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Cannabis -vs- Lung Cancer

ttp://www.ncbi.nlm.nih.gov/pubmed/25069049Cannabinoids have been shown to promote the expression of the intercellular adhesion molecule 1 (ICAM-1) on lung cancer cells as part of their anti-invasive and antimetastatic action. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study addressed the impact of cannabinoid-induced ICAM-1 on cancer cell adhesion to lymphokine-activated killer (LAK) cells and LAK cell-mediated cytotoxicity. Cannabidiol (CBD), a non-psychoactive cannabinoid, enhanced the susceptibility of cancer cells to adhere to and subsequently be lysed by LAK cells, with both effects being reversed by a neutralizing ICAM-1 antibody. Increased cancer cell lysis by CBD was likewise abrogated when CBD-induced ICAM-1 expression was blocked by specific siRNA or by antagonists to cannabinoid receptors (CB1, CB2) and to transient receptor potential vanilloid 1. In addition, enhanced killing of CBD-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated antigen-1 (LFA-1) suggesting intercellular ICAM-1/LFA-1 crosslink as crucial event within this process. ICAM-1-dependent pro-killing effects were further confirmed for the phytocannabinoid Δ(9)-tetrahydrocannabinol (THC) and R(+)-methanandamide (MA), a hydrolysis-stable endocannabinoid analogue. Finally, each cannabinoid elicited no significant increase of LAK cell-mediated lysis of non-tumor bronchial epithelial cells, BEAS-2B, associated with a far less pronounced (CBD, THC) or absent (MA) ICAM-1 induction as compared to cancer cells. Altogether, our data demonstrate cannabinoid-induced upregulation of ICAM-1 on lung cancer cells to be responsible for increased cancer cell lysis by LAK cells. These findings provide proof for a novel antitumorigenic mechanism of cannabinoids.

http://www.ncbi.nlm.nih.gov/pubmed/22198381:  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.

http://www.ncbi.nlm.nih.gov/pubmed/21097714Non-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. We observed expression of CB1 (24%) and CB2 (55%) in NSCLC patients. Furthermore, we have shown that the treatment of NSCLC cell lines (A549 and SW-1573) with CB1/CB2- and CB2-specific agonists Win55,212-2 and JWH-015, respectively, significantly attenuated random as well as growth factor-directed in vitro chemotaxis and chemoinvasion in these cells. We also observed significant reduction in focal adhesion complex, which plays an important role in migration, upon treatment with both JWH-015 and Win55,212-2. In addition, pretreatment with CB1/CB2 selective antagonists, AM251 and AM630, prior to JWH-015 and Win55,212-2 treatments, attenuated the agonist-mediated inhibition of in vitro chemotaxis and chemoinvasion. In addition, both CB1 and CB2 agonists Win55,212-2 and JWH-133, respectively, significantly inhibited in vivo tumor growth and lung metastasis (∼50%). These effects were receptor mediated, as pretreatment with CB1/CB2 antagonists abrogated CB1/CB2 agonist-mediated effects on tumor growth and metastasis. Reduced proliferation and vascularization, along with increased apoptosis, were observed in tumors obtained from animals treated with JWH-133 and Win55,212-2. Upon further elucidation into the molecular mechanism, we observed that both CB1 and CB2 agonists inhibited phosphorylation of AKT, a key signaling molecule controlling cell survival, migration, and apoptosis, and reduced matrix metalloproteinase 9 expression and activity. These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387667:  ​Different plant-derived cannabinoids and cannabis-based pharmaceutical drugs have been the subject of intensive research for their potential antitumor activity, especially in cancer cells that overexpress CB1 and/or CB2 receptors compared to normal tissues [62]. Many studies were conducted in different cell lines with cannabis extracts or individual isolated compounds and the results are sometimes confounding, because efficient anticancer effects, such as decreased proliferation of cancer cells, activation of apoptosis, inhibition of cell migration and decreased tumor vascularization are mainly recorded in breast, prostate and glioma cancer cell lines. In contrast, protumorigenic activity of natural cannabinoids, i.e., increased cell proliferation, has been reported in lung, breast, and hepatoma cell lines [63]. It appears that the balance between protumorigenic and antitumor effects of cannabinoids critically depends on their concentration, among other factors. For example, Hart et al. [64] showed that the treatment of glioblastoma U373-MG and lung carcinoma NCI-H292 cell line with nanomolar concentrations of THC (instead of commonly used micromoral concentrations) led to increased cell proliferation. The authors also emphasized that nanomolar concentrations of THC are more likely to be detected in the serum of patients after drug treatment [64]. Therefore, in cancer therapy, it is very important to consider the risk of acceleration of tumor growth due to the concentration-dependent proliferative potential of cannabinoids [64].

