. 2020 Apr 5;19(9):961–989. doi: 10.1080/15384101.2020.1742952

Table 2.

The effect of various cannabinoids on cancer cells in vitro and in vivo.

Cancer type/Compound	Experiment details	Dose	Exposure time	Method/effect	Potential mechanism	Reference
Glioblastoma
CBD	U87, U373	IC50 25 µM	24 h	cell viability by MTT, apoptosis	ROS activation	Massi et al. [103]
	U87 xenograft of athymic nude mice	0.5 mg/mouse	18 d	70% reduction of tumor growth		Massi et al. [103]
CBD	U87	IC50 5 µM	6 h	cell migration by Boyden chamber	likely independent of CB1, CB2, TRPV1	Vaccani et al. [95]
CBD	U251	IC50 0.126 µM	3 d	cell migration by Boyden chamber		Marcu et al. [145]
CBD	U87	25 µM	14 h	caspase activity, CaspACE Assay	activation of caspases 3, 8 and 9; glial cells not affected (concentrations up to 50 µM) – no ROS production, no increased GSH	Massi et al. [119]
		25 µM	10 h	ELISA assay for cytochrome C	cytochrome c activation	Massi et al. [119]
		25 µM	5 h	DCFH-DA, apoptosis	ROS activation	Massi et al. [119]
CBD	U87			tumor growth, 5-LOX measurement, luekotriene B4 measurement	5-LOX activation	Massi et al. [104]
	U87 xenograft of athymic nude mice	0.5 mg/mouse	23 d	AEA and FAAH measurement	AEA degradation through FAAH; ↑ FAAH activity in vivo	Massi et al. [104]
CBD	U251	1 µM	3 d	invasion assay, western blot	Id1 downregulation ↑ mTOR, reduced PLCG1	Soroceanu et al. [96]
	primary tumor-derived cultures	1-1.5 µM	48 h	neurosphere formation	¯Sox2	Soroceanu et al. [96]
	U251 xenograft of athymic nude mice	15 mg/kg	4 w	tumor growth/95% reduction	downregulated Id-1	Soroceanu et al. [96]
CBD	glioma stem cell (GSC) line 3832	IC50 3.5 µM		cell viability	ROS activation	Singer et al. [99]
	glioma stem cell (GSC) line 387	IC50 2.6 µM		cell viability	ROS activation	Singer et al. [99]
	GSC3832 and 387 xenografts	15 mg/kg	3-4 w	tumor growth, induced apoptosis	inhibited pAKT and Ki67, stimulated caspase-3, inhibits Id1 and Sox2	Singer et al. [99]
CBD	SF126	IC50: 1.2 µM	3 d	cell viability	Reduced Id1	Marcu et al. [145]
	U251	IC50: 0.6 µM	3 d	cell viability	Reduced Id1	Marcu et al. [145]
	U87	IC50: 0.6 µM	3 d	cell viability	Reduced Id1	Marcu et al. [145]
CBD	T98 G, U87 MG, GL261	5.2–11.0 µM	3 d	decreased cell viability	autophagy	Scott et al. [101]
CBD-rich extract	T98 G, U87 MG, GL261	10.0–11.0 µM	3 d	decreased cell viability	autophagy	Scott et al. [101]
Δ9-THC	U87 MG	IC50: 1.5 µM	3 d	cell viability (MTT)	autophagy and apoptosis	Torres et al. [128]
Δ9-THC	C6.9 glioma xenograft in mice	500 µg/d THC	8 d	Inhibition of tumor growth	Downregulation of MMP-2	Blasquez et al. [130]
Δ9-THC	2 glioblastoma multiforme patients	1.29 or 1.46 mg/day	30 and 26 d	Inhibition of tumor growth	Downregulation of MMP-2	Blasquez et al. [130]
Δ9-THC	T98 G, U87 MG, GL261	12.0–14.0 µM	3 d	decreased cell viability	autophagy	Scott et al. [101]
Δ9-THC	U87 MG	6.0 µM	8 h	Increased autophagy	ER stress pathway: upregulation of p8 and TRB3; inhibition of Akt and mTORC via TRB3 (this triggers autophagy)	Salazar et al. [124]
Δ9-THC	U87 MG xenografts	15 mg/kg/d		increases autophagy	increases TRB3 expression, decreases S6 phosphorylation, active caspase-3 increased	Salazar et al. [124]
Δ9-THC	T98 G, U87 MG, GL261	2–4 µM	72 h	Cell viability	Increased Mdk and amphiregulin	Lorente et al. 2009 [189], Lorente et al. 2011 [190]
Δ9-THC	SF126	IC50: 2.5 µM	3 d	cell viability	Reduced Id1	Marcu et al. [145]
	U251	IC50: 3.3 µM	3 d	cell viability	Reduced Id1	Marcu et al. [145]
	U87	IC50: 3.3 µM	3 d	cell viability	Reduced Id1	Marcu et al. [145]
Δ9-THC	U251	IC50 85 nM	3 d	cell migration by Boyden chamber		Marcu et al. [145]
THC-rich extract	T98 G, U87 MG, GL261	11.0–13.0 µM	3 d	decreased cell viability	autophagy	Scott et al. [101]
Δ9-THC:CBD	U251	0.1:0.1 µM		cell migration by Boyden chamber	No increase over THC or CBD alone	Marcu et al. [145]
Δ9-THC:CBD	U251	0.4 µM: 1.7 µM	3 d	apoptosis, downregulation of pERK	PARP, increased ROS and caspases 3, 7, 9 activity	Marcu et al. [145]
Δ9-THC:CBD	U87 MG	0.7:0.7 µM	72 h	decreased cell viability	enhanced apoptosis and autophagy	Torres et al. [128]
	T98 G	1.2:1.2 µM	72 h	decreased cell viability	enhanced apoptosis and autophagy	Torres et al. [128]
	HG19	2.4:2.4 µM	72 h	decreased cell viability	enhanced apoptosis and autophagy	Torres et al. [128]
Δ9-THC:CBD	U87 MG xenograft	7.5:7. 5 mg/kg/d	6d	Reduction of tumor growth	Combo effect was stronger	Torres et al. [128]
Δ9-THC:CBD	T98 G	10.0:10.0 µM	4 h	pERK	Increase in pERK	Torres et al. [128]
Δ9-THC+TMZ	U87 MG	IC50: THC (1.8 µM):TMZ (100 µM)	3 d	cell viability (MTT)	autophagy and apoptosis	Torres et al. [128]
Δ9-THC+CBD+TMZ	U87 MG	0.9:0.9:75.0 µM	72 h	decreased cell viability	enhanced apoptosis and autophagy	Torres et al. [128]
	T98 G	1.1:1.1:200.0 µM	72 h	decreased cell viability	enhanced apoptosis and autophagy	Torres et al. [128]
Δ9-THC+CBD+TMZ	U87 MG xenograft	3.7:3.7:5.0 mg/kg/d		reduction in tumor growth	enhanced apoptosis and autophagy	Torres et al. [128]
Δ9-THC+TMZ	T98 G xenograft	15.0: 5.0 mg/kg/d		reduced tumor growth	caspase 3 activation	Torres et al. [128]
THC:CBD:Radiation	T98 G, U87 MG, GL261	10.0:10.0 µM: 5 Gy	4 h + 1 h	decreased cell viability	Decrease in pAKT2, pERK, Increased gamma-H2AX	Scott et al. [101]
THC:CBD:Radiation	GL261 xenograft	4 mg/kg; 100.0:100.0 µM: 5 Gy		Decreased tumor growth, increased apoptosis and angiogenesis	Caspase 3 activation	Scott et al. [101]
WIN-55,212-2	C6.9 glioma	EC50: 14.7 µM	48 h	decreased cell viability	Down-regulation of ERK1/2 and inhibition of AKT, activation of caspase 9	Ellert-Miklaszewska et al. [131]
JWH-133	C6.9 glioma xenograft in mice	50 µg/day	8 d	Inhibition of tumor growth	Downregulation of MMP-2	Blasquez et al. [130]
KM-233	U87 MG	12 mg/kg/d	20 d	80% reduction of tumor	Change in phosphorylation profiles of MEK, ERK1/2, Akt, BAD, STAT3, and p70S6 K in U87 MG human GBM cells	Gurley et al. [168]
Human Leukemia
CBD	EL-4 cells (mouse lymphoma)	2.5–10.0 µM	24 h	decreased cell viability	Enhanced apoptosis, CB2 mediated	McKallip et al. [105]
	Jurkat cells	5.0 µM	24 h	decreased cell viability	Decreased PARP, CB2 mediated	McKallip et al. [105]
	MOLT-4 cells	2.5 µM	24 h	decreased cell viability	Increased caspases, decreased PARP, increased cytochrome c, increased ROS, increased Nax4, p22	McKallip et al. [105]
	EL-4 xenograft	12.5 or 25 mg/kg		Decreased tumor growth	Apoptosis	McKallip et al. [105]
CBD	HL60	IC50: 8.0 µM	48 h	decreased cell viability	Enhanced apoptosis	Scott, Dalgleish, & Liu [147]
Δ9-THC	HL60	IC50: 13.0 µM	48 h	decreased cell viability	Enhanced apoptosis	Scott, Dalgleish, & Liu [147]
Δ9-THC	CEM, HL60, MOLT4	IC50: CEM – 18 µM; HL60 – 14.0 µM; MOLT4 – 33.0 µM	24 h	increased apoptosis	Reduced pERK	Liu et al. [143]
Δ9-THC	CEM	1 µM		↑ sensitivity to chemotherapeutic agents (increased effect of cytarabine, doxorubicin, and vincristine)	Reduced pERK	Holland et al. [106]
Δ9-THC or CBD	CCRF-CEM (leukemia), CEM/VLB100 (multidrug resistant)	10 µM	72 h	↑ cytotoxic effects of vinblastine (reduced IC50 of vinblastine by 3 fold in resistant cells)		Holland et al. [106]
Δ9-THC or CBD	CEM/VLB100 cells	10 µM	72 h	↑ P-glycoprotein substrate accumulation	↓ P-glycoprotein expression	Holland et al. [106]
Δ9-THC:CBD	HL60	IC50: 4.0 + 4.0 µM	48 h	decreased cell viability	Enhanced apoptosis	Scott, Dalgleish, & Liu [147]
Human Lung Cancer
CBD	A549	0.1–10 µM	24 – 72 h	↓invasion	increased TIMP1 expression	Ramer et al. [108]
	A549 xenograft	5 mg/kg	28 d	↓metastasis	84% inhibition of metastasis	Ramer et al. [108]
CBD	A549, H460, H358	from 0.1 µM	48 – 72 h	↓invasion	↓PAI-1 secretion	Ramer et al. [109]
	A549 xenograft	5 mg/kg	42 d	↓tumor growth	↓PAI-1 expression	Ramer et al. [109]
CBD	A549, H460	IC50: A549 – 3.47 µM; H460 – 2.80 µM	2-48 h	decreased cell viability	↑ PPARgamma, COX-2, PGE2, PGD2, 15d-PGJ2	Ramer et al. [107]
	primary tumor-derived cells	IC50 0.124 µM			increased PPARgamma, COX-2	Ramer et al. [107]
	A549 xenograft	5 mg/kg	72 d	reduced tumor volume	increased PPARgamma, COX-2 mRNA	Ramer et al. [107]
CBD	MDA-MB231 and MDA-MB436	IC50: 1.3 and 1.6 µM	3 d	decreased cell viability, decreased cell migration (Boyden chamber)	Decreased Id1 expression	McAllister et al. [116]
Δ9-THC	MDA-MB231 and MDA-MB436	IC50: 1.2 and 2.5 µM	3 d	decreased cell viability, decreased cell migration (Boyden chamber)	Decreased Id1 expression	McAllister et al. [116]
Δ9-THC	A549, SW-1573	up to 20 µM	24 h	no effect on cell viability		Preet et al. [141]
