Review Article

Cannabinoid Effects on Experimental Colorectal Cancer Models Reduce Aberrant Crypt Foci (ACF) and Tumor Volume: A Systematic Review

Table 1

Summary of study characteristics.

Author, yearAnimal modelSample size and number of groups in the AOM modelSample size and number of groups in the xenograft modelCannabinoid and doseMain outcome measuresLength of the experiment

Aviello, et al. 2012 [7]ICR male mice AOM-induced CRCN = 10 per group.
Group 1 = 
Vehicle
Group 2 = 
AOM plus vehicle
Group 3 = 
AOM plus CBD
Group 4 = 
AOM plus CBD
N/AExperimental group 3: CBD 1 mg/kg IP
Experimental group 4: CBD 5 
mg/kg IP
Three times per week
1. Decrease in ACF formation
2. Increase in expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and caspase-3
3. Increase in phosphorylation of AKT
4. MTT assay for the antiproliferative effect
5. Increase in endocannabinoids levels
Three months

Borrelli, et al. 2014 [38]ICR male and female mice AOM-induced CRC/Xenograft model of HCT 116 colon carcinoma cellsN = 10 per group.
Group 1 = 
Vehicle
Group 2 = 
AOM plus vehicle
Group 3 = 
AOM plus CBG
Group 4 = 
AOM plus CBG
HCT 116 cells (2.5 × 106) were injected subcutaneously into the right flank of each athymic mice. At 10 days after inoculation (once tumors had reached a size of 550–650 mm3), mice were randomly assigned to one control group and three treated groupsAOM model:
Experimental group 3: CBG 1 
mg/kg IP
Experimental group 4: CBG 5 
mg/kg IP three times per week
Xenograft model:
Experimental group 1: CBG 1 
mg/kg IP
Experimental group 3: CBG 3 
mg/kg IP
Experimental group 4: CBG 10 
mg/kg IP t
hree times per week
1. Decrease in tumor growth
2. Decrease in ACF formation
3. Decrease in CB receptors expression
4. MTT assay for antiproliferative effect
5. CBG antagonism at TRPM8 receptor
6. Increase in ROS production
7. Increase in CHOP mRNA expression
8. Increase in caspase 3/7 enzymatic assay
Three months

Izzo, et al. 2008 [35]C57BL/6N female mice AOM-induced CRCN = 6 per group.
Group 1 = 
vehicles
Group 2 = 
AOM plus the vehicle
Group 3 = 
AOM plus AA-5HT
Group 4 = 
AOM plus VDM11
Group 5 = 
AOM plus HU210
N/AAA-5HT: 5 mg/kg IP
N-(2-methyl-3-hydroxy-phenyl)-5,8,11,14-eicosa-tetraenamide]) : 5 
mg/kg IP
HU210 : 
0.1 
mg/kg IP
Given daily during the experiment
1. Decrease in ACF formation
2. Increase in endocannabinoids levels
3. Increased expression of caspase-3 and caspase-9
Six months

Kargl, et al. 2013 [28]CD1 male mice AOM/DSS-induced CRCN = 12 per group
Group 2 = 
AOM/DSS plus the vehicle
Group 1 = 
AOM/DSS plus O-1602
N/AO-1602 3 mg/kg IP every second day over four weeks1. Decrease in tumor growth
2. Decrease in phosphorylation of NFκβ and STAT3
3. Increase in expression of BAX and P534
. Increase in a
nnexin V/PI expression
5. Decreased expression of TNF-α
Twelve weeks

Pagano, et al. 2017 [56]ICR male or female mice AOM-induced CRC/Xenograft model of HCT 116 colon carcinoma cells (N = 10)N = 10 per group.
Group 1 = 
Vehicles
Group 2 = 
AOM plus vehicle
Group 3 = 
AOM plus URB-602
HCT 116 cells (2.5 × 106) were injected subcutaneously into the right flank of each athymic mice and at 10 days after inoculation (once tumors had reached a size of 250–300 mm3), mice were randomly assigned to one control and treated group.
N = 5 animals per group
AOM and xenograft model:URB-602
5 
mg/kg IP three times a week
1. Increase in expression of monoacylglycerol lipase (MAGL) in CRC cells and xenograft tissue
2. Decrease in tumor growth
3. Increase in endocannabinoid levels
4. Decreased expression of VEGF and FGF-2
5. Decrease in cyclin-D1
and p27KIP expression
Three months

Romano, et al. 2014 [8]ICR male mice AOM-induced CRC/Xenograft model of HCT 116 colon carcinoma cells††
Group 1 = 
Vehicle
Group 2 = 
AOM plus vehicle
Group 3 = 
AOM plus CBD BDS
HCT 116 cells (2.5 × 106) were injected subcutaneously into the right flank of each athymic mice and at 10 days after inoculation (once tumors had reached a size of 300 mm3), mice were randomly assigned to control and treated group with CBD BDSAOM and xenograft model:
CBD BDS 5 
mg/kg IP three times a week
1. Decrease in tumor growth
2. Decrease in ACF formation
3. MTT assay for the antiproliferative effect
Three months

Santoro, et al. 2009 [57]C57BL/6N female mice AOM-induced CRCN = 9 per group.
Group 1 = 
Vehicle
Group 2 = 
AOM plus vehicle
Group 3 = 
AOM plus rimonabant
N/ARimonabant 3 mg/kg IP given daily during the experiment1. Decrease in ACF formation
2. Increase in expression of cyclin B1
/cdk1 complex
3. Decreased phosphorylation of p38/MAPK and PARP-1
4. Increase in mitotic index, polyploidy, and chromosome aberrations
5. Decreased phosphorylation of Chk1
Six months

Thapa, et al. 2012 [58]BALB/c nude mice xenograft model of HT-29 of colon carcinoma cellsN/AHT 29 cells (5 × 106) were injected subcutaneously into the rear flanks of each BALB/c nude mice and once tumors had reached a size of 50 mm3, mice were randomly assigned to control and treated groups. n = 6 animal per groupLYR-8 10 mg/kg IP given daily during the experiment1. Decrease in tumor growth
2. Decreased expression of COX-2, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF-1α)
Unknown

FAAH inhibitor. VDM11 inhibitor. MAGL inhibitor. All doses were started one week before the first injection of AOM. ††Sample size is not described in the article. CBD: cannabidiol, CBG: cannabigerol, IP: intraperitoneal, AOM: azoxymethane, AA-5HT: N-arachidonoyl-serotonin, BDS: botanical drug substance, ACF: aberrant crypt foci, ROS: reactive oxygen species, N/A: not applicable.