A Narrative Review of the Antitumor Activity of Monoterpenes from Essential Oils: An Update

Table 1

Essential oil monoterpenes with antitumor activity.

Compound	Antitumor activity and/or mechanism	Animal/cell line tested	IC50, % reference growth inhibition, dose, or selectivity	Reference
1,8-Cineole	Active (apoptosis and negligible necrotic effect)	A2780 (ovary cancer cells) and MRC5 (nontumorigenic human fetal lung fibroblasts)	0.26 μg/mL and 10.50 μg/mL (IC50), selective	[17]
	Active (cell cycle arrest and inhibition cell migration)	A549 (lung adenocarcinoma cells) and WI-38 (normal human embryonic lung fibroblasts)	8.30 μg/mL, 5.84 μg/mL, and >10 μg/mL (IC50), selective	[19]
	Active (changes in mitochondrial membrane potential, apoptosis, and cell cycle arrest)	A431 (skin carcinoma) and HaCaT (human keratinocytes) cell lines	30 μg/mL (IC50), selective	[18]
α-Phellandrene	Active (altered gene expression)	WEHI-3 (mouse leukemia cells)	10 μM^a	[101]
	Active (reduced spleen weight, affected surface markers, increased macrophage phagocytosis, natural killer cell activity, and B- and T-cell proliferation)	Balb/c mice with mouse leukemia WEHI-3 cell injection	0, 25, and 50 mg/kg^b	[102]
	Active (increase in reactive oxygen species, decrease in mitochondrial membrane potential levels, increase in the necrotic cell number, NO production, LDH leakage, and ATP depletion)	J5 (human liver tumor cells)	~30 μM (IC50)	[100]
α-Pinene	Active (inhibition of cell growth; upregulation of Chk1 and Chk2 levels, and downregulation of Cyclin B, CDC25, and CDK1 levels; inhibition of tumor cell growth in vitro and in vivo; reduction of the average tumor size and the average tumor weight)	BEL-7402 (liver cancer cell) in vitro and balb nude mice	0.5-0.125 mg/L^a; 2.67 mL/kg^b; 79.3% (in vitro inhibitory rate) and 69.1%^c;	[110]
			~70%^c
	Active (inhibition of the cell cycle and apoptosis)	PA-1 (cancer cells of the human ovary)	20 μg/mL (IC50), 5-100 μg/mL^a	[33]
	NA (prevention of UVA-induced cytotoxicity)	HaCaT (human skin epidermal keratinocytes)	30 μM^a	[35]
	Active (apoptosis)	H460 and A549 non-small-cell lung cancer cell lines)	0.21 and 36.0 μM (IC50), 2.5-20.0 μM, and 0.0125-0.4 mg/mL^a	[23]
	Active (cell cycle arrest, apoptosis, and oxidative stress)	HepG2 (liver cancer cells), MCF-7 (breast cancer cells), A549 (lung cancer cells), and PC-12 (neuroma cancer cells)	~100-1500 μmol/L (IC50), 0-64 μmol/L^a	[34]
α-Thujone	Active (expression of CD107a, p-Akt, and p-ERK1/2)	HCT116 (human colon cancer cell line), SW620 (colon cancer cell line), and CD3AK (anti-CD3 antibody induced activated killer)	~0.01-0.15 μmol/L (IC50), 0-37.5 μmol/L^a	[20]
	Active (apoptosis, inhibition of cell motility, oxidative stress, autophagy, and cell necrosis)	T98G and U87 (human glioblastoma multiforme cells) and C8-D1A (mouse astrocytes)	250 and 500 μg/mL (IC50), 100-500 μg/mL, and 660 μM–3.2 mM^a	[21]
Borneol	Active (“upper guiding drug”: guide luteolin in the ubiquitin-proteasome pathway and the ubiquitin-signal autophagic degradation)	Purification of 26S or 20S proteasome from pig red blood cells (RBCs) and HepG2 (hepatocellular carcinoma cells)	>1000 μM (IC50), 100 and 500 μM^a	[37]