Δ9-THC	A549, SW-1573	up to 20 µM	72 h	induced apoptosis and inhibited proliferation	inhibiting the EGF-induced phosphorylation of ERK1/2, JNK1/2 and AKT	Preet et al. [141]
Δ9-THC	A549, SW-1573	10 µM	72 h	inhibited migration	inhibiting the EGF-induced phosphorylation of ERK1/2, JNK1/2 and AKT	Preet et al. [141]
Δ9-THC	A549 xenograft	5 mg/kg	28 d	50-60% reduction in tumor growth		Preet et al. [141]
CBN	Lewis lung adenocarcinoma	50 mg/kg	20 d	increased animal survival		Manson et al. [149]
Human breast cancer
CBD	MDA-MB231	1.5 µM	3 d	↓ invasion, ↓ metastasis	↑ ROS, ↓ Id1, ↑ pERK	McAllister et al. [97]
	4T1	IC50: 1.5 µM				McAllister et al. [97]
	4T1 xenograft	1 mg/kg	15 d	decreased cell proliferation	↓ G1/S transition, Id1	McAllister et al. [97]
	4T1 xenograft	1 or 5 mg/kg	15 d	reduced primary tumor growth and metastasis		McAllister et al. [97]
CBD	MCF-7 and ZR-75-1 (estrogen receptor +); SK-BR-3 (ER -)	0–10 µM	24 h	↓ cell viability	Increased apoptosis, cytotoxicity seems to be independent of CB1, CB2, and TRPV1 receptors	Shrivastava et al. [98]
	MDA-MB-231	5–7.5 µM	16 h	↓ cell viability	↓ pAKT, ↓mTOR, ↓4EBP1, ↑PARP, ↑caspases, ↑t-Bid translocation (internal stimuli)	Shrivastava et al. [98]
CBD	MDA-MB-231, 4T1	IC50: 1.8–1.9 µM	3 d	decreases cell proliferation	↑ ROS, ↑ apoptosis, ↓ Id1	Murase et al. [113]
CBD	4T1 xenograft	0.3–1.0 mg/kg	6 w	↓ cell viability, ↓ advanced stage metastasis		Murase et al. [113]
CBD	SUM159, SCP2	9 µM	48 h	↓ cell proliferation, ↓ colony formation, ↓ migration	↓ Nf-kB, ↓pEGFR, ↓pAKT	Elbaz et al. [112]
	4T1 and MVT-1 xenografts	10 mg/kg	3 w	inhibited tumor growth, angiogenesis and metastasis	decreased proliferative activity, vessel formation and p‐EGFR expression, lower activation of AKT, and ERK proteins	Elbaz et al. [112]
CBD	MCF-7	IC50: 8.2 µM	4 d	decreases cell proliferation	Activation of CB and TRPV1 receptors	Ligresti et al. [153]
CBD-rich extract	MCF-7	IC50: 6.0 µM	4 d	decreases cell proliferation		Takeda et al. [151], Watanabe et al. [150]
CBC	MCF-7	IC50: 14.2 µM	4 d	decreases cell proliferation		Ligresti et al. [153]
CBG	MCF-7	IC50: 9.8 µM	4 d	decreases cell proliferation		Ligresti et al. [153]
CBG	MDA-MB231 and MDA-MB436	IC50: 2.3 and 2.1 µM	3 d	decreased cell viability, decreased cell migration (Boyden chamber)	Decreased Id1 expression	McAllister et al. [116]
CBN	MDA-MB231 and MDA-MB436	IC50: 1.2 and 2.6 µM	3 d	decreased cell viability, decreased cell migration (Boyden chamber)	Decreased Id1 expression	McAllister et al. [116]
Δ9-THC	MCF-7	EC50: 26.0 µM		inhibited 17beta-estradiol-induced proliferation		von Bueren et al. [136]
Δ9-THC	MCF-7	5 µM	72 h	decreases cell proliferation	blocks of the G2-M transition; upregulates JunD	Caffarel et al. [137], Caffarel et al. [138]
