title: Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms.
abstract: OBJECTIVE
  Cannabinoid receptor activation induces prostate carcinoma cell (PCC) apoptosis, but cannabinoids other than Δ(9) -tetrahydrocannabinol (THC), which lack potency at cannabinoid receptors, have not been investigated. Some of these compounds antagonize transient receptor potential melastatin type-8 (TRPM8) channels, the expression of which is necessary for androgen receptor (AR)-dependent PCC survival.
  
  
  METHODS
  We tested pure cannabinoids and extracts from Cannabis strains enriched in particular cannabinoids (BDS), on AR-positive (LNCaP and 22RV1) and -negative (DU-145 and PC-3) cells, by evaluating cell viability (MTT test), cell cycle arrest and apoptosis induction, by FACS scans, caspase 3/7 assays, DNA fragmentation and TUNEL, and size of xenograft tumours induced by LNCaP and DU-145 cells.
  
  
  RESULTS
  Cannabidiol (CBD) significantly inhibited cell viability. Other compounds became effective in cells deprived of serum for 24 h. Several BDS were more potent than the pure compounds in the presence of serum. CBD-BDS (i.p.) potentiated the effects of bicalutamide and docetaxel against LNCaP and DU-145 xenograft tumours and, given alone, reduced LNCaP xenograft size. CBD (1-10 µM) induced apoptosis and induced markers of intrinsic apoptotic pathways (PUMA and CHOP expression and intracellular Ca(2+)). In LNCaP cells, the pro-apoptotic effect of CBD was only partly due to TRPM8 antagonism and was accompanied by down-regulation of AR, p53 activation and elevation of reactive oxygen species. LNCaP cells differentiated to androgen-insensitive neuroendocrine-like cells were more sensitive to CBD-induced apoptosis.
  
  
  CONCLUSIONS
  These data support the clinical testing of CBD against prostate carcinoma.
authors.affiliation: Istituto di Cibernetica, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy. l.depetrocellis@cib.na.cnr.it
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Iappelli
authors.forename: Roberta
authors.initials: R
authors.lastname: Verde
authors.forename: Colin G
authors.initials: CG
authors.lastname: Stott
authors.forename: Luigia
authors.initials: L
authors.lastname: Cristino
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Orlando
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002185:Cannabidiol / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000077143:Docetaxel; D015536:Down-Regulation / Q000187:drug effects; D013759:Dronabinol / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000494:pharmacology; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*; D043823:Taxoids / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology; D050051:Transient Receptor Potential Channels / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D002186:Cannabinoids; D009570:Nitriles; D017382:Reactive Oxygen Species; D011944:Receptors, Androgen; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D043823:Taxoids; D014105:Tosyl Compounds; D050051:Transient Receptor Potential Channels; D000077143:Docetaxel; D002185:Cannabidiol; D013759:Dronabinol; C053541:bicalutamide; D053148:Caspase 3