Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents

Department of Pharmaceutical Sciences, University of Salerno, Italy.
Best Practice & Research: Clinical Endocrinology & Metabolism (Impact Factor: 4.6). 03/2009; 23(1):117-31. DOI: 10.1016/j.beem.2009.02.001
Source: PubMed


Cannabinoids (the active components of Cannabis sativa) and their derivatives have received renewed interest in recent years due to their diverse pharmacological activities. In particular, cannabinoids offer potential applications as anti-tumour drugs, based on the ability of some members of this class of compounds to limit cell proliferation and to induce tumour-selective cell death. Although synthetic cannabinoids may have pro-tumour effects in vivo due to their immunosuppressive properties, predominantly inhibitory effects on tumour growth and migration, angiogenesis, metastasis, and also inflammation have been described. Emerging evidence suggests that agonists of cannabinoid receptors expressed by tumour cells may offer a novel strategy to treat cancer. In this chapter we review the more recent results generating interest in the field of cannabinoids and cancer, and provide novel suggestions for the development, exploration and use of cannabinoid agonists for cancer therapy, not only as palliative but also as curative drugs.

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Available from: Simona Pisanti
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    • "Cannabinoids can play an important role in the palliation of pain, nausea, vomiting, and appetite for cancer patients; however, this is beyond the scope of this review. The palliative uses of cannabinoids have been reviewed elsewhere.49–51 "
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    ABSTRACT: Cannabinoids have been attracting a great deal of interest as potential anticancer agents. Originally derived from the plant Cannabis sativa, there are now a number of endo-, phyto- and synthetic cannabinoids available. This review summarizes the key literature to date around the actions, antitumor activity, and mechanisms of action for this broad range of compounds. Cannabinoids are largely defined by an ability to activate the cannabinoid receptors - CB1 or CB2. The action of the cannabinoids is very dependent on the exact ligand tested, the dose, and the duration of exposure. Some cannabinoids, synthetic or plant-derived, show potential as therapeutic agents, and evidence across a range of cancers and evidence in vitro and in vivo is starting to be accumulated. Studies have now been conducted in a wide range of cell lines, including glioma, breast, prostate, endothelial, liver, and lung. This work is complemented by an increasing body of evidence from in vivo models. However, many of these results remain contradictory, an issue that is not currently able to be resolved through current knowledge of mechanisms of action. While there is a developing understanding of potential mechanisms of action, with the extracellular signal-regulated kinase pathway emerging as a critical signaling juncture in combination with an important role for ceramide and lipid signaling, the relative importance of each pathway is yet to be determined. The interplay between the intracellular pathways of autophagy versus apoptosis is a recent development that is discussed. Overall, there is still a great deal of conflicting evidence around the future utility of the cannabinoids, natural or synthetic, as therapeutic agents.
    Full-text · Article · Aug 2013 · Cancer Management and Research
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    • "We demonstrated that the local administration of a CB2 receptor agonist reduced mechanical hyperalgesia in a murine model of tumor pain. CB2 receptor agonists have several significant pharmacological advantages over CB1 receptor agonists as well as opiates in this model: tolerance does not develop to the antihyperalgesic effect (Hald et al., 2008; Leichsenring et al., 2009; Lozano-Ondoua et al., 2010), the growth of a variety of tumor cell types is impaired (Lozano-Ondoua et al., 2010; Pisanti et al., 2009) and effects on the central nervous system associated with the use of the other drugs are lacking. Moreover, the data address two strategies recently cited for enhancing the therapeutic potential of cannabinoids: targeting multiple cannabinoid receptors and developing peripherally restricted ligands (Pertwee, 2009). "
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    ABSTRACT: In light of the adverse side-effects of opioids, cannabinoid receptor agonists may provide an effective alternative for the treatment of cancer pain. This study examined the potency and efficacy of synthetic CB1 and CB2 receptor agonists in a murine model of tumor pain. Intraplantar injection of the CB1 receptor agonist arachidonylcyclopropylamide (ED(50) of 18.4 μg) reduced tumor-related mechanical hyperalgesia by activation of peripheral CB1 but not CB2 receptors. Similar injection of the CB2 receptor agonist AM1241 (ED50 of 19.5 μg) reduced mechanical hyperalgesia by activation of peripheral CB2 but not CB1 receptors. Both agonists had an efficacy comparable with that of morphine (intraplantar), but their analgesic effects were independent of opioid receptors. Isobolographic analysis of the coinjection of arachidonylcyclopropylamide and AM1241 determined that the CB1 and CB2 receptor agonists interacted synergistically to reduce mechanical hyperalgesia in the tumor-bearing paw. These data extend our previous findings that the peripheral cannabinoid receptors are a promising target for the management of cancer pain and mixed cannabinoid receptor agonists may have a therapeutic advantage over selective agonists.
    Full-text · Article · May 2011 · Behavioural pharmacology
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    • "The ubiquitous regulatory actions of the ES in health and disease emphasize its role in several physio-pathological processes and suggest distinct targets through which this signalling system could be modulated for therapeutic gain [3] [4]. Increasing evidence suggests that cannabinoids exert both direct and indirect effects on cancer by different mechanisms of action in different types of malignancies [5] [6]. Cannabinoids have been found to control cell growth and death in many cancer types, both in vitro and in vivo [7] [8] [9], as well as the neoangiogenesis and metastatic spreading [10- 13], but the mechanisms underlying the antitumor effects are sometimes cell type specific. "
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    ABSTRACT: Rimonabant (SR141716), a cannabinoid CB1 receptor antagonist known for anti-obesity activity, has more recently been shown to inhibit tumor cell growth. Here we demonstrated the antitumor potential of SR141716 in leukemia-derived cell lines and its low toxicity in normal cells (PBMC). SR141716 (1-20microM range of doses) reduced Jurkat and U937 cell number by activating death signals as well as affecting cell cycle progression. The most prominent response in U937 to SR141716 was a G(0)/G(1) block, while in Jurkat cells there was activation of cell death processes. SR141716-treated cells exhibited the morphological and biochemical features of apoptosis and to some extent necrosis. Apoptotic mode of cell death was confirmed in both cell lines by analysis of cell morphology, phosphatidylserine exposure and DNA fragmentation. Moreover, the drug was found to induce an early and robust mitochondrial membrane depolarization. In Jurkat cells the apoptotic process was typically caspase-dependent, while in U937 caspase-independent pathways were also activated. The contribution of PARP activation to SR141716-induced apoptosis in U937 was suggested by protein PARylation, AIF release and apoptosis reversal by PARP inhibitors. Moreover, SR141716 negatively modulated, especially in U937, the PI3K/AKT pathways. In conclusion, our data indicate that SR141716 elicits alternative response and/or cell death pathways depending on the cell type affected.
    Full-text · Article · Aug 2010 · Biochemical pharmacology
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