Table 1.
Pre-clinical in vitro studies encompassing various cannabinoids in cancer models
| Cancer Cell line | Cannabinoid (s) | Inhibitory concentrations | In vitro actions | References | |
|---|---|---|---|---|---|
| PDAC | MIA PaCa2, PANC-1, Capan-2, BxPC-3 | Δ9-THC, SR141716, SR144528 | 0–5 µM | Apoptosis via CB2 and p8, ATF4 and TRIB3 and caspase-3 activation | Carracedo et al. (2006) |
| AsPC-I, HPFA-II, PANC-I, BxPC-3 | CBD | 0–10 µM | Antiproliferative effects via GPR55 | Ferro et al. (2018) | |
| BRAIN | Human Glioblastoma, U373-MG | Δ9-THC, AEA, HU-210, WIN 55,212–2 | 100 nM–10 µM | Accelerated cell proliferation via EGFR and MMP | McAllister et al. (2011) |
| Human Glioblastoma, U878MG, U373MG | CBD, SR141716, SR144528 | 5–40 µM | Antiproliferative effects correlated to induction of apoptosis | Singer et al. (2015) | |
|
Human Glioblastoma multiforme, SF126, U87-MG, U251, SF188, U373-MG, Human GBM cultures |
Δ9-THC, WIN 55,212–2 | 0.1 nM-2 µM | Antiproliferative effects and increase of apoptosis | Ellert-Miklaszewska et al. (2021) | |
| Rat C6 glioma cells | WIN 55,212–2, WIN 55,212–3 | 1–30 µM | Cell viability reduction, morphological changes to cells | Matas et al. (2007) | |
| Rat C6 glioma cells | Δ9-THC, CBD, CBD-A, CBG, CBC, AM251, JWH-133, AM630, SR141716A, SR144528 | 0–50 µM | CBD most potent. CBD, CBG and CBD-A activated TRPV1 | Ligresti et al. (2006) | |
| Murine Neuroblastoma, N18TG2 | AEA | 1–5 µM | Apoptosis and decrease in cleavage of PARP-1 | Marcu et al. (2010) | |
| Human Astrocytoma, U87MG | Δ9-THC, SR141716 | 1–10 µM | Apoptosis and autophagy via ER stress | Salazar et al. (2009) | |
| Human Glioma cancer, U251, SF126, U87 | Δ9-THC, CBD | 0.1–10 µM | Inhibition of cell proliferation, apoptosis | Qamri et al. (2009) | |
| Human Glioblastoma, U87-MG, T98G | CBD | 0–20 µM | Decrease in cell invasion via MMP-9, TIMP-1, TIMP-4, u-PA, PAI-1, VEGF | Solinas et al. (2013) | |
| Human Glioma, T98G, U87MG, Murine Glioma, GL261 | CBD, Δ9-THC (Pure and BDS) | 0–20 µM | Increase in radiosensitivity associated with increase in apoptosis and autophagy | Scott et al. (2014) | |
|
Human Glioblastoma, U251, 3832, 387 Primary glioma stem cells (GSC) lines |
CBD | 0–5 µM | Activation of p-p38 pathway, downregulation of key stem cell regulators; Sox2, Id1 and p-STAT3 | Singer et al. (2015) | |
| Human Neuroblastoma, SK-N-SH, IMR-32, NUB-6 and LAN-1 | Δ9-THC, CBD | 0–50 µg/mL | Cell viability reduction and apoptosis | Fisher et al. (2016) | |
| Human Glioblastoma, U87MG, Glioblastoma patient derived stem cell like cells (GIC) | Δ9-THC, CBD | 0–5 µM | Very significant reduction of the GIC population, induction of apoptosis | López-Valero et al. (2018) | |
| Human Glioma cells, U87MG (U87), A172, SW1783, U373MG (U373), T98G (T98), SW1088, and LN405 | Δ9-THC, CBD, SR141716, SR144528 | 0.9–3 µmol/L | Reduction in cell viability and induction of apoptosis and autophagy | Torres et al. (2011) | |
| Human Glioma cells, GOS3, U87 MG (U87), A172, SW1783, U118 MG (U118), U373 MG (U373), T98G (T98), SW1088, CCF-STTG1 (CCF) and LN405 | Δ9-THC, SR141716, SR144528 | 0–2.5 µM |
Sensitive and resistance cell line determined via reduction in cell viability Increased Mdk expression confers resistance of glioma cells to Δ9-THC pro-autophagic and antitumoural action |
Lorente et al. (2011) | |
