Cytotoxic Activity of Essential Oils of Some Species from Lamiaceae Family

Cancer is considered one of the most lethal diseases in the world, with a preva-lence of 439.2 cases and 163.5 deaths per 100,000 inhabitants, in the period from 2011 to 2015; this disease has a greater impact in underdeveloped countries. For the treatment of this disease, a combination of chemotherapy with surgery or radiation is generally used, however, it is not exempt from adverse effects or resistance of the tumor to this type of treatment, for this reason the search for new treatments is constant. The plants are a possible source to achieve this; Lamiaceae is a family of plants widely distributed on the planet and has been used traditionally for the treatment of different diseases, and various essential oils with the potential for cancer treatment have been isolated from this species. The scope of this review is to present 46 essential oils isolated from different species of Lamiaceae which have been tested against different cancer cell lines.


Introduction
Cancer is a complex disease due to its multiple etiologies, and cancer cells are different to normal cells in many ways. The main characteristics of cancer cells are the cell growth out-of-control in a part of the body that spreads to surrounding tissue, and cancer cells are less specialized than the normal cells. Cancer cells ignore signals that normally tell cells to stop dividing or that begin the process of apoptosis. Also, these cells frequently evade the immune system.
These cells influence the normal cells, molecules, and blood vessels which feed tumors supplying with oxygen and nutrients, which they need to grow. These blood vessels also remove waste products from tumors [1].
Cancer has a large global impact; between 2011 and 2015, the number of new cases of cancer was 439.2 per 100,000 habitants, the cancer mortality rate was 163.5 per 100,000, and cancer mortality was higher for men than women [2].
In 2012, approximately 57% of new cancer cases were detected in less developed countries such as those in Central America and some parts of Africa and Asia, compounds. The cytotoxicity of the EO in MCF-7, Vero, SW480 (adenocarcinoma cell), and JET 3 (choriocarcinoma cells) cell lines was dose-dependent, with IC 50 values of 15.6, 15.6, 125, and 250 μg/mL, respectively [7].
S. intermedia L. is used to treat diarrhea, nausea, cramps, muscle pain, indigestion, and infectious diseases. A sample was collected in Iran, and the major components were thymol (34.5%), γ-terpinene (18.2%), and p-cymene (10.5%). The cytotoxic activity was tested in the 5637 (urinary bladder carcinoma) and KYSE (human Asian squamous cell carcinoma) cell lines, and an IC 50 value of 156 μg/mL was obtained in both cases [8].
S. khuzistanica Jamzad is used as analgesic and antiseptic in Iran. The aerial parts were collected in southern Iran. The EO was analyzed by GC/FID and GC/MS. The EO yield was 0.42% (w/w), and the main component was carvacrol (92.87%). MTT cytotoxicity assay was employed. The EO reduced the viability of Vero, SW480 (colon adenocarcinoma), MCF-7, and JET 3 cell lines, with IC 50 values of 31.2, 62.5, 125, and 125 μg/mL, respectively [10].
S. montana subsp. pisidica L. is used for its antiseptic, aromatic, carminative, digestive, and expectorant properties and in the treatment of insect bites. The major compounds of the EOs obtained from the aerial parts collected in Korab and Galicica were carvacrol, thymol, carvacrol methyl ether, and β-linalool. The cytotoxic effect of the EOs was tested against MDA-MB-361, MDA-MB-453 (human mammary metastatic carcinoma), HeLa, LS174 (human colorectal adenocarcinoma), and MRC5 (fibroblast of lung cells) cell lines. The EO from Korab had higher activity than the oil from Galicica, particularly against the HeLa and MDA-MB-453 cell lines, with IC 50 values of 63.5 and 72.3 μg/mL, respectively [11].
S. bakhtiarica Bunge. is traditionally used for its antiseptic, carminative, stimulant, diaphoretic, diuretic, anesthetic, antispasmodic, analgesic, antioxidant, sedative, and antimicrobial properties. S. bakhtiarica is an endemic plant in the southern region of Iran. Leaves of S. bakhtiarica were collected in the Fars Province of Iran. The chemical composition of the EO was determined by GC/MS, and the main components were phenol (56.35%), thymol (13.82%), p-cymene (8.79%), and carvacrol (2.88%). An MTT cytotoxicity assay was used to test the effect of the EO on HEK (human normal embryonic kidney cells), MDA-MB-231, and SKOV3 (human ovary cancer cells) cell lines. The EO showed antitumor activity against the SKOV3 and MDA-MB-231 cell lines (IC 50 values of 74.6 μg/mL and IC 50 of 83.7 μg/ mL, respectively) [12].

Thymus
The genus Thymus consists of approximately 215 species distributed throughout Europe, Asia, and North Africa. Most of these plants are important in food, pharmaceutical, and cosmetic fields. Many species have been investigated for their preservative effects on foods, protecting the food from lipid peroxidation. In traditional medicine, the leaves and flowering aerial parts of Thymus species have been used extensively for their tonic, antiseptic, antitussive, and carminative properties in the treatment of colds, coughs, sore throats, cystitis, insomnia, bronchitis, and indigestion.