Δ9-THC	MMTV-neu – Erb overexpressing mice	0.5 mg/animal/day	3 m	Decreased tumor growth and metastases	Downregulation of Act1 and Erb2	Caffarel et al. [125]
Δ9-THC	MCF-7	IC50: 14.2 µM	4 d	decreases cell proliferation		Takeda et al. [151], Watanabe et al. [150]
THC-rich extract	MCF-7	IC50: 21.0 µM	4 d	decreases cell proliferation		Takeda et al. [151], Watanabe et al. [150]
CBN	MCF-7			stimulated proliferation	HER2 upregulated	Takeda et al. [151], Watanabe et al. [150]
JWH-015	MCF-7, MDA-MB-231	20 µM	12 h	↓ metastasis (hormone-sensitive breast cancer)	Inhibits CXCL12/CXCR4 signaling	Nasser et al. [163]
AEA	MCF-7	IC50: 1.4 µM	4 d	decreases cell proliferation	Via activation of CB1 receptor	Melck et al. [133]; Melck et al. [135]
AEA	MCF-7	IC50: 1.0 µM	3 d	decreases cell proliferation	Blocks transition from G1 to S	De Petrocellis et al. [134]
O-1663	MDA-MB-231, 4T1	IC50: 0.83–0.85 µM		decreases cell proliferation	More efficient than CBD in upregulating Id2 and survival, ↑autophagy	Murase et al. [113]
O-1663	4T1 xenograft	0.3–1 mg/kg	6 w	↑ survival	More efficient than CBD in upregulating Id2 and survival, ↑autophagy	Murase et al. [113]
JWH-018, JWH-073, JWH-122, JWH-210	MCF-7	2–23 µM	3 d	Anti-estrogenic properties in MCF-7 cells		Koller et al. [165]
WIN55, 212–2 and JWH-133	MDA-MB-231	10 µM	24 h	decreases cell proliferation	Block G1 to S phase transition through COX-2/PGE-2 signaling pathway	Qamri et al. [157]
Human cervical cancer
CBD	HeLa, C33A	10 µM	24 h	↓ invasion	induces TIMP1	Ramer et al. [108]
CBD	HeLa	10 µM	24 h	decreases cell proliferation, increases apoptosis	Apoptosis: increased subG0/G1 and annexin V	Lukhele & Motadi [117]
Human prostate cancer
CBD, THC, CBG, CBC, CBN	LNCaP and DU-145	IC50: 15–25 µM	16 h	↓ cell viability	↓ IL-8, G1/S transition ↑ calcium, ROS, p53, p21, PUMA, tunel, CHOP, calcium	De Petrocellis et al. [118]
CBD, THC, CBG, CBC, CBN enriched cannabis extracts	LNCaP and DU-145	IC50: 6–15 µM	16 h	↓ cell viability		De Petrocellis et al. [118]
CBD + bicalutamide	LNCaP and DU-145 xenografts	25 mg/kg	4-5 w	↓ tumor growth		De Petrocellis et al. [118]
CBD, CBG, THC, CBC	DU-145	IC50: 20–50 µM	4 d	decreases cell proliferation	Activation of CB and TRPV1 receptors	Ligresti et al. [153]
anandamide, HU210, 2-AG	DU-145	IC50: 0.1–0.3 µM	3 d	Decreased proliferation	inhibits NGF, Trk, PRLr receptor expression	Melck et al. [133]
Human melanoma
Δ9-THC	CHL-1, A375	5 µM	48 h	↓ cell viability	↑ autophagy	Armstrong et al. [146]
Δ9-THC	CHL-1 xenograft	15 mg/kg	20 d	↓ tumor growth	↑ apoptosis	Armstrong et al. [146]
Δ9-THC+CBD	CHL-1, A375	1 µM + 1 µM	48 h	↓ cell viability	↑ apoptosis	Armstrong et al. [146]
Δ9-THC rich extract	CHL-1 xenograft	7.5 mg/kg	20 d	↓ tumor growth		Armstrong et al. [146]