| BREAST | Human Breast adenocarcinoma, MDA-MB-231, MCF-7, murine mammary carcinoma, 4T1 | Δ9-THC | 0- 20 µM | No decrease observed in cell viability for all cell lines and low level of cannabinoid receptors | McKallip et al. (2005) |
| Human Breast adenocarcinoma, EVSA-T | Δ9-THC | 3 and 5 µM | Antiproliferative effects rely on JunD activity and participation of p8 | Caffarel et al. (2008) | |
| Human Breast adenocarcinoma, MDA-MB-231, T47D, murine breast cancer, TSAE-1 | Met-F-AEA, SR141716A | 2.5–20 µM | Reduction in cell viability in dose-dependent manner and decrease of tyrosine phosphorylation of FAK and Src | Santoro et al. (2009) | |
| Human Breast adenocarcinoma, MDA-MB-231, T47D, MCF-7 | SR141716 | 0.1–1 µM |
Cell cycle arrest, decreased expression of cyclins D and E Antiproliferative effect requires lipid raft/caveolae integrity to occur |
Sarnataro et al. (2005) | |
| Human Breast adenocarcinoma, EVSA-T, MDA-MB-231, MDA-MB-468, SKBR3, MCF-7, T-47D | Δ9-THC, SR141716, SR144528 | 1–12 µmol/L | Reduction in cell proliferation via the CB2 receptor, cell cycle arrest, induction of apoptosis | Caffarel et al. (2006) | |
| Human Breast adenocarcinoma, MDA-MB-231, MCF-7 | Δ9-THC, CBD, CBG, CBC, AM251, JWH-133, AM630, SR141716A, SR144528 | 0–50 µM | CBD apoptotic effect via activation of the CB2 receptor and TRPV1 | Ligresti et al. (2006) | |
| Human Breast adenocarcinoma, MDA-MB-231, MDA-MB-231-Luc, MDA-MB-468 | WIN 55,212–2, JWH-133, AM251, SR144528 | 0–10 µM |
All cell lines express both CB1 and CB2 receptors Inhibition of cell proliferation and migration via COX-2 signalling and apoptosis |
Hirao-Suzuki et al. (2020) | |
|
Human Breast adenocarcinoma, MDA-MB231 Murine mammary carcinoma, 4T1.2 |
CBD | 1.5 µM | Inhibition of cell proliferation and invasion through modulation of ERK and ROS, downregulation of Id-1 expression and upregulation of Id-2 | Nallathambi et al. (2018) | |
| Human Breast adenocarcinoma, MDA-MB-231, SKBR3, MCF-7, ZR-75–1 | CBD, AM251, AM630, Capazepine | 0–10 µM | Decrease in cell viability, autophagy and apoptosis via ER stress, inhibition of Akt, mTOR signalling | Lin et al. (2019) | |
| Human Breast adenocarcinoma, SUM159, MDA-MB-231-SCP2, MVT-1, murine mammary carcinoma, 4T1.2 | CBD | 3–15 µM | Cell proliferation decreased, inhibition of the epidermal growth factor (EGF)-induced cell proliferation, migration, and invasion | Grimaldi et al. (2006) | |
| Human Breast adenocarcinoma, MCF-7, Murine mammary carcinoma, 4T1 | JWH-015, SR141716, SR144528 | 0–10 µM | Decrease in cell viability, apoptosis and reduced ERK1/2 levels, effects were dependent in a non-Gαi -mediated, calcium-dependency | McAllister et al. (2011) | |
| Human Breast adenocarcinoma, MDA-MB-231 | AEA, AM251 | 0–0.5 µM | Reduction in CD44+/CD24−/low/ESA+ cancer stem cell (CSC) invasiveness | Mohammadpour et al. (2017) | |
| Human Breast adenocarcinoma, MDA-MB-231 | CBDA, GSK0660, GW501516, ST-247 | 1–50 µM | CBDA inhibits PPARβ/δ mediated transcriptional activation and AP-1 | Gazzerro et al. (2010) | |
| Human Breast Cancer, MDA-MB-231, MCF-7 | CBD | 1–50 µM | Co-administration of CBDsol and paclitaxel or docetaxel showed a synergistic effect | Fraguas-Sánchez et al. (2020) | |
| GASTROINTESTINAL | Human Colon cancer, DLD-1, CaCo-2, SW620 | SR141716 | 0.1–20 µM | Reduction in cell proliferation and cell cycle arrest | Aviello et al. (2012) |