https://pubmed.ncbi.nlm.nih.gov/32049991:  Patients with non-small cell lung cancer (NSCLC) develop resistance to antitumor agents by mechanisms that involve the epithelial-to-mesenchymal transition (EMT). This necessitates the development of new complementary drugs, e.g., cannabinoid receptors (CB1 and CB2) agonists including tetrahydrocannabinol (THC) and cannabidiol (CBD). The combined use of THC and CBD confers greater benefits, as CBD enhances the effects of THC and reduces its psychotropic activity. We assessed the relationship between the expression levels of CB1 and CB2 to the clinical features of a cohort of patients with NSCLC, and the effect of THC and CBD (individually and in combination) on proliferation, EMT and migration in vitro in A549, H460 and H1792 lung cancer cell lines.

​The tumor samples were classified according to the level of expression of CB1, CB2, or both. Patients with high expression levels of CB1, CB2, and CB1/CB2 showed increased survival reaching significance for CB1 and CB1/CB2 (p = 0.035 and 0.025, respectively). Both cannabinoid agonists inhibited the proliferation and expression of EGFR in lung cancer cells, and CBD potentiated the effect of THC. THC and CBD alone or in combination restored the epithelial phenotype, as evidenced by increased expression of CDH1 and reduced expression of CDH2 and VIM, as well as by fluorescence analysis of cellular cytoskeleton. Finally, both cannabinoids reduced the in vitro migration of the three lung cancer cells lines used.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409346:  Low levels of THC induced lung cancer cell proliferation. Metalloprotease and epidermal growth factor receptor (EGFR) activity were found to be fundamental in mediating this increase in cell proliferation [50]. Another study looked at the anti-tumor effects of whole cannabis extracts versus individual compounds alone. In lung cancer cells, they found that treatment with pure THC did not significantly decrease cell survival, relative to control [70]. In contrast, other studies found that THC inhibited epidermal growth factor (EGF) stimulated growth of non-small cell lung cancer and reduced the expression of EGFR, as well as chemotaxis and invasion [71,72]. THC inhibited contact-dependent macrophage cell killing of tumor cells in a cannabinoid-receptor independent manner [73]. Similarly, THC treatment suppressed host immune reactivity to lung cancer and in murine models of lung cancer, administration of THC caused increased tumor growth and decreased tumor immunogenicity [75]. A different study found that THC was able to inhibit tumor growth and lung metastases in a murine model of lung cancer [71]. In non-small cell lung cancer (NSCLC) cells, treatment with THC was able to suppress the epithelial-mesenchymal transition, restore the epithelial phenotype and reduced the proliferation of these cells in vitro. In addition, THC reduced the migration of NSCLC cells [72]. THC-loaded nanoparticles for the treatment of lung cancer caused significant cytotoxicity against human and murine lung cancer cells in vitro and in vivo [74].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385325:  It has been described that CBD can act on tumour cells, directly or indirectly, through different pathways and that these effects might vary in different tumour cells. CBD acts as an inverse agonist for CB2 receptor and an antagonist for CB1 receptor.12 However, CBD has low affinity to either CB1 or CB2 receptors.9 In addition, CBD has anti-cancer effects acting as an agonist for the transient receptor potential vanilloid (TRPV) 1 and 2 leading to changes in intracellular Ca2+ levels.5,13

It is also reported that CBD can induce apoptosis in cancer cells via the production of reactive oxygen species (ROS), caspase activation4,13,14 and activation of p53 dependent apoptotic pathways in cancer cells14,15 and down-regulation of mammalian target of rapamycin (mTOR) and cyclin D1.16 CBD can also upregulate TNF/TNFR1 and TRAIL/TRAIL-R2 signalling by modulation of both ligand and receptor levels followed by apoptosis.14 Furthermore, CBD inhibits human umbilical vein endothelial cells (HUVEC) endothelial cells migration, invasion and sprouting in vitro, and angiogenesis in vivo through down-modulation of several angiogenesis-related molecules.17

