The enzyme cyclooxygenase (COX) catalyzes the first step of the synthesis of prostanoids. In the early 1990s, COX was demonstrated to exist as two distinct isoforms. COX-1 is constitutively expressed as a "housekeeping" enzyme in most tissues. By contrast, COX-2 can be up-regulated by various pro-inflammatory agents, including lipopolysaccharide, cytokines, and growth factors. Whereas many of the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., gastrointestinal ulceration and bleeding, platelet dysfunctions) are caused by a suppression of COX-1 activity, inhibition of COX-2-derived prostanoids facilitates the anti-inflammatory, analgesic, and antipyretic effects of NSAIDs. During the past few years specific inhibitors of the COX-2 enzyme have emerged as important pharmacological tools for treatment of pain and arthritis. However, although COX-2 was initially regarded as a source of pathological prostanoids only, recent studies have indicated that this isoenzyme mediates a variety of physiological responses within the organism. The present review assesses recent advances in COX-2 research, with particular emphasis on new insights into pathophysiological and physiological functions of this isoenzyme.

Cannabinoids, in addition to having palliative benefits in cancer therapy, have been associated with anticarcinogenic effects. Although the antiproliferative activities of cannabinoids have been intensively investigated, little is known about their effects on tumor invasion. Matrigel-coated and uncoated Boyden chambers were used to quantify invasiveness and migration, respectively, of human cervical cancer (HeLa) cells that had been treated with cannabinoids (the stable anandamide analog R(+)-methanandamide [MA] and the phytocannabinoid Δ ⁹ -tetrahydrocannabinol [THC]) in the presence or absence of antagonists of the CB ₁ or CB ₂ cannabinoid receptors or of transient receptor potential vanilloid 1 (TRPV1) or inhibitors of p38 or p42/44 mitogen–activated protein kinase (MAPK) pathways. Reverse transcriptase–polymerase chain reaction (RT-PCR) and immunoblotting were used to assess the influence of cannabinoids on the expression of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs). The role of TIMP-1 in the anti-invasive action of cannabinoids was analyzed by transfecting HeLa, human cervical carcinoma (C33A), or human lung carcinoma cells (A549) cells with siRNA targeting TIMP-1. All statistical tests were two-sided. Without modifying migration, MA and THC caused a time- and concentration-dependent suppression of HeLa cell invasion through Matrigel that was accompanied by increased expression of TIMP-1. At the lowest concentrations tested, MA (0.1 μM) and THC (0.01 μM) led to a decrease in invasion (normalized to that observed with vehicle-treated cells) of 61.5% (95% CI = 38.7% to 84.3%, P < .001) and 68.1% (95% CI = 31.5% to 104.8%, P = .0039), respectively. The stimulation of TIMP-1 expression and suppression of cell invasion were reversed by pretreatment of cells with antagonists to CB ₁ or CB ₂ receptors, with inhibitors of MAPKs, or, in the case of MA, with an antagonist to TRPV1. Knockdown of cannabinoid-induced TIMP-1 expression by siRNA led to a reversal of the cannabinoid-elicited decrease in tumor cell invasiveness in HeLa, A549, and C33A cells. Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.

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‐up‐regulating 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.—Ramer, R., Bublitz, K., Freimuth, N., Merkord, J., Rohde, H., Haustein, M., Borchert, P., Schmuhl, E., Linnebacher, M., Hinz, B. Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule‐1. FASEB J. 26, 1535‐1548 (2012). www.fasebj.org

Drugs that target the endocannabinoid system are of interest as pharmacological options to combat cancer and to improve the life quality of cancer patients. From this perspective, cannabinoid compounds have been successfully tested as a systemic therapeutic option in a number of preclinical models over the past decades. As a result of these efforts, a large body of data suggests that the anticancer effects of cannabinoids are exerted at multiple levels of tumour progression via different signal transduction mechanisms. Accordingly, there is considerable evidence for cannabinoid-mediated inhibition of tumour cell proliferation, tumour invasion and metastasis, angiogenesis and chemoresistance, as well as induction of apoptosis and autophagy. Further studies showed that cannabinoids could be potential combination partners for established chemotherapeutic agents or other therapeutic interventions in cancer treatment. Research in recent years has yielded several compounds that exert promising effects on tumour cells and tissues in addition to the psychoactive Δ⁹-tetrahydrocannabinol, such as the non-psychoactive phytocannabinoid cannabidiol and inhibitors of endocannabinoid degradation. This review provides an up-to-date overview of the potential of cannabinoids as inhibitors of tumour growth and spread as demonstrated in preclinical studies.

The endocannabinoid system has emerged as an important target for the treatment of many diverse diseases. In addition to the well‐established palliative effects of cannabinoids in cancer therapy, phytocannabinoids, synthetic cannabinoid compounds and inhibitors of endocannabinoid degradation have attracted attention as possible systemic anticancer drugs. Results emerging from preclinical studies suggest cannabinoids elicit effects at different levels of cancer progression, including inhibition of proliferation, neovascularization, invasion and chemoresistance, induction of apoptosis and autophagy as well as enhancement of tumour immune surveillance. Although the clinical use of cannabinoid receptor ligands is limited by their psychoactivity, non‐psychoactive compounds, such as cannabidiol, have gained attention due to preclinically established anticancer properties and a favourable risk‐to‐benefit profile. Thus, cannabinoids may complement the currently used collection of chemotherapeutic agents, as a broadly diversified option for cancer treatment, while counteracting some of their severe side effects.Linked Articles: This article is part of a themed section on 8^thEuropean Workshop on Cannabinoid Research. To view the other articles in this section visithttp://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc