Cannabis -vs- Gastric Cancer Cannabinoids exert a number of interesting effects that are dependent on the cell line or tumor type. Synthetic cannabinoids and the endocannabinoid system are implicated in inhibiting cancer cell proliferation and angiogenesis, reducing tumor growth and metastases, and inducing apoptosis. Some studies suggest that abnormal regulation of the endocannabinoid system may promote cancer by fostering physiological conditions that allow cancer cells to proliferate and migrate. For this reason, the endocannabinoid is an attractive target for pharmacological intervention in the treatment of cancer. Modulation of the endocannabinoid system to treat cancer may provide a targeted treatment of cancer, which has been shown in several studies that demonstrated selective action of cannabinoids on tumor cells while not having effects on normal cells.

The endocannabinoid system is involved in a complex set of signaling pathways including activity at the CB1, CB2, TRPV1, and GPR55 receptors, and through receptor-independent actions. The complexity of the signaling pathways involved in endocannabinoid action both in normal and malignant tissues offer a significant research obstacle, however, several important pathways have been elucidated. These include modulation of pathways critical to cell proliferation, cell cycle, and apoptosis. The diversity of receptors and signaling pathways that the endocannabinoid system modulates offers an interesting opportunity for the development of specific molecules to perturb the system selectively, as has already been achieved in the development of agonist and antagonists of the CB1, CB2, TRPV1, and GPR55 receptors. In addition, recent work has revealed that COX-2, which is involved in the progression of several types of cancer, modulates endocannabinoid tone at sites of inflammation [135]. The oxygenation of endocannabinoids by COX-2 or other enzymes may also play a critical role in the influence of endocannabinoids on cancer.Although there is a strong set of data in vitro, in cellular model systems, and in mouse model systems, there is a dearth of clinical data on the effects of cannabinoids in the treatment of cancer in humans. This fact is quite surprising considering the large library of compounds that have been developed and used to study the effects of cannabinoids on cancer in model systems. Despite the lack of preclinical and clinical data, there is a strong agreement that pharmacological targeting of the endocannabinoid system is emerging as one of the most promising new methods for reducing the progression of cancer. cannabis sesquiterpenoid β-caryophyllene shows increasing promise in this regard. It is anti-inflammatory comparable to phenylbutazone via PGE-1 (Basile et al 1988), but simultaneously acts as a gastric cytoprotective (Tambe et al 1996). The analgesic attributes of β-caryophyllene are increasingly credible with the discovery that it is a selective CB2 agonist (Gertsch et al 2007), with possibly broad clinical applications. α-Pinene also inhibits PGE-1 (Gil et al 1989), while linalool displays local anesthetic effects (Re et al 2000). down-regulated the expression of TIMP1, a stromal factor with multiple functions. TIMPs are commonly described as negative regulators of MMPs. Nasser et al. (2006) showed that TIMP1 is an inhibitor of high-grade glioma invasion. In line with this, Ramer et al. (2010a) recently reported a CBD-driven increase in TIMP1 in lung cancer cells that correlated with diminished invasiveness. Nevertheless, there is increasing evidence to suggest that TIMPs are multifunctional proteins, possessing a dual role in regulating cell proliferation and angiogenesis. In vitro, TIMP1 promotes growth of human keratinocytes and several other cell types (Bertaux et al., 1991; Hayakawa et al., 1992), inhibits apoptosis (Alexander et al., 1996; Guedez et al., 1998; Li et al., 1999) and regulates angiogenesis (Yoshiji et al., 1998; Lafleur et al., 2002). Moreover, increased expression of TIMP1 protein has been observed in multiple tumour types, including breast, colon, gastric and lung cancers, as well as in lymphoma and carcinomas of unknown primary origin (Zeng et al., 1995; Mimori et al., 1997; Ree et al., 1997; Guedez et al., 2001; Schrohl et al., 2004; Gouyer et al., 2005; Karavasilis et al., 2005).

Based on these considerations, it is noteworthy that inhibition of proteins such as MMP2 and MMP9 and TIMP1 further confirms the wide spectrum of CBD action on MMP and TIMP molecules, key factors in cell motility, invasion and proliferation, and suggests a complex picture through which CBD can impair cell growth and invasion.

In addition to the MMP/TIMP system, CBD also down-regulated the uPA and the plasminogen activator inhibitor SerpinE1/PAI-1, two important factors in extracellular matrix remodelling and consequent angiogenesis. The uPA plays a pivotal role in the degradation of extracellular matrix, and suppression of uPA and uPAR by shRNA attenuates angiogenin-mediated angiogenesis in endothelial and glioblastoma cell lines (Raghu et al., 2010). Thus, CBD shares similarities with other therapeutic approaches that, by inhibiting the uPA/uPAR functions, have been shown to possess anti-angiogenic and anti-tumour effects (for review, see Ulisse et al., 2009). three agents tested exhibited similar concentration-dependent effects in the induction of changes in cell morphology and cell loss, as well as in the decrease of cell viability and DNA laddering in the human gastric adenocarcinoma cell line (AGS). Differences among the cannabinoids tested were mostly observed in the density of cells found in early and late apoptosis and necrosis, favoring AEA and CP as the more effective inducers of apoptotic mechanisms, and Meth-AEA as a more effective inducer of necrosis through transient and rapid apoptosis.

Through a comparative approach, our results support and confirm the therapeutic potential that cannabinoid receptor agonists exert in gastric cancer cells and open possibilities to use cannabinoids as part of a new gastric cancer therapy.