| Human Colon adenocarcinoma, Caco-2, HCT 116 | CBG, AM251, AM630, AMTB (TRPM8 antagonist), CBD, CBDV, CBC | 1–50 µM | Apoptosis, increase in ROS production and upregulation of CHOP expression | Borelli et al. (2014) | |
| Human Colorectal carcinoma, DLD-1, HCT116 | CBD BS (botanical substance), CBD, AM630, SR141716, SR144528 | 0.3–5 µM | Antiproliferative effects, no effect on cell viability | Romano et al. (2014) | |
| Human Colorectal cancer, Caco-2 | CBD | 0.1–10 µM | PhysO2 cells significantly more sensitive to antiproliferative effects of CBD than AtmosO2 | Macpherson et al. 2014 | |
| Human Colon cancer, DLD-1 | SR141716 | 0.1–10 µM | Inhibition of cell proliferation at higher concentrations | Gazzerro et al. (2010) | |
| Human Colon cancer, SW480 | CBD, WIN 55,212–2 | 0–15 µM | Induction of cellular ACPP, DUSP1, DUSP10, cleavage of PARP, Apoptosis | De Petrocellis et al. (2013) | |
| Human colorectal carcinoma, Caco-2, HCT116 | CBD, SR141716, AM251, SR144528, AM630, GW9662, Capsazepine | 0.01–10 µM | Reduction in cell viability and expression of phospho-Akt | Aviello et al. (2012) | |
| Human Colon cancer, HCT116, SW48 | SR141716 | 0–20 µM | Inhibition of cell growth, increase of caspase-3 and cleavage of PARP | Proto et al. (2017) | |
|
Human Colon cancer, HCT116 and DLD-1 Organoids |
SR141716 | 0.1–20 µM | Reduction in colon CSCs proliferation and tumour differentiated cells | Fiore et al. (2018) | |
| Human Hepatocellular carcinoma, HepG2, HuH-7 | Δ9-THC, JWH-015, SR141716, SR144528 | 1–8 µM | Reduction in cell viability occurred via CB2 receptor and autophagy | Vara et al. (2011) | |
| Human Hepatocellular carcinoma, BEL7402 | WIN 55, 212–2, AM630, JWH-015 | 0, 5 or 10 µM | CB2 mediated downregulation of phosphorylated ERK1/2 | Xu et al. (2016) | |
| Human Gastric adenocarcinoma, AGS | AEA, Meth-AEA (R- ( +)), CP 55,940 | 0.5–5 µM | Concentration-dependent effects in cell morphology and loss changes | Ortega et al. (2016) | |
| Gastric cancer, SGC7901, AGS cells | WIN 55,212–2 | 5 µM | Inhibition of cell migration, invasion and EMT | Xian et al. (2016) | |
| PROSTATE | Human Prostate Cancer, PC-3 | Δ9-THC, AM251, WIN55,212–2 | 0.5–10 µM | Reduction in cell viability and apoptosis | Ruiz et al. (1999) |
| Human Prostate Cancer, LNCaP, DU145, PC-3 | AEA | 1–10 µM | Decrease of EGFR levels in all cell lines via CB1 leading to an inhibition of EGF-stimulated growth | Mimeault et al. (2003) | |
| Human Prostate Cancer, LNCaP | MET-AEA, HU-210, JWH-015, SR141716, SR144528 | 0.05–5 µM | Involvement of PI3K pathway and modification of androgen receptor expression | Sanchez et al. (2003) | |
| Human Prostate carcinoma, LNCaP, PC3 | WIN-55,212–2, SR141716, SR144528 | 1–30 µM | Induction in p27/KIP1 and downregulation in cyclin and CDK levels. Upregulation of ERK1/2 and inhibition of PI3k/Akt pathways | Sarfaraz et al. (2006) | |
| Human Prostate cancer, LNCaP, 22RV1, DU-145, PC-3 | CBC, CBD, CBG, CBN, CBDA, CBGA, CBDV, CBGV, THC, THCA, THCV, THCVA | 1–10 µM | Decrease in cell viability and activation of the intrinsic apoptotic pathway | De Petrocellis et al. (2013) | |
| Human Prostate adenocarcinoma, PC-3, Primary cultures; BPH, LGG, HGG, PrC | AEA, 2-AG, Methanandamide (AM-356), SR141716 | 2.5, 5 and 10 µM | Cell cycle arrest and induction of apoptosis | Orellana-Serradell et al. (2015) | |
| Human Prostate cancer, LNCaP, PC-3 | WIN 55,212–2, SR141716, SR144528 | 0- 10 µM | WIN prevents neuroendocrine differentiation by downregulation of PI3K/Akt/mTOR signalling | Morell et al. (2016) | |
| LUNG | Human Lung carcinoma, NCI-H292 | Δ9-THC, AEA, HU-210, WIN 55,212–2 | 0.1–10 µM | Increase in cell proliferation dependent on EGFR and MMP | Hart et al. (2004) |
| Human NSCLC, EGF-induced, A549, SW-1573 | Δ9-THC | 1–20 µM | Apoptosis and inhibition of proliferation via EGF-induced phosphorylation of ERK1/2, JNK1/1 and Akt | Preet et al. (2008) | |
|
Human Lung adenocarcinoma, A549, H460 Primary non-small-cell lung carcinoma cells |
CBD, AM251, AM630, Capsazepine, NS-398 | 0–10 µM | Decrease in the viability of the cells and upregulation of COX-2 and PPAR-γ expression, PGE2, PGD2, and 15d-PGJ2 | Ramer et al. (2013) | |
| Human NSCLC; A549 (epithelial), CALU1 (mesenchymal) | JWH-015, SR144528 | 0–5 µM | Decreased migratory and invasive abilities via reduction in FAK, VCAM1, MMP2 | Ravi et al. (2016) | |
| Human Lung cancer; A549 | WIN 55,212–2 | 5–20 µM | Decline in cell viability due to apoptosis | Müller et al. (2017) | |
| BLOOD | Human Leukaemia; CEM (acute lymphoblastic), HEL-92 (erythroblastic), HL60 (acute promyelocytic), MOLT-4 (acute lymphoblastic) and PBMCs | Δ9-THC | 0–100 µM | Cell death via activation of MAPK | Powles et al. (2005) |
| Human Leukaemia, Jurkat, MOLT-4 and murine lymphoma, EL-4 | CBD, SR141716A, SR144528, CAPZ | 0- 10 µM | Significant reduction in cell viability and apoptosis through the CB2 receptor | McKallip et al. (2006) | |
| Human Myeloma, U266, U266-LR7, RPMI, RPMI-LR5, MM1.S, MM1.R | WIN 55,212–2 | 5–50 µM | Apoptosis | Barbado et al. (2017) | |
| Human T acute lymphoblastic leukaemia, Jurkat | CBD | 0.01–10 µM | Reduction in cell viability and cell cycle changes | Kalenderoglu et al. (2017) | |
| SKIN | Melanoma, A375, MelJuso and murine melanoma, B16 | Δ9-THC, WIN-55,212–2, SR141716, SR144528 | 0.5–1 µM | Reduction in cell viability, angiogenesis, and metastasis via CB receptors | Blázquez et al. (2006) |
| Human Melanoma, CHL-1, A375, SK-MEL-28BD | Δ9-THC, CBD | 0–10 µM | Decrease in cell viability | Armstrong et al. (2015) | |
| Murine squamous, non-melanoma skin cancer; JWF2 | AEA, AMG9810, AM251, AM630 | 2.5- 40 µM | Reduction in cell viability and apoptosis via ER stress | Soliman et al. (2016) | |
| Human renal carcinoma, 786-O, SMKT-R2, SMKT-R3, Caki-2, RCC-6, 769-P, Caki-1, ACHN | WIN 55,212–2, JWH-133, SR141716A, AM630 | 0–25 µM | Reduction in cell proliferation and induction of apoptosis | Khan et al. (2018) | |
| Human ovarian cancer, SKOV-3 | CBD | 10–50 µM | Inhibition of cell proliferation | Fraguas-Sánchez et al. (2020) | |
| Rat Adrenal Gland; PC12 cells | DHA-DA, AEA | 0–80 µM | NOS activation, increased Ca2+ signalling leading to apoptosis via GPR55 activation | Akimov et al. (2021) |
MET-AEA (methanandamide, non-hydrolyzable analogue of AEA), AEA (anandamide), DHA-DA (N-docosahexaenoyl dopamine), AM251 (CB1 antagonist), HU-210 (CB1 agonist), JWH-015 (CB2 agonist), JWH-133 (CB2 agonist), WIN 55,212–2 (CB1 agonist), SR141716 (CB1 inverse agonist), SR144528 (CB2 inverse agonist), N-oleoylethanolamine (NOE) (acidic ceramidase inhibitor), LY294002 (PI3K inhibitor), PD98059 (ERK inhibitor), PBMCs (peripheral blood mononuclear cells), AM630 (CB2 antagonist), GW9662 (PPAR-γ antagonist), GSK066 (PPARβ/δ antagonist), GSK501516 (PPARδ antagonist), AMG9810 (TRPV1 antagonist)