Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms

Authors

  • Luciano De Petrocellis,

    Corresponding author
    1. Istituto di Cibernetica, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy
      Luciano De Petrocellis or Vincenzo Di Marzo, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, 80078, Pozzuoli (NA), Italy. E-mail: l.depetrocellis@cib.na.cnr.it or vdimarzo@icb.cnr.it
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    • These authors devoted equal experimental effort to this work

  • Alessia Ligresti,

    1. Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli , Italy
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    • These authors devoted equal experimental effort to this work

  • Aniello Schiano Moriello,

    1. Istituto di Cibernetica, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy
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  • Mariagrazia Iappelli,

    1. Istituto di Cibernetica, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy
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  • Roberta Verde,

    1. Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli , Italy
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  • Colin G Stott,

    1. GW Pharma Ltd, Salisbury, UK
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  • Luigia Cristino,

    1. Istituto di Cibernetica, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy
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  • Pierangelo Orlando,

    1. Istituto di Biochimica delle Proteine, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Napoli, Italy,
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    • These authors devoted equal experimental effort to this work

  • Vincenzo Di Marzo

    Corresponding author
    1. Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli , Italy
      Luciano De Petrocellis or Vincenzo Di Marzo, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, 80078, Pozzuoli (NA), Italy. E-mail: l.depetrocellis@cib.na.cnr.it or vdimarzo@icb.cnr.it
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Luciano De Petrocellis or Vincenzo Di Marzo, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, 80078, Pozzuoli (NA), Italy. E-mail: l.depetrocellis@cib.na.cnr.it or vdimarzo@icb.cnr.it

Abstract

BACKGROUND AND PURPOSE

Cannabinoid receptor activation induces prostate carcinoma cell (PCC) apoptosis, but cannabinoids other than Δ9-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.

EXPERIMENTAL APPROACH

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.

KEY 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 Ca2+). 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 AND IMPLICATIONS

These data support the clinical testing of CBD against prostate carcinoma.

LINKED ARTICLE This article is commented on by Pacher et al., pp. 76–78 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02121.x

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