Table 1.
Pre-clinical assessment of cannabinoids on tumor development.
| Cancer type | Model type -cell line | Animal species/strain | Cannabinoid | Dose (route) | Findings | References |
|---|---|---|---|---|---|---|
| Glioma | Xenograft—C6.9 | Immune deficient mice | Delta-9-THC | 500 ug/day (p.t.) | Decreased tumor size and tumoral TIMP-1 expression | Blázquez et al., 2008b |
| JWH-133 | 50 ug/day (p.t.) | Decreased tumor size and tumoral TIMP expression, ceramide inhibition increased tumor growth | ||||
| Xenograft—C6 | Rag 2-/- mice | WIN 55,212-2 | 50 ug/day (i.t.) | Decreased tumor size | Galve-Roperh et al., 2000 | |
| Delta-9-THC | 500 ug/day (i.t.) | |||||
| Orthotopic—C6 | Wistar rat | WIN 55,212-2 | 50–250 ug/day (i.t.) | Increased survival | ||
| Delta-9-THC | 500–2500 ug/day (i.t.) | |||||
| Xenograft—U87MG | Nude mice | Delta-9-THC | 15 mg/kg/day (p.t.) | Decreased tumor size, TUNEL and p8 levels increased in tumor | Salazar et al., 2009 | |
| Orthotopic—U87MG | CB-17 SCID mice | KM-233 | 2–12 mg/kg twice/day (i.p.) | Decreased tumor size | Gurley et al., 2012 | |
| Patient Derived Xenograft | Athymic Balb/c (nu/nu) | KM-233 | 12 mg/kg, twice/day (i.p.) | Tumor growth delay | ||
| Xenograft—C6 | Rag 2-/- mice | JWH-133, WIN55,212-2 | 50 ug/day (i.t.) | Decreased tumor size, effect of JWH-133 prevented by CB2R antagonism | Sánchez et al., 2001 | |
| Xenograft—astrocytoma cells | Rag 2-/- mice | JWH-133 | 50 ug/day (i.t.) | Decreased tumor size | ||
| Xenograft—U87MG | Nude mice | Delta-9-THC + TMZ | 15 mg/kg THC, 5 mg/kg TMZ (p.t.) | Greater reduction in tumor size than THC or TMZ alone | Torres et al., 2011 | |
| Delta-9-THC + CBD | 7.5 mg/kg THC 7.5 mg/kg CBD (p.t.) | Greater reduction in tumor size than THC or CBD alone | ||||
| Delta-9-THC + CBD + TMZ | 3.7 mg/kg THC 3.7 mg/kg CBD 5.0 mg/kg TMZ (p.t.) | Greater reduction in tumor size than THC, CBD, or TMZ alone | ||||
| Xenograft—T98G | Nude mice | Delta-9-THC + TMZ | 15 mg/kg THC 5.0 mg/kg TMZ (p.t.) | Greater reduction in tumor size than THC or TMZ alone | ||
| Xenograft—C6.9 | Immune deficient mice | Delta-9-THC | 500 ug/day (p.t.) | Decreased tumor growth and tumor MMP-2 expression | Blázquez et al., 2008a | |
| JWH-133 | 50 ug/day (p.t.) | Decreased tumor size and tumoral MMP-2 expression, ceramide inhibition reduces tumor growth | ||||
| Xenograft—C6 | Rag2-/- mice | JWH-133 | 50 ug/day (i.t.) | Decreased tumor size and tumor expression of VEGFR | Blázquez et al., 2004 | |
| Xenograft—U87MG | Athymic CD1 nude (nu/nu) | CBD | 0.5 mg/day (p.t.) | Decreased tumor size | Massi et al., 2004 | |
| Xenograft—C6 cells or primary astrocytoma | Rag2-/- mice | JWH-133 | 50 ug/day (i.t.) | Decreased tumor size and blood vessel size and functionality | Blázquez et al., 2003 | |