In summary, the data presented here indicate that CBD may have had a role in the striking response in a patient with histologically proven adenocarcinoma of the lung as a result of self-administration of CBD oil for a month and in the absence of any other identifiable lifestyle, drug or dietary changes. Further work is needed both in vitro and in vivo to better evaluate the various mechanisms of action of CBD on malignant cells, and its potential application in the treatment of not only lung cancer but also other malignancies.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015420:  The tumor samples were classified according to the level of expression of CB1, CB2, or both. Patients with high expression levels of CB1, CB2, and CB1/CB2 showed increased survival reaching significance for CB1 and CB1/CB2 (p = 0.035 and 0.025, respectively). Both cannabinoid agonists inhibited the proliferation and expression of EGFR in lung cancer cells, and CBD potentiated the effect of THC. THC and CBD alone or in combination restored the epithelial phenotype, as evidenced by increased expression of CDH1 and reduced expression of CDH2 and VIM, as well as by fluorescence analysis of cellular cytoskeleton. Finally, both cannabinoids reduced the in vitro migration of the three lung cancer cells lines used.

The expression levels of CB1 and CB2 have a potential use as markers of survival in patients with NSCLC. THC and CBD inhibited the proliferation and expression of EGFR in the lung cancer cells studied. Finally, the THC/CBD combination restored the epithelial phenotype in vitro.

https://pubmed.ncbi.nlm.nih.gov/17621270:  Delta(9)-Tetrahydrocannabinol (THC) is the primary cannabinoid of marijuana and has been shown to either potentiate or inhibit tumor growth, depending on the type of cancer and its pathogenesis. Little is known about the activity of cannabinoids like THC on epidermal growth factor receptor-overexpressing lung cancers, which are often highly aggressive and resistant to chemotherapy. In this study, we characterized the effects of THC on the EGF-induced growth and metastasis of human non-small cell lung cancer using the cell lines A549 and SW-1573 as in vitro models. We found that these cells express the cannabinoid receptors CB(1) and CB(2), known targets for THC action, and that THC inhibited EGF-induced growth, chemotaxis and chemoinvasion. Moreover, signaling studies indicated that THC may act by inhibiting the EGF-induced phosphorylation of ERK1/2, JNK1/2 and AKT. THC also induced the phosphorylation of focal adhesion kinase at tyrosine 397. Additionally, in in vivo studies in severe combined immunodeficient mice, there was significant inhibition of the subcutaneous tumor growth and lung metastasis of A549 cells in THC-treated animals as compared to vehicle-treated controls. Tumor samples from THC-treated animals revealed antiproliferative and antiangiogenic effects of THC. Our study suggests that cannabinoids like THC should be explored as novel therapeutic molecules in controlling the growth and metastasis of certain lung cancers.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624994:  Currently, there is no effective therapy against lung cancer due to the development of resistance. Resistance contributes to disease progression, recurrence, and mortality. The presence of so-called cancer stem cells could explain the ineffectiveness of conventional treatment, and the development of successful cancer treatment depends on the targeting also of cancer stem cells. Cannabidiol (CBD) is a cannabinoid with anti-tumor properties. However, the effects on cancer stem cells are not well understood. The effects of CBD were evaluated in spheres enriched in lung cancer stem cells and adherent lung cancer cells. We found that CBD decreased viability and induced cell death in both cell populations. Furthermore, we found that CBD activated the effector caspases 3/7, increased the expression of pro-apoptotic proteins, increased the levels of reactive oxygen species, as well as a leading to a loss of mitochondrial membrane potential in both populations. We also found that CBD decreased self-renewal, a hallmark of cancer stem cells. Overall, our results suggest that CBD is effective against the otherwise treatment-resistant cancer stem cells and joins a growing list of compounds effective against cancer stem cells. The effects and mechanisms of CBD in cancer stem cells should be further explored to find their Achilles heel.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693730:  Ramer and colleagues have published many studies on the effects of CBD on lung cancers (Table S3) [91,92,93,94]. They consistently used the WST-1 assay to assess the viability of lung cancers. CBD decreased the viability of two NSCLC cell lines, A549 (a lung adenocarcinoma cell line) and H460 (a large cell lung carcinoma cell line), with IC50 values of 3.47 µM and 2.80 µM, respectively [94]. There was a 29% and 63% reduction in A549 invasion after incubation with 0.001 µM or 0.1 µM CBD, respectively, for 72 h [92]. There was no significant cell death detected in A549 cells after treatment with 0.001 µM or 0.1 µM CBD. Various lung cancer cell lines (e.g., A549, H358, and H460) have been shown to express CB1, CB2, and TRPV1, which the anti-invasive function of CBD partly relies on [91,92,93]. CBD also significantly reduced tumor size and lung metastatic nodules (from an average of 6 nodules to only 1 nodule) in an A549 xenograft tumor model [92,93].

