The endocannabinoid signaling system in cancer

Pisanti, Simona; Picardi, Paola; Am, D'Alessandro; Laezza, Chiara; Bifulco, Maurizio

doi:10.1016/j.tips.2013.03.003

Cited by 156 publications

(145 citation statements)

References 105 publications

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“…Evidence suggests that these contradictory findings may reflect dose-dependent effects where macromolar concentrations of exogenous CBs have antitumor properties while clinically relevant micromolar doses have tumor promoting properties. This biphasic dose-effect is also observed with THC [19,20]. These data, along with the findings from the current study, suggest that CBD alone may be a viable alternative than THC or synthetic CB compounds and prove clinically efficacious in CIN in oncology settings.…”

supporting

confidence: 77%

Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice

et al. 2016

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Introduction !Pain is a common complaint in oncology patients and can diminish their quality of life [1,2]. Cisplatin is a common and effective chemotherapeutic against a variety of tumors. However, it has a dose-limiting effect, where 40-80 % of patients develop neuropathic pain 3-6 months into treatment [3]. Moreover, CIN does not abate upon discontinuation of treatment, a phenomenon known as "coasting" [4]. A large meta-analysis revealed that CIN was prevalent in 68 %, 60%, and 30 % of patients one, three, and greater than six months after cisplatin discontinuation, respectively [5]. Several approaches to prevent CIN have yielded disappointing results, as these compounds also interfere with cisplatinʼs antitumor properties [6,7]. Current treatment for CIN includes nortriptyline, gabapentin, and lamotrigine. Each of these have shown efficacy against other neuropathic pain syndromes, but show little efficacy in CIN [8]. Collectively, these observations suggest a need to identify novel targets for the treatment of CIN. Targeting the cannabinoid system has shown efficacy in a variety of clinical syndromes including pain. Synthetic cannabinoids produce analgesia in a number of nociceptive assays and these effects can be produced by targeting either CB1 and/or CB2 receptors [9][10][11]. There is also recent evidence that CB targets may be efficacious in treating CIN. For example, selective CB1 and CB2 receptor agonists, as well as compounds that increase endocannabinoid tone, attenuate tactile allodynia in rodent models of CIN [12][13][14].Abstract ! Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy. Abbreviations

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confidence: 77%

Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice

et al. 2016

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“…Srebfs are established downstream targets of EC signaling (Jeong et al, 2008). Although defects in EC signaling or methionine metabolism components are independently associated with hepatic steatosis, fibrosis or liver cancer (Huang et al, 2011;Mato et al, 2008;Pisanti et al, 2013), here we highlight a previously unknown pathway between EC signaling, Srebf and methionine metabolism that impacts liver development and function. Further studies are necessary to define the cell types involved and whether this regulation involves autocrine, paracrine or other signaling mechanisms.…”

Section: Ec Signaling Regulates Methionine Metabolism Via Srebfsmentioning

confidence: 81%

Cannabinoid receptor signaling regulates liver development and metabolism

et al. 2016

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Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation. Functional assays reveal abnormal biliary anatomy and lipid handling. Adult cnr2 mutants are susceptible to hepatic steatosis. Metabolomic analysis reveals reduced methionine content in Cnr mutants. Methionine supplementation rescues developmental and metabolic defects in Cnr mutant livers, suggesting a causal relationship between EC signaling, methionine deficiency and impaired liver development. The effect of Cnr on methionine metabolism is regulated by sterol regulatory element-binding transcription factors (Srebfs), as their overexpression rescues Cnr mutant liver phenotypes in a methioninedependent manner. Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function.

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“…8 Thus, new strategies to overcome chemotherapeutic resistance are under exploration and it's necessary to design new drugs for a more selective tumor therapy. Strong evidence suggests that the endogenous cannabinoid system, comprising cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and degradation, may provide new targets for tumor intervention, [9][10][11] and elucidate the potential role of endocannabinoids in the control of CRC growth and progression. 12,13 Endocannabinoid ( EC ) levels are strongly elevated in colorectal adenomatous polyps but slightly reduced in carcinomas.…”

Section: Introductionmentioning

confidence: 99%

Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells

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Pisanti

et al. 2015

Cancer Biology & Therapy

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Some compounds of a series of novel pyrrolo-1,5-benzoxa(thia)zepine, a well-known group of tubulin targeting agents, display anti-tumor effects mainly inducing cell cycle arrest and apoptosis in several human cancer models. A member of this family, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), has previously shown potent pro-apoptotic activity in a variety of human tumor cell types, with minimal toxicity toward normal blood and bone marrow cells. In this study, we evaluated the PBOX-15-mediated effects in human colorectal cancer cell (CRC) lines, DLD-1 and HT-29. The compound, used at concentrations equal to or greater than 1 mM, inhibited the proliferation of human CRC cells, inducing a significant cell cycle arrest in the G2/M phase. In DLD-1 cells, treatments prolonged over 48 h triggered a strong activation of the intrinsic apoptotic pathway as indicated by activation of caspase-9, caspase-3 and PARP cleavage. Moreover, nanomolar concentrations of PBOX-15, significantly improved the oxaliplatin and 5-fluouracilinduced anti-proliferative effects in DLD1 cell line. The observed synergistic interaction of both PBOX-15/ Oxaliplatin and PBOX-15/5FU may involve activation of p38 MAPK and JNK pathway, which in turn significantly increased caspase-3 cleavage in DLD-1 cells, treated with PBOX-5/Oxaliplatin but not with PBOX-15/5FU. Moreover, PBOX-15/5FU-treated cells showed an increase in expression of the proapoptotic protein Bax. Taken together, these results show that PBOX-15 could represent a promising compound for the treatment of human CRC and a strong candidate for novel therapeutic options.

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The endocannabinoid signaling system in cancer

Cited by 156 publications

References 105 publications

Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice

Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice

Cannabinoid receptor signaling regulates liver development and metabolism

Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells

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