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 μMa | [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/kgb | [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/La; 2.67 mL/kgb; 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/mLa | [33] | |
| NA (prevention of UVA-induced cytotoxicity) | HaCaT (human skin epidermal keratinocytes) | 30 μMa | [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/mLa | [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/La | [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/La | [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 mMa | [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 μMa | [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/mLa, 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 μMa | [39] | |
|
| ||||
| Bornyl acetate | Active (apoptosis, DNA fragmentation, and G2/M cell cycle arrest) | SGC-7901 (human gastric cancer cells) | ~48 μM (IC50), 0-96 μMa | [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/mLa, 10 mg/kgb, 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 μMa | [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 μMa, and 100 mg/kgb | [43] | |
| Active (ERK1/2-independent suppression of apoptosis and ERK1/2-dependent modulation of autophagy) | HeLa (human cervical cancer cell) | 556 μM (IC50), 550 μMa | [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/mLa, 50 and 100 mg/kgb, 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 μMa | [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 μMa | [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/La | [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/kgb | [52] | |
| NA (carvacrol has nonmutagenic and antioxidant features and decreased cell viability at high doses) | Human blood cells | 0-200 mg/La | [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 μMa | [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 μMa | [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/La | [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 μMa, and 75 and 150 mg/kgb | [27] | |
| Active (apoptosis) | Swiss albino mice with skin T tumorigenesis | 20 mg/kgb, 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 mMa | [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 μMa | [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/mLa | [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 mMa, 0.4 mg/kgb | [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/mLa | [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 μMa, 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 μMa | [56] | |
| Active (apoptosis) | Ramos (human Burkitt's lymphoma cell line) and PBMCs (normal human peripheral blood mononuclear cells) | 77.19 μM (IC50), 0–160 μMa, 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/kgb, 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/kgb, 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/kgb, 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/kgb, 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 μMa | [103] |
|
| ||||
| Dehydroperillic acid | Active (inhibition of DNA synthesis) | A549 and HepG2 (human lung adenocarcinoma and hepatocellular carcinoma cells) | 125 and >500 μg/mL (IC50), SI = 400 and 100 | [79] |
|
| ||||
| Fenchone | Active (cell cycle arrest) | Ehrlich carcinoma cell line in the peritoneal cavities of mice | 60 mg/kgb, ~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/La | [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/kgb, 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), SI = 6.5 | [68] | |
| Active (oxidative stress) | HCT 116 (human colon cancer cell) in vitro and in SCID mice subcutaneous tumors | 200 mg/kgb, 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/kgb, 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 μMa, 15 mg/kgb, and ~50%c | [98] |
|
| ||||
| Perillaldehyde 8,9-epoxide | Active (tumor growth inhibition) | Sarcoma 180-inoculated Swiss mice | 100 and 200 mg/kgb, 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 μMa, 100 mg/kgb, 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/kgb, 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 μMa | [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/La | [92] | |
| Active (mitochondria-mediated apoptosis) | HCT-116 (colorectal carcinoma cells) | 100-200 μg/mLa, 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.