| Orthotopic—U251 | Athymic nude (nu/nu) | CBD | 15 mg/kg (i.p.) | Decreased tumor size, decreased Id-1 and Ki67 expression in tumor | Aguado et al., 2007 | |
| Xenograft | Athymic nude (nu/nu) | CBD | 15 mg/kg (i.p.) | Decreased tumor size, Decreased Id-1 and K167 expression in tumor | Aguado et al., 2007 | |
| Xenograft—U87MG | Nude mice | Delta-9-THC | 15 mg/kg/day (p.t.) | Reduced tumor size and increased TRB1, LC3, caspase 3, and decreased S6 in tumors | Salazar et al., 2009 | |
| Xenograft—T98G | Athymic nude | Delta-9-THC | 1.5 or 15 mg/kg/day (p.t.) | Decreased tumor size and anti-tumor effect reversed by GRP55 knockdown | Sánchez et al., 2001 | |
| Orthotopic—3832 or 387 cells | Athymic nude (nu/nu) | CBD | 15 mg/kg, 5 days/week (i.p.) | Initial decrease in tumor size followed by resistance | Singer et al., 2015 | |
| Orthotopic—GL261 | C57Bl/6 | CBD + Delta-9-THC | 2 mg/kg each (i.p.) | CBD and THC enhanced killing effect of ionizing radiation | Scott et al., 2014 | |
| Xenograft—glioma stem cells | Athymic nude | HU-210, JWH-133 | 30 uM treatment before inoculation (p.t.) | Decreased tumor growth rate and size decreased stem cell markers increased differentiation markers in tumor | Duntsch et al., 2006 | |
| Xenograft—C6.9 | Immune deficient mice | Delta-9-THC | 500 ug/day (p.t.) | Decreased tumor size and MMP expression in tumor | Blázquez et al., 2008a | |
| JWH-133 | 50 ug/day (p.t.) | Decreased tumor size and MMP expression in tumor, ceramide inhibition prevented tumor regression | ||||
| Colon cancer | Azoxymethane-induced colon cancer model | Male ICR mice | CBD | 5 mg/kg 3x weekly (i.p.) | Reduced aberrant crypt foci (ACF), number of polyps and tumors | Aviello et al., 2012 |
| Azoxymethane-induced colon cancer model | Male ICR mice | Cannabis extract rich in CBD | 5 mg/kg (i.p.) | Reduced aberrant crypt foci (ACF), number of polyps and tumors | Romano et al., 2014 | |
| Xenograft—HCT-116 | Athymic nude female | CBG | 3 and 10 mg/kg (i.p.) | Reduced the growth | Borrelli et al., 2014 | |
| Azoxymethane-induced colon cancer models | Male ICR mice | 5 mg/kg (i.p.) | Reduced ACF, number of tumor/mouse | |||
| Xenograft—HT-29 | Nude mice | HU-331 | 5 mg/kg (i.p.) | Reduced angiogenesis | Kogan et al., 2006 | |
| Xenograft—HT-29 | Nude mice | HU-331 | 5 mg/kg (i.p., s.c.,i.t.) | Reduced tumor growth | Kogan et al., 2004 | |
| General in vivo toxicity | Sabra male mice, SCID-NOD Mice | HU-331 | 7.5 mg/kg (i.p.) | Less toxicity than doxorubicin | Kogan et al., 2007 | |
| Xenograft—HT-29 | male nude mice | 5 mg/kg (i.p.) | Reduced tumor growth and less cardiotoxic than doxorubicin | |||