	Active (cell cycle arrest, production of reactive oxygen species, and DNA damage)	HepG2 (hepatocellular carcinoma cells) and L02 (normal liver cell lines)	>60 μg/mL (IC50), 10-80 μg/mL^a, selective	[36]
	Active (cell cycle arrest, DNA damage, ROS production, enhanced dysfunction of MAPKs and PI3K/AKT pathways, and xenograft growth in vivo)	U251, U87 (human glioma cells), and HUVECs (human umbilical vein endothelial cells)	80 μg/mL (IC50), 20-80%^c	[38]
	Active (apoptosis, ROS production, and DNA damage)	U87 and U251 (human glioma cells) and HUVECs (human umbilical vein endothelial cells)	~40 μg/mL (IC50), 5–80 μM^a	[39]
Bornyl acetate	Active (apoptosis, DNA fragmentation, and G2/M cell cycle arrest)	SGC-7901 (human gastric cancer cells)	~48 μM (IC50), 0-96 μM^a	[22]
β-Pinene	Active (altered cell morphology, pyknotic nuclei, membrane blebs and cell shrinkage, and activated caspases)	SCC9 and SCC25 (human oral tongue cancer cells) and primary normal human gingival fibroblast	~67 μg/mL (IC50), selective	[16]
Camphene	Active (apoptosis, loss of mitochondrial membrane potential, and inhibition of tumor growth)	B16F10-Nex2 (murine melanoma cell line), A2058 (melanoma cell line), SKBR-3 (breast cancer cell line), HeLa (cervical cancer cell line), HL-60 (human myeloid leukemia cell line), U87-MG (human glioblastoma cell line) in vitro, and C57Bl/6 mice	~27 and 110.1 μg/mL (IC50), 0100 μg/mL^a, 10 mg/kg^b, and 60%^c	[42]
Carvacrol	Active (alteration in soluble factors)	HCT-116 and HT-29 (human colorectal carcinoma)	42 and 92 μM (IC50), 25–200 μM^a	[50]
	Active (apoptosis and DNA damage)	AGS (human gastric adenocarcinomas), WS-1 (normal human fibroblast cells) in vitro and Wistar rats with oral gavage application of carvacrol	82.57 μM (IC50), 0–600 μM^a, and 100 mg/kg^b	[43]
	Active (ERK1/2-independent suppression of apoptosis and ERK1/2-dependent modulation of autophagy)	HeLa (human cervical cancer cell)	556 μM (IC50), 550 μM^a	[49]
	Active (ROS production and apoptosis)	A549, PC-9 (human lung adenocarcinoma), BEAS-2B (normal bronchial epithelium cells) in vitro, and athymic nude mice with xenografting of A549 cells	100 μg/mL (IC50), 25–150 μg/mL^a, 50 and 100 mg/kg^b, 34.2%, and 62.1%^c	[44]
	Active (downregulation of AXL expression, inhibited phosphorylation of AXL, and suppressed cell proliferation and migration)	A549 (human lung adenocarcinoma) and H460 (human lung cancer cells)	~100 and 300 μM (IC50), 0-300 μM^a	[51]
	Active (apoptosis, reactive oxygen species generation, disruption in the mitochondrial membrane potential, and cell cycle arrest)	DU145 (human prostate cancer cells) and J774A.1 (normal mouse macrophage cells)	~50 and 100 μM (IC50), 10-500 μM^a	[45]
	Active (inhibits proliferation and migration, cell cycle arrest, and apoptosis)	HCT116 and LoVo (human colon cancer cell lines)	530.2 and 544.4 μmol/L (IC50), 200–900 μmol/L^a	[46]
	Active (suppressed the elevation of serum tumor marker enzymes, carcinoembryonic antigen, and α-feto protein and inhibited the cell proliferation)	Wistar albino rats with induction of hepatocarcinogenesis	15 mg/kg^b	[52]
	NA (carvacrol has nonmutagenic and antioxidant features and decreased cell viability at high doses)	Human blood cells	0-200 mg/L^a	[53]
