherapy and reduce side effects.. We established BL cell lines with altered AF1q expression using lentivirus. After confirmation of gene expression by RT-PCR, cells were treated with CBD followed by co-culture of killing assay.. AF1q increased oncogenic growth and colony formation, and induced resistance against cell-mediated cytotoxic chemotherapy through attenuation of ICAM-1 expression in BL. CBD was able to reverse the acquired resistance mediated by AF1q/ICAM-1 regulatory axis.. CBD holds potential to enhance the efficacy of immunotherapy for BL with hyperactive AF1q/ICAM-1 regulatory axis, and warrants further study.

Topics: Breast Neoplasms; Burkitt Lymphoma; Cannabidiol; Cell Line, Tumor; Cell Proliferation; Cell Survival; Coculture Techniques; Drug Resistance, Neoplasm; Female; Humans; Immunotherapy; Intercellular Adhesion Molecule-1; Lentivirus; Leukocytes, Mononuclear; Lymphocytes; Neoplasm Metastasis; Neoplasm Proteins; Proto-Oncogene Proteins

Tumour cell migration and adhesion constitute essential features of metastasis. G-protein coupled receptor 55 (GPR55), a lysophospholipid receptor, has been shown to play an important role in carcinogenesis. Here, we investigated the involvement of GPR55 in migration and metastasis of colon cancer cells.. Adhesion and migration assays using the highly metastatic colon cancer cell line HCT116 and an in vivo assay of liver metastasis were performed. The GPR55 antagonist CID16020046, cannabidiol, a putative GPR55 antagonist and GPR55 siRNA were used to block GPR55 activity in HCT116 colon cancer cells.. HCT116 cells showed a significant decrease in adhesion to endothelial cells and in migration after blockade with CID16020046 or cannabidiol. The inhibitory effects of CID16020046 or cannabidiol were averted by GPR55 siRNA knock down in cancer cells. The integrity of endothelial cell monolayers was increased after pretreatment of HCT116 cells with the antagonists or after GPR55 siRNA knockdown while pretreatment with lysophosphatidylinositol (LPI), the endogenous ligand of GPR55, decreased integrity of the monolayers. LPI also induced migration in GPR55 overexpressing HCT116 cells that was blocked by GPR55 antagonists. In a mouse model of metastasis, the arrest of HCT116 cancer cells in the liver was reduced after treatment with CID16020046 or cannabidiol. Increased levels of LPI (18:0) were found in colon cancer patients when compared with healthy individuals.. GPR55 is involved in the migratory behaviour of colon carcinoma cells and may serve as a pharmacological target for the prevention of metastasis. © 2015 The British Pharmacological Society.

Topics: Animals; Azabicyclo Compounds; Benzoates; Cannabidiol; Cell Adhesion; Cell Line, Tumor; Cell Movement; Colonic Neoplasms; Humans; Liver Neoplasms; Lysophospholipids; Mice; Neoplasm Metastasis; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; RNA, Small Interfering

Although the global incidence of cutaneous melanoma is increasing, survival rates for patients with metastatic disease remain <10%. Novel treatment strategies are therefore urgently required, particularly for patients bearing BRAF/NRAS wild-type tumors. Targeting autophagy is a means to promote cancer cell death in chemotherapy-resistant tumors, and the aim of this study was to test the hypothesis that cannabinoids promote autophagy-dependent apoptosis in melanoma. Treatment with Δ(9)-Tetrahydrocannabinol (THC) resulted in the activation of autophagy, loss of cell viability, and activation of apoptosis, whereas cotreatment with chloroquine or knockdown of Atg7, but not Beclin-1 or Ambra1, prevented THC-induced autophagy and cell death in vitro. Administration of Sativex-like (a laboratory preparation comprising equal amounts of THC and cannabidiol (CBD)) to mice bearing BRAF wild-type melanoma xenografts substantially inhibited melanoma viability, proliferation, and tumor growth paralleled by an increase in autophagy and apoptosis compared with standard single-agent temozolomide. Collectively, our findings suggest that THC activates noncanonical autophagy-mediated apoptosis of melanoma cells, suggesting that cytotoxic autophagy induction with Sativex warrants clinical evaluation for metastatic disease.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Cannabidiol; Cannabinoids; Cannabinol; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dacarbazine; Dronabinol; Drug Combinations; Humans; Male; Melanoma; Membrane Proteins; Mice; Mice, Nude; Microscopy, Confocal; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Plant Extracts; Proto-Oncogene Proteins B-raf; ras Proteins; Skin Neoplasms; Temozolomide

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, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.

Topics: Aged; Animals; Cannabidiol; Female; Humans; Intercellular Adhesion Molecule-1; Lung Neoplasms; Male; Mice; Mice, Nude; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Random Allocation; RNA, Small Interfering; Tissue Inhibitor of Metalloproteinase-1; TRPV Cation Channels; Tumor Cells, Cultured; Up-Regulation

Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Therefore, effective, targeted, and non-toxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity profile, down-regulated Id-1 gene expression in aggressive human breast cancer cells in culture. Using cell proliferation and invasion assays, cell flow cytometry to examine cell cycle and the formation of reactive oxygen species, and Western analysis, we determined pathways leading to the down-regulation of Id-1 expression by CBD and consequently to the inhibition of the proliferative and invasive phenotype of human breast cancer cells. Then, using the mouse 4T1 mammary tumor cell line and the ranksum test, two different syngeneic models of tumor metastasis to the lungs were chosen to determine whether treatment with CBD would reduce metastasis in vivo. We show that CBD inhibits human breast cancer cell proliferation and invasion through differential modulation of the extracellular signal-regulated kinase (ERK) and reactive oxygen species (ROS) pathways, and that both pathways lead to down-regulation of Id-1 expression. Moreover, we demonstrate that CBD up-regulates the pro-differentiation factor, Id-2. Using immune competent mice, we then show that treatment with CBD significantly reduces primary tumor mass as well as the size and number of lung metastatic foci in two models of metastasis. Our data demonstrate the efficacy of CBD in pre-clinical models of breast cancer. The results have the potential to lead to the development of novel non-toxic compounds for the treatment of breast cancer metastasis, and the information gained from these experiments broaden our knowledge of both Id-1 and cannabinoid biology as it pertains to cancer progression.

Topics: alpha-Tocopherol; Animals; Antineoplastic Agents; Antioxidants; Breast Neoplasms; Cannabidiol; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Inhibitor of Differentiation Protein 1; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Signal Transduction; Transplantation, Isogeneic