| Colitisis induced colon cancer model (Azoxymethane, AOM+dextran sulfate sodium, DSS) | Male CD1 mice | O-1602 | 3 mg/kg (i.p.) | Reduced number and area of tumors. Decreased histoscore tumor burden and the expression of proliferation marker PCNA. Reduced key mediators that link the inflammation with colorectal cancer such as: inflammatory mediator TNF-α, and oncogenic transcription factors STAT3 and NFκB | Kargl et al., 2013 | |
| Liver Cancer | Xenograft—HepG2 | Male athymic nude | Delta-9-THC | 15 mg/kg (p.t.) | Increased PPAR gamma expression | Vara et al., 2013 |
| JWH-015 | 1.5 mg/kg (p.t.) | PPAR-dependent reduction in tumor growth | ||||
| Xenograft—HepG2—and HuH-7 | Athymic mice | Delta-9-THC | 15 mg/kg (p.t.) | Increase pAMPK, Reduced pAKT, pS6. Autogaphy-dependent reduction in tumor growth | Vara et al., 2011 | |
| JWH-015 | 1.5 mg/kg (p.t.) | |||||
| Orthotopic—HepG2 | Athymic mice | Delta-9-THC | 15 mg/kg (i.p.) | Decreased ascites formation, increased pAMPK, Reduced pAKT, pS6. Reduced alpha fetoprotein levels | Vara et al., 2011 | |
| JWH-015 | 1.5 mg/kg (i.p.) | |||||
| Xenograft—Mz-ChA-1 (cholangiocarcinoma) | Nude mice | AEA | 10 mg/kg (i.p.) | GPR55-dependent reduction of tumor growth | Huang et al., 2011b | |
| O-1602 | 10 mg/kg (i.p.) | |||||
| Athymic mice | AEA | 10 mg/kg (i.p.) | Reduction in tumor growth and VEGF expression | DeMorrow et al., 2008 | ||
| Pancreatic | Xenograft—MiaPaCa2 | Nude mice | Delta-9-THC | 15 mg/kg (p.t.) | Reduced tumor growth | Carracedo et al., 2006 |
| JWH-133 | 1.5 mg/kg (p.t.) | |||||
| Orthotopic—MiaPaCa2 | WIN 55,212-2 | 1.5 mg/kg (2 days) then 2.25 mg/kg (2 days) then 3.0 mg/kg (10 days) (i.p.) | Reduced the growth and the spreading of pancreatic tumor cells | |||
| Breast | Orthotopic—4T1.2 MVT-1 | BALB/c | CBD | 10 mg/kg (p.t.) | Decreased tumor growth. Decreased pAkt and EGFR levels | Elbaz et al., 2015 |
| Orthotopic—MVT-1 | FVB | |||||
| Xenograft—MBA-MD-321 | Athymic nu/nu | CBD-rich extract | 6.5 mg/kg (i.t.) | Decreased tumor growth | Ligresti et al., 2006 | |
| Intraplanar—MBA-MD-321 | BALB/c | CBD | 5.0 mg/kg (i.p.) | Decreased tumor metastasis | ||
| Orthotopic—4T1 | BALB/c | CBD | 1.0, 5.0 mg/kg (i.p.) | Decreased tumor growth and metastasis | McAllister et al., 2011 | |
| Orthotopic—4T1 | BALB/c | CBD O-1663 | 0.5, 1.0, 10 mg/kg CBD; 1.0 mg/kg O-1663 (i.p.) | Decreased tumor growth and metastasis | Murase et al., 2014 | |
| Xenograft—MDA-MB-231 | Athymic nu/nu | CBD O-1663 | 0.5, 1.0, 10 mg/kg CBD; 1.0 mg/kg O-1663 (i.p.) | Decreased tumor metastasis. O-1663 demonstrated greater potency compared to CBD | ||
| Xenograft—4T1 | BALB/c | Delta-9-THC | 12.5, 25, 50 mg/kg (s.c.) | Increased tumor growth and Metastasis | McKallip et al., 2005 | |