	Active (apoptosis, collapse of mitochondrial membrane potential, generation of free radicals, and depletion of the intracellular antioxidant pool)	HL-60 (human acute promyelocytic leukemia cells) and Jurkat (T lymphoma cells)	50 μM and 100 μM (IC50), 0–200 μM^a	[47]
	Active (apoptosis, production of reactive oxygen species (ROS), mitochondrial membrane potential disruption, and prevented cell cycle in G0/G1)	PC-3 (prostate cancer cell line)	39.81 and 46.71 μM (IC50), 10-500 μM^a	[48]
Carvone	Active (increased the total antioxidant capacity levels and increased the total oxidative stress levels)	Primary rat neuron cultures and rat brain NB cell line N2a	>400 mg/L (IC50), 10-400 mg/L^a	[24]
	Active (synergistic anticancer action with doxorubicin)	MCF 7 (invasive breast ductal carcinoma), H9C2 (normal cardiomyocyte) in vitro, and BALB/c (Bagg albino) mice	14.22 μM (IC50), 6.25 μM-100 μM^a, and 75 and 150 mg/kg^b	[27]
	Active (apoptosis)	Swiss albino mice with skin T tumorigenesis	20 mg/kg^b, prevented tumor occurrence	[28]
	Active (inhibited the cell migration, apoptosis, cell cycle arrest, DNA damage, and ROS)	MCF 7 and MDA MB 231 (breast cancer cell lines) and MCF 10A (nontumorigenic epithelial cell line)	1.0 and 1.2 mM (IC50), 0-10 and 20 mM^a	[25]
	Active (apoptosis, cell cycle arrest, and inhibited the cell invasion and expression of p-P38 protein)	KMS-5 (human myeloma cell line)	20 μM (IC50), 0-100 μM^a	[26]
Citral	Active (arrested the cell migration, regulated several genes, and apoptosis)	AGS (human gastric adenocarcinomas) and MRC-5 (human lung normal cell lines)	~7.5 μg/mL (IC50), 7.5-200 μg/mL^a	[54]
	Active (apoptosis)	MDA-MB-231, MDA-MB-468, and SKBR3 (breast cancer cell lines) in vitro and NOD/SCID female mice with MDA-MB-231 vector control or ALDH1A3 overexpression cells	100 mM^a, 0.4 mg/kg^b	[58]
	Active (impaired the clonogenic property of the cancer cells, suppressed lipogenesis and apoptosis)	PC-3 and PC3M (prostate cancer cells) and MRC-5 (human fetal lung fibroblast cell line)	10 and 12.5 μg/mL (IC50), 0-100 μg/mL^a	[55]
	Active (inhibited the enzyme activity and the cell proliferation)	MCF-7 (breast cancer cell line), human embryonic (fetal) kidney, and HEK-293 cell lines	172 μM (IC50), 0-400 μM^a, selective	[59]
	Active (apoptosis, reduced the mitochondrial membrane potential, elevated intracellular ROS level, and cell cycle arrest)	HCT116 and HT29 (colorectal cancer cell lines) and CCD841-CoN (normal colon cells)	52.63-181.21 μg/mL (IC50), 3.12–200 μM^a	[56]
	Active (apoptosis)	Ramos (human Burkitt’s lymphoma cell line) and PBMCs (normal human peripheral blood mononuclear cells)	77.19 μM (IC50), 0–160 μM^a, selective	[57]
	Active (reduction the size and number of cells with ALDH+ activity of the tumors in 4T1-challenged BALB/c mice and delayed tumorigenicity)	BALB/c mice with 4T1 breast cancer cells	50 mg/kg^b, 50%^c	[60]
Citronellol	Active (upregulation of TNF-α pathway and increase in reactive oxygen species production)	NCI-H1299 (non-small-cell lung cancer) in vitro and in nude mice subcutaneous tumors	49.74 μg/mL (IC50), selective, 50 mg/kg^b, and 80%^c	[61]
	Active (oxidative damage and modulation of the expression of apoptotic proteins)	MCF-7 and MDA-MB-231 (human mammary tumor cells)	35 and 80 μM (IC50)	[62]
