Non-small cell lung cancer has one of the highest mortality rates among cancer-suffering patients. It is well known that the unwanted psychotropic effects of cannabinoids (CBs) are mediated via the CB(1) receptor (R), and selective targeting of the CB(2)R would thus avoid side effects in cancer treatment. Therefore, the aim of our study was to evaluate the effect of selective CB(2)R agonist, JWH-133, on A549 cells (non-small lung cancer) and human umbilical vein endothelial cells (HUVECs). Cytotoxicity assay and DNA fragmentation assay were employed to evaluate the influence of JWH-133 (3-(1,1-dimethylbutyl)- 1-deoxy-Δ8-tetrahydrocannabinol) on investigated cancer cells. In addition, migration assay and gelatinase zymography were performed in HUVECs to asses JWH-133 anti-angiogenic activity. Our study showed that JWH-133 exerted cytotoxic effect only at the highest concentration used (10(-4) mol/l), while inhibition of colony formation was also detected at the non-toxic concentrations (10(-5)-10(-8) mol/l). JWH-133 was also found to be able to induce weak DNA fragmentation in A549 cells. Furthermore, JWH-133 at non-toxic concentrations inhibited some steps in the process of angiogenesis. It significantly inhibited endothelial cell migration after 17 h of incubation at concentrations of 10(-4)-10(-6) mol/l. In addition, JWH-133 inhibited MMP-2 secretion as assessed by gelatinase zymography. The present study demonstrates the in vitro anti-proliferative and anti-angiogenic potential of CB(2)R agonist, JWH-133, in nonsmall lung cancer cells and HUVECs. Our results generate a rationale for further in vivo efficacy studies with this compound in preclinical cancer models.
"on cannabinoids acting at cannabinoid type - 1 receptors , there are significant advantages to developing drugs that act selectively at cannabinoid type - 2 receptors . For example , cannabinoid type - 2 receptor ago - nists have been shown to produce anti - angiogenic and anti - proliferative effects in the treatment of various forms of cancers ( Vidinsky et al . , 2012 ) , to reduce chronic neuropathic pain ( Wilkerson et al . , 2012 ) , and to beneficially modulate cytokine levels in immunologically - based disease states ( Cabral and Griffin - Thomas , 2009 ) . Since cannabinoid type - 2 receptors participate in inflammatory processes via modulation of cytokine release , both agonists ( Ehrhart et a"
[Show abstract][Hide abstract] ABSTRACT: Our laboratory recently reported that a group of novel indole quinuclidine analogs bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/Go-proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase. Therefore, intrinsic activity was quantified by measuring the ability of compounds to modulate levels of intracellular cAMP in intact cells. Concerning cannabinoid type-1 receptors endogenously expressed in Neuro2A cells, a single analog exhibited agonist activity, while eight acted as neutral antagonists and two possessed inverse agonist activity. For cannabinoid type-2 receptors stably expressed in CHO cells, all but two analogs acted as agonists; these two exceptions exhibited inverse agonist activity. Confirming specificity at cannabinoid type-1 receptors, modulation of adenylyl cyclase activity by all proposed agonists and inverse agonists was blocked by co-incubation with the neutral cannabinoid type-1 antagonist O-2050. All proposed cannabinoid type-1 receptor antagonists attenuated adenylyl cyclase modulation by cannabinoid agonist CP-55,940. Specificity at cannabinoid type-2 receptors was confirmed by failure of all compounds to modulate adenylyl cyclase activity in CHO cells devoid of cannabinoid type-2 receptors. Further characterization of select analogs demonstrated concentration-dependent modulation of adenylyl cyclase activity with potencies similar to their respective affinities for cannabinoid receptors. Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors.
European Journal of Pharmacology 08/2014; 737:140–148. DOI:10.1016/j.ejphar.2014.05.007 · 2.53 Impact Factor
"As also observed with CB1Rs, CB2R stimulation produces analgesic effects (Sanchez Robles et al., 2012). Because of CB2R effects on cell-to-cell signaling and cell migration, drugs acting at CB2Rs are being investigated for possible modulation of cancer cell proliferation, metastasis and angiogenesis (Liu et al., 2012; Vidinsky et al., 2012). CB2Rs are generally not expressed in the CNS, but can be upregulated in selected regions of the brain or spinal cord in response to injury and disease (Ashton et al., 2007; Walter et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: Abstract In 2008, the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) detected unregulated, psychoactive synthetic cannabinoids (SCBs) in purportedly all-natural herbal incense products (often known as K2 or Spice) that were being covertly abused as marijuana substitutes. These drugs, which include JWH-018, JWH-073 and CP-47,497, bind and activate the cannabinoid receptors CB1R and CB2R with remarkable potency and efficacy. Serious adverse effects that often require medical attention, including severe cardiovascular, gastrointestinal and psychiatric sequelae, are highly prevalent with SCB abuse. Consequently, progressively restrictive legislation in the US and Europe has banned the distribution, sale and use of prevalent SCBs, initiating cycles in which herbal incense manufacturers replace banned SCBs with newer unregulated SCBs. The contents of the numerous, diverse herbal incense products was unknown when SCB abuse first emerged. Furthermore, the pharmacology of the active components was largely uncharacterized, and confirmation of SCB use was hindered by a lack of known biomarkers. These knowledge gaps prompted scientists across multiple disciplines to rapidly (1) monitor, identify and quantify with chromatography/mass spectrometry the ever-changing contents of herbal incense products, (2) determine the metabolic pathways and major urinary metabolites of several commonly abused SCBs and (3) identify active metabolites that possibly contribute to the severe adverse effect profile of SCBs. This review comprehensively describes the emergence of SCB abuse and provides a historical account of the major case reports, legal decisions and scientific discoveries of the "K2/Spice Phenomenon". Hypotheses concerning potential mechanisms SCB adverse effects are proposed in this review.
Drug Metabolism Reviews 09/2013; 46(1). DOI:10.3109/03602532.2013.839700 · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cannabinoids have potential therapeutic value e.g. in pain relief, cancer therapy, control of nausea and vomiting, and appetite stimulation, but their therapeutic benefits are limited by unwanted central nervous system (CNS) side-effects. Separating the therapeutic effects of cannabinoid agonists from their undesired CNS effects can be achieved by either increasing the selectivity of the ligands for the CB2 receptor or by developing peripherally restricted CB1/CB2 ligands. A vast number of structurally diverse CB2 ligands have been developed during the past 3 years, stemming from the screening hits, which are further optimized towards lead compounds and drug candidates. Some of CB2 ligands may ultimately enter into clinical use as pain relief, anticancer, or antipruritic agents. This review focuses on the recent literature dealing with selective CB2 receptor ligands, with a particular emphasis on the CB2 agonists developed from 2009 onwards.
Current Medicinal Chemistry 10/2013; 21(2). DOI:10.2174/09298673113206660296 · 3.85 Impact Factor
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