| SCID-NOD | Delta-9-THC | 25 mg/kg (s.c.) | No effect on tumor growth | |||
| Xenograft (intraplanar)—EMT6 | BALB/c | Delta-9-THC | 25, 50 mg/kg (i.p.) | No effect on immune response | ||
| Xenograft (intraplanar)—4T1 | BALB/c | Delta-9-THC | 25, 50 mg/kg (i.p.) | Decreased anti-tumor immune response in CB2 dependent manner | ||
| GEMM—MMTV-neu | MMTV-neu | Delta-9-THC | 0.5 mg/animal (p.t.) | Decreased tumor growth, multiplicity, and metastasis. Decreased Akt levels | Caffarel et al., 2010 | |
| JWH-133 | 0.05 mg/animal (p.t.) | |||||
| Xenograft—N202.1 | Athymic nu/nu | Delta-9-THC | 0.5 mg/animal (p.t.) | Decreased tumor growth is Akt mediated | ||
| JWH-133 | 0.05 mg/animal (p.t.) | |||||
| Xenograft—MDA-MB-231 | SCID | WIN-55,212-2, JWH-133 | 5.0 mg/kg (i.p.) | Decreased tumor growth, angiogenesis, and metastasis | Qamri et al., 2009 | |
| GEMM—MMTV-PyMT | MMTV-PyMT | WIN-55,212-2, JWH-133 | 5.0 mg/kg (i.p.) | Decreased tumor growth and progression | ||
| GEMM—MMTV-PYMT | MMTV-PyMT | JWH-015 | 5.0 mg/kg (p.t.) | Decreased tumor volume and weight. Decreased CXCR4 phosphorylation | Nasser et al., 2011 | |
| Orthotopic—NT2.5 | FVB | |||||
| Orthotopic—SUM159 | Nude Mice | JWH-015 | 10.0 mg/kg (p.t.) | Decreased tumor volume and weight. Decreased EGFR and IGF-1R signaling | McKallip et al., 2005 | |
| Orthotopic—MCF-7 | ||||||
| Xenograft—MDA-MB-231 | Athymic nu/nu | Synthetic CB2 agonist | 2.0 mg/kg (i.p.) | Decrease tumor growth | Morales et al., 2015 | |
| Allograft—TSA-E1 | C57BL/6 | Met-F-AEA | 0.5 mg/kg (i.p.) | Decreased metastasis | Grimaldi et al., 2006 | |
| Prostate | Xenograft—LNCaP | MF-1 nude | CBD | 1.0, 10, 100 mg/kg (i.p.) | Decreased tumor growth | De et al., 2013 |
| Xenograft—DU-145 | MF-1 nude | CBD | 1.0, 10, 100 mg/kg (i.p.) | Potentiated tumor growth | ||
| Xenograft—PC-3 | Athymic nu/nu | JWH-015 | 0.15 mg/kg (s.c.) | Decreased tumor growth | Olea-Herrero et al., 2009 | |
| Lung | Xenograft—A549 | NMRI nu/nu | CBD | 5.0 mg/kg (s.c.) | Decreased tumor growth, plasminogen Activator inhibitor- 1 | Ramer et al., 2010a |
| Xenograft—A549 | NMRI nu/nu | CBD | 5.0 mg/kg (i.p.) | Decreased tumor metastasis | Ramer et al., 2010b | |
| Xenograft—A549 | NMRI nu/nu | CBD | 5.0 mg/kg (i.p.) | CBD upregulated ICAM-1 and TIMP-1. ICAM-1 was required for anti-metastatic properties of CBD | Ramer et al., 2012 | |
| Xenograft—A549 | NMRI nu/nu | CBD | 5.0 mg/kg (i.p.) | CBD decreased tumor growth this was reversed by co-administration with PPAR-γ antagonist | Ramer et al., 2013 | |
| Allograft—LL2 | C57BL/6 | Delta-9-THC | 5.0 mg/kg (p.t.) | No significant effect on tumor growth | McKallip et al., 2005 | |