Cuminaldehyde	Active (inhibition of topoisomerase I and II activities)	COLO 205 (human colorectal adenocarcinoma cells) in vitro and in nude mice subcutaneous tumors	16.31 μM (IC50), 20 mg/kg^b, and 69.4%^c	[93]
	Active (inhibition of telomerase, topoisomerase I and II activities)	A549 (human lung adenocarcinoma cells) in vitro and in nude mice subcutaneous tumors	18.33 μM (IC50), 10 or 20 mg/kg^b, and 50%^c	[94]
p-Cymene	Active (inhibition of MMP-9 expression and increase of TIMP-1 production)	HT-1080 (human fibrosarcoma cells)	200-600 μM^a	[103]
Dehydroperillic acid	Active (inhibition of DNA synthesis)	A549 and HepG2 (human lung adenocarcinoma and hepatocellular carcinoma cells)	125 and >500 μg/mL (IC50), and 100	[79]
Fenchone	Active (cell cycle arrest)	Ehrlich carcinoma cell line in the peritoneal cavities of mice	60 mg/kg^b, ~90%^c	[95]
Geraniol and geranyl acetate	Active (apoptosis, DNA damage, and cell cycle arrest)	Colo-205 (colon cancer cells)	20 and 30 μM (IC50)	[63]
Geraniol	Active (downregulation of the activation of NF-κB)	4NQO-induced tongue carcinogenesis in rats	ND	[64]
	Active (downregulation of E2F8)	PC-3 (prostate cancer cells)	1 mmol/L^a	[65]
	Active (inhibition of the mevalonate pathway)	A549 (human lung adenocarcinoma cells) in vitro and in nude mice subcutaneous tumors	797.2 μM (IC50), 50 and 75 mmol G/kg^b, and ~83%^c	[66]
	Active (apoptosis with involvement of the mitochondrial pathway)	Human Ishikawa endometrium cell line	~141 μM (IC50)	[67]
Limonene	Active (apoptosis, cell cycle arrest, and suppression of cell migration and invasion)	T24 (human bladder cancer cell)	9 μM (IC50)	[29]
Linalool	Active (inhibition of cell growth through cell cycle arrest)	A549 (human lung adenocarcinoma cells)	~1 and 1.7 mM (IC50), selective	[19]
	Active (cell cycle arrest, loss of mitochondrial membrane potential, and suppression of PI3K/AKT signaling pathway)	OECM 1 (human oral cancer cells)	10 μM (IC50),	[68]
	Active (oxidative stress)	HCT 116 (human colon cancer cell) in vitro and in SCID mice subcutaneous tumors	200 mg/kg^b, 55%^c	[69]
	Active (apoptosis and cell cycle arrest)	T-47D, SW 620, and HepG2 (breast, colorectal, and liver cancer cells)	224, 222, and 290 μM (IC50)	[70]
	Active (cell cycle arrest and apoptosis through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways)	HepG2 (hepatocellular carcinoma cells)	~1.1, 1.6, and 1.8 mM (IC50)	[71]
	Active (cell cycle arrest and apoptosis through CDKIs)	U937 and HeLa (leukemia and cervical cancer cells)	2.59 and 11.02 μM (IC50)	[72]
	Active (oxidative stress)	Sarcoma-180 cells and sarcoma-180 solid tumor model in Swiss albino mice	~2 mM/L (IC50), 200 mg/kg^b, and ~75%^c	[73]
Myrtenal	Active (V-ATPase inhibition)	B16F0, B16F10, and SkMel-5 (murine and human melanoma cell lines) in vitro and in C57BL-6 mice subcutaneous and intravenously administration	5-200 μM^a, 15 mg/kg^b, and ~50%^c	[98]
Perillaldehyde 8,9-epoxide	Active (tumor growth inhibition)	Sarcoma 180-inoculated Swiss mice	100 and 200 mg/kg^b, 38.4 and 58.7%^c	[77]
	Active (apoptosis and necrosis)	OVCAR-8, HCT-116, SF-295, and HL-60 (human ovarian, colon, brain, and leukemia tumor cells)	0.64-1.75 μL/mg (IC50)	[78]
Perillyl alcohol	Active (inhibition of HIF-1)	HeLa, SK-Hep1, and HCT116 (human cervical, hepatic, and colon cancer cells) in vitro and in nude mice subcutaneous tumors	5-200 μM^a, 100 mg/kg^b, and 64.11%^c	[75]