WIN-55, 212–2 or JWH-133	B16 xenograft	50–120 mg/kg	8-12 d	reduced malignant tumors	G1 cell cycle arrest via p-Akt inhibition and hypophosphorylation of the pRb retinoblastoma protein tumor suppressor	Blazquez et al. [158]
WIN-55, 212–2 or JWH-133	B16	0.1–1 µM	48 h	Anti-proliferative effect in epidermal cell lines (PDV.C57 and HaCa4)	G1 cell cycle arrest via p-Akt inhibition and hypophosphorylation of the pRb retinoblastoma protein tumor suppressor	Blazquez et al. [158]
Human Pancreatic Cancer
Δ9-THC	MIA PaCa2	2 µM	66 h	decreases cell proliferation	CB2 receptor and ceramide-dependent upregulation of p8 and ATF-4 and TRB3	Carracedo et al. [132]
Δ9-THC	MIA PaCa2 xenograft	15 mg/kg	15 d	↓ tumor growth	↑ apoptosis, increased TRB3 expression	Carracedo et al. [132]
JWH	MIA PaCa2 xenograft	1.5 mg/kg	15 d	↓ tumor growth	↑ apoptosis, increased TRB3 expression	Carracedo et al. [132]
ACEA, AM251, JWH-015, AM630	MiaPaCa2	8.6–19.2 µM	72 h	decreases cell proliferation	Receptor-independent; induced apoptosis; activation of JAC-STAT pathway	Fogli et al. [171]
Oral cancer
Δ9-THC, smoking cannabis	OSCC			Induced apoptosis in oral squamous cell carcinoma		Lopes et al. [140]
Thyroid carcinoma
JWH-133, WIN-55,212-2	ARO	1-2 µM	24 h	Increased apoptosis	Induced apoptosis in ARO (anaplastic thyroid cancer cell line) and ARO-IL2 cells	Shi et al. [159]
JWH-133, WIN-55,212-2	ARO xenograft	50 µg/ml in 50 µl	60 d	↓ tumor growth		Shi et al. [159]
Met-F-AEA	ARO, NPA	5 µM	72 h	Cell growth inhibition	Activation of p53 and p21 mediated pathway	Cozzolino et al. [155]
Bone cancer
WIN55,212-2	NCTC-2472 xenograft	0.5 mg/kg	18 d	Increased apoptosis		Hald et al. [160]
AM1241	NCTC-2472 xenograft	3 mg/kg	10-14 d	Reduction in bone loss; reduced pain		Lozano-Ondoua et al. 2010
JWH-015	66.1 cells xenograft	6 mg/kg	18 d	Increased survival, decreased tumor-associated pain	Cytokine/chemokine suppression (of a mammary cell line implanted into the femur intermedullary space)	Lozano-Ondoua et al. [166]
Lymphoma
Win-55,212-2	MCL	5 µM	24 h	Decreases cell viability		Flygare et al. [142]
AEA	MCL	5 µM	24 h	Decreases cell viability		Flygare et al. [142]
Δ9-THC	CEM, HL60, MOLT4	1 µM	72 h	Induced apoptosis	MAPK/ERK pathway; reduces phosphorylated ERK expression; sensitizes to cytotoxic agents	Liu et al. [143]
R(+)-methanandamide and WIN-55,212–2	MCL	10 µM	4 h	Induced apoptosis	Associated with ceramide accumulation and p38, depolarization of the mitochondrial membrane, and caspase activation	Gustafsson et al. [162]
Win-55,212-2	MCL	1.5–5.0 µM	48 h	Paraptosis-like cell death		Wasik et al. [161]
Colorectal Cancer
CBG	HCT 116 xenograft	3-10 mg/kg	10 d	Inhibits tumor growth	Likely via TRPM8 (CBG is an antagonist) (CB2 antagonists enhance the effect of CBG on cell viability)	Borrelli et al. [152]
	Caco-2 and HCT 116	10 µM	6-24 h	Decreases cell viability	Increased ROS	Borrelli et al. [152]