One mechanism of the pro-apoptotic effect of CBD is through the activation of COX-2, a pathway for endocannabinoid degradation, and PPAR-γ [94]. CBD treatment, at 3 µM in A549, H460, and primary lung tumor cells from a patient with brain metastasis, resulted in the upregulation of COX-2 and PPAR-γ both mRNA and protein. These observations were also confirmed in vivo. COX-2-derived products (PGE2, PGD2, and 15d-PGJ2) were also elevated in CBD-treated lung cancer cells. By suppressing COX-2 and PPAR-γ activity with antagonists or siRNA, CBD’s pro-apoptotic and cytotoxic effects were severely attenuated. Consistently, in a lung tumor mouse model, PPAR-γ inhibition by GW9662 reversed the tumor-suppressive effects of CBD.

While Ramer et al. discussed plasminogen activator inhibitor-1's (PAI-1) pro- vs. anti-tumorigenic actions, they provided evidence supporting the former [92]. At 1 µM CBD, there was a decrease in PAI-1 mRNA and protein in A549, H358, and H460. This was confirmed in vivo using the A549 mouse model with 5 mg/kg CBD three times a week. In vitro, CBD’s anti-invasive property was reduced by siRNA knockdown of PAI-1 and was increased with the treatment of a recombinant PAI-1. The CBD-mediated decrease in PAI-1 is due, in part, to the activation of CB1, CB2, and TRPV1, as their antagonists reversed the effect. Therefore, CBD works as an agonist of CB1, CB2, and TRPV1 in lung cancers.

​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909073:  Drug resistance is the key factor contributing to the therapeutic failure of lung cancer and the deaths related to lung cancer. Our study demonstrated that small molecular weight non-psychotropic phytochemical, cannabidiol (CBD), inhibits growth and metastasis of drug-resistant non-small cell lung cancer cells (NSCLC) cells in-vitro and in-vivo. We further discovered that CBD mediates its anti-cancer effects in part via an ion channel receptor, TRPV2, present on lung adenocarcinoma. Moreover, we showed that CBD induces apoptosis of cisplatin-resistant cells by modulating oxidative stress pathways. Overall, these studies indicate that CBD could be used as a promising therapeutic strategy in TRPV2 expressing cisplatin-resistant NSCLC.

Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy to combat the growth of cisplatin-resistant (CR) NSCLC cells. We have shown that treatment with the plant-derived, non-psychotropic small molecular weight molecule, cannabidiol (CBD), significantly induced apoptosis of CR NSCLC cells. In addition, CBD treatment significantly reduced tumor progression and metastasis in a mouse xenograft model and suppressed cancer stem cell properties. Further mechanistic studies demonstrated the ability of CBD to inhibit the growth of CR cell lines by reducing NRF-2 and enhancing the generation of reactive oxygen species (ROS). Moreover, we show that CBD acts through Transient Receptor Potential Vanilloid-2 (TRPV2) to induce apoptosis, where TRPV2 is expressed on human lung adenocarcinoma tumors. High expression of TRPV2 correlates with better overall survival of lung cancer patients. Our findings identify CBD as a novel therapeutic agent targeting TRPV2 to inhibit the growth and metastasis of this aggressive cisplatin-resistant phenotype in NSCLC.