	Active (signaling mechanism mediated by Na/K-ATPase)	U251 and U87 (glioblastoma cells)	1.4 and 1.1 mM (IC50)	[74]
	Active (apoptosis)	AsPC-1, PANC-1, MIA PaCa-2, and BxPC-3 (pancreatic cancer cells) in vitro and in nude mice subcutaneous tumors	~100%^c	[76]
Rotundifolone	Active (antioxidant and antiproliferative activities)	U87MG (glioblastoma cells)	30 mg/L (IC50)	[109]
Terpineol	Active (suppression of cell migration and induction of apoptosis and cell cycle arrest)	Hep-G2 (hepatocellular carcinoma cells) in vitro and in nude mice subcutaneous tumors	19.5 μM (IC50), 20 mg/kg^b, and ~75%^c	[80]
	Active (apoptosis)	HT29, HCT116, COLO320, DLD1, AGS, COLO357, Panc-1, MIA-PACA, DU145, and CL-1 (human colorectal, gastric carcinoma, pancreas and prostate cancer cells) in vitro and in nude mice subcutaneous tumors	0.1% and 1%^b, 40% and 70%^c	[81]
	Active (inhibition of cell growth and induction of apoptosis)	BEL-7402 (human liver cancer cells)	0.32 mg/mL (IC50)	[82]
Thymoquinone	Active (apoptosis)	786-O (human renal carcinoma cells)	3.8–12.9 μM (IC50)	[31]
Thymol and carvacrol	Active (apoptosis)	SKOV-3 (ovarian cancer cells)	258.38-322.50 μM (IC50)	[83]
Thymol	Active (apoptosis)	PC-3, DU145, MDA-MB-231, and KLN205 (prostate, breast, and lung cancer cells)	208.36-799 μM (IC50)	[84]
	Active (cell cycle arrest and mitochondria-mediated apoptosis)	T24, SW280, and J28 (bladder cancer cells)	90.1-130.5 μM (IC50), selective	[85]
	Active (mitochondria-mediated apoptosis and tumor reduction)	Cal27, SCC4, and SCC9 (oral squamous cell carcinoma cells) in vitro and in nude mice subcutaneous tumors	300-550 μM (IC50)	[86]
	Active (mitochondria-mediated apoptosis)	AGS (human gastric carcinoma cells)	100-400 μM^a	[87]
	None	HepG2 (hepatocarcinoma cells)	NA	[91]
	Active (mitochondria-mediated apoptosis)	A549 (non-small-cell lung cancer cells)	745 μM (IC50)	[88]
	NA	Cultured human blood cells	10-200 mg/L^a	[92]
	Active (mitochondria-mediated apoptosis)	HCT-116 (colorectal carcinoma cells)	100-200 μg/mL^a, selective	[89]
	Active (mitochondria-mediated apoptosis)	MCF-7 and MDA-MB231 (breast cancer cells)	47 and 56 μg/mL (IC50)	[90]

Keys: Akt: protein kinase; ALDH: aldehyde dehydrogenase; ATP: adenosine triphosphate; AXL: receptor tyrosine kinase; CD107a: (or LAMP-1) lysosomal-associated membrane protein-1; CD3AK: anti-CD3 antibody induced activated killer; CDC25: cell division cycle 25 A; CDK1: cyclin-dependent kinase 1; CDKI: cyclin-dependent kinase inhibitor; Chk1: checkpoint kinase 1; Chk2: checkpoint kinase 2; DNA: deoxyribonucleic acid; E2F8: E2F transcription factor 8; ERK: extracellular signal-regulated kinase; IC50: half-maximal inhibitory concentration; LDH: lactate dehydrogenase; MAPK: mitogen-activated protein kinase; MMP-9: matrix metalloproteinase 9; mTOR: mammalian target of rapamycin; Na/K-ATPase: sodium-potassium pump; NF-kB: nuclear factor kappa B; p-Akt: phosphorylated protein kinase B; p-ERK: phosphorylated extracellular signal-regulated kinase; PI3K: phosphoinositide 3-kinase; p-P38: phospho-p38; ROS: reactive oxygen species; TIMP-1: tissue inhibitor of metalloprotease-1; TNF-α: tumor necrosis factor alpha; UVA: ultraviolet A; V-ATPase: vacuolar ATPase.