Cannabinoid WIN 55,212-2 induces cell cycle arrest and apoptosis, and inhibits proliferation, migration, invasion, and tumor growth in prostate cancer in a cannabinoid-receptor 2 dependent manner

Prostate. 2019 Feb;79(2):151-159. doi: 10.1002/pros.23720. Epub 2018 Sep 21.


Background: Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including in prostate cancer. In the present study, we explored the anti-cancer effects of the synthetic cannabinoid WIN 55,212-2 (WIN) in prostate cancer.

Methods: Established prostate cancer cells (PC3, DU145, LNCaP) were treated with varying concentrations of WIN. Cell proliferation was determined by the MTS assay. The anti-migration and anti-invasive potential of WIN was examined by the wound healing assay and the matrigel invasion assay. Cell cycle analysis was performed by flow cytometry, and mechanistic studies were performed by Western blot. Athymic mice (n = 10) were inoculated with human PC3 cells. Once tumors reached 100 mm3 , animals were randomized into two groups: saline control and WIN (5 mg/kg), delivered by intraperitoneal injection three times per week for 3 weeks.

Results: WIN significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in Go/G1 phase in a dose-dependent manner. Mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, Cdk4, and pRb. Pre-treatment with a CB2 antagonist, AM630, followed by treatment with WIN resulted in a reversal of the anti-proliferation and cell cycle arrest previously seen with WIN alone. In vivo, administration of WIN resulted in a reduction in the tumor growth rate compared to control (P < 0.05).

Conclusions: The following study provides evidence supporting the use of WIN as a novel therapeutic for prostate cancer.

Keywords: WIN 55,212-2; cannabinoid; cannabinoid receptor 2; cell cycle; prostate cancer.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Benzoxazines / pharmacology*
  • Cannabinoid Receptor Antagonists / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Indoles / pharmacology
  • Male
  • Mice
  • Mice, Nude
  • Morpholines / pharmacology*
  • Naphthalenes / pharmacology*
  • Neoplasm Invasiveness
  • PC-3 Cells
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Random Allocation
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Resting Phase, Cell Cycle / drug effects
  • Xenograft Model Antitumor Assays


  • Benzoxazines
  • CNR2 protein, human
  • Cannabinoid Receptor Antagonists
  • Indoles
  • Morpholines
  • Naphthalenes
  • Receptor, Cannabinoid, CB2
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • iodopravadoline