| Allograft—3LL | C57BL/6 | Delta-9-THC | 5.0 mg/kg (i.p.) | Increased tumor growth in immunocompetent mode | Zhu et al., 2000 | |
| Xenograft—L1C2 | BALB/c | Delta-9-THC | 5.0 mg/kg (i.p.) | No effect on tumor growth in immunosuppressed model | ||
| Xenograft—A549 | SCID | Delta-9-THC | 5.0 mg/kg (p.t.) | Decreased Tumor growth and metastasis. Decreased Akt | Preet et al., 2008 | |
| Xenograft—3LL | C57BL/6 | Met-F-AEA | 0.5 mg/kg (i.p.) | Decreased tumor metastasis | Bifulco et al., 2001 | |
| Allograft—3LL | C57BL/6 | Met-AEA | 5.0 mg/kg (i.p.) | Increased tumor growth in a COX-2 dependent manner | ||
| Xenograft—L1C2 | BALB/c | Met-AEA | 5.0 mg/kg (i.p.) | Increased tumor growth in a COX-2 dependent manner | Gardner et al., 2003 | |
| Thyroid | Xenograft—KiMol | Athymic Nude | VDM-11 | 5.0 mg/kg (i.t.) | Decreased tumor size | Bifulco et al., 2004 |
| AA-5-HT | 5.0 mg/kg (i.t.) | |||||
| Met-AEA | 0.7 mg/kg (p.t.) | Decreased tumor size, anti-tumor effect blocked by CB1 antagonist | Bifulco et al., 2001 | |||
| Met-AEA | 0.5 mg/kg (p.t.) | Decreased tumor size, anti-tumor effect blocked by CB1 antagonist, VEGF expression decreased in tumor | ||||
| Xenograft—ARO cells | Balb/c (nu/nu) nude mice | JWH-133 | 50 ug/ml (i.t.) | CB2 overexpressing ARO cells reduced tumor weight vs. ARO-empty vector cells | ||
| Melanoma | Xenograft—CHL-1 | Athymic nude mice | Delta-9-THC | 15 mg kg (p.o.) | Reduced tumor growth, Ki67 and increased TUNEL positive cells | Armstrong et al., 2015 |
| Xenograft—HCmel12 (intracutaneous) | Cnr1/2−/− mice were crossed into the Hgf-Cdk4R24C melanoma mouse model to generate mice with a dark skin phenotype which develop CB1 and CB2 receptor-deficient melanomas. | Delta-9-THC | 5 mg/kg (s.c.) | CB receptors-dependent reduction in tumor growth | Glodde et al., 2015 | |
| Xenograft—B16 | C57BL/6 mice and Nude | WIN-55,212–2 | 50 ug/day (p.t.) | Reduced tumor growth, cell proliferation, apoptosis, and angiogenesis | Blázquez et al., 2006 | |
| JWH-133 | ||||||
| Xenograft B–16 (intraplantar) | C57BL/6 mice | WIN-55,212–2 | 50 ug/day (p.t.) | Reduced metastasis in lung and liver | ||
| JWH-133 | JWH-133 | |||||
| NMSC | Xenograft—PDV.C57 | Nude (NMRI nu) mice | WIN-55,212-2 | 6.7 ug/ul (flow pump—0.52 uL/h (11 days) | Inhibited skin tumor growth, angiogenesis and EGFR activation | Casanova et al., 2003 |
| JWH-133 | ||||||
| DMBA/TPA skin carcinogenesis model | Female ICR mice | JWH-018 | 0.02 and 0.2 uM (t.o.) | Inhibited inflammation, promotion of skin papillomas, tumor incidence | Nakajima et al., 2013 | |
| JWH-122 | 0.2 and 2 uM (t.o.) | |||||
| JWH-210 | 0.2 and 2 uM (t.o.) |
p.t., peritumor; i.t., intratumor; i.p., intraperitoneal; s.c., cubcutaneous; t.o., topical; p.o. oral.