Mentha
The genus Mentha includes 20 species found all over the world. Most Mentha species are perennial, contain essential oils, and are widely cultivated as industrial crops for essential oil production. Many EO chemotypes have a distinct aromatic flavor conferred by different terpene. The whole herb of these species has been used to extract many compounds that have been evaluated as antifungal, antiviral, antimicrobial, insecticidal, antioxidant, antiamoebic, antihemolytic, antiallergenic, and antitumoral agents.
M. spicata L. is a medicinal plant, and its EO inhibits free radical reactions, retards the oxidative rancidity of lipids, and shows antimicrobial and antitumor activities. The major compounds in the EO from M. spicata collected in China were carvone (65.33%), limonene (18.19%), dihydrocarvone (2.97%), and camphene (2.34%). The cytotoxicity was evaluated in a HeLa cell line, and an IC 50 value of approximately 2.08 μg/mL was obtained [21].
M. piperita L. is commonly known as peppermint. It is widely grown in temperate areas of the world, particularly Europe, North America, and North Africa. The EO extracted from its aerial parts was analyzed by GC/MS, and the main component was menthol (47.5%). The cytotoxic activity of the EO was tested against HeLa, A549, and MRC-5 (human fibroblast lung cells) using MTT assay. The IC 50 values were 165.24, 183.00, and 197.08 μg/mL, respectively. EO was obtained from M. piperita collected in Guatemala in a yield of 0.50% w/w. The IC 50 values of the EO against the AGS, A375, and A431 cell lines were 0.35, 0.40, and 0.23 μL/mL, respectively [22].
M. pulegium L. is commonly known as pennyroyal. This plant is traditionally used in the treatment of infectious diseases. Analysis of the EO by GC/MS revealed pulegone (68.7%) as the main component. The cytotoxic activity of the EO was tested against HeLa, A549, and MRC-5 cell lines using MTT assay. The IC 50 values of the EO were 168.58, 253.64, and 189.48 μg/mL, respectively [23].

Ocimum
The genus Ocimum includes approximately 150 species, comprising annual and perennial herbs and shrubs native to the tropical and subtropical regions of Asia, Africa, and Central and South America. Ocimum species are commercially cultivated aromatic crops in India and other countries for the EO and high-value aromatic chemicals used extensively in food, perfumery, cosmetic and pharmaceutical preparations, and as spices. Ocimum species are known for their diverse use in folk medicine for the treatment of various gastric and urinary diseases, insomnia, inflammation, and constipation due to their diverse biological actions, such as carminative, stimulant, antiseptic, antimicrobial, antioxidant, antipyretic, insecticidal, and antispasmodic activities.
O. kilimandscharicum Guerke, popularly known as "Basil African blue," is a semi-evergreen shrub native to East Africa and used in traditional medicine for the treatment of constipation, abdominal pain, cough, and diarrhea. The chemical composition of the EO was determined by GC/MS, and the main components were camphor (51.81%), 1,8-cineole (20.13%), and limonene (11.23%). The EO was evaluated against OVCAR-03 cell line (human epithelial ovarian adenocarcinoma) using a sulforhodamine B (SRB) colorimetric assay, with an IC 50 of 31.90 μg/mL [27].

Salvia
The Salvia genus comprises more than 960 species, which are known as Sage in folk medicine and have been used in the treatment of different ailments, such as stomach pain, diarrhea, fever, inflammation, headaches, bruises, and sprains.
Aerial parts of these plants usually contain flavonoids, triterpenoids, and essential oils. Diterpenoids are the main compounds in the roots. These compounds show a variety of activities, and different pharmacological models have been used to explain their mechanisms of activity.
S. officinalis L. is used in traditional medicine to treat microbial infections, cancer, malaria, and inflammation and to disinfect homes after sickness. This plant was collected in south-central Italy in 2008-2009. The leaves were used to obtain an EO, the composition of which was determined by GC/MS, with a yield of 0.55-2.2% on a dry mass basis. The main components were α-thujone, camphor, borneol, DOI: http://dx.doi.org/10.5772/intechopen.86392 γ-muurolene, and sclareol. The anticancer activity was tested in the cell lines M14, A375, and A2058. The IC 50 values were 8.2, 12.1, and 11.7 μg/mL, respectively [28].
S. lavandulifolia Vahl is a medicinal plant native to the Iberian Peninsula. It is used to treat gastric problems and inflammatory disorders. The composition of its EO was determined by GC/MS, and camphor (29.1%) was the main component. The cytotoxic activity of the EO was tested against HeLa, A549, and MRC-5 cell lines using MTT assay. The IC 50 values of the EO were 133.56, 140.10, and 131.50 μg/mL, respectively [30].

Lavandula
The genus Lavandula includes more than 20 species, and the EOs from the species of this genus have been applied in food, pharmaceutical, and agricultural industries as biological products. L. angustifolia Mill. was collected in the southeastern region of Brazil. The yield obtained for its EO was 0.28% (w/w), and the major components were borneol (22.4%), epi-α-muurolol (13.4%), α-bisabolol (13.1%), precocene I (13%), and eucalyptol (7.9%). The cytotoxic activity was tested in the cell line GM07492-A and was observed only at a high concentration (IC 50 of 243.7 μg/mL) [32].
L. angustifolia Mill was collected in Bulgaria. Analysis of the EO extracted from its aerial parts revealed linalool (40.3%) as the main component. The cytotoxic activity of the EO was tested against HeLa (IC 50 of 80.62 μg/mL), A549 (88.90 of μg/mL), and MRC-5 (75.19 of μg/mL) cell lines using MTT assay [30].

Origanum
Origanum species are herbaceous perennial shrubs native to Europe and North Africa. These plants have aromatic leaves. This genus includes important culinary plants, such as marjoram and oregano.
O. onites Elmalı is used in Turkey as a condiment or aromatic tea, and a sample of this species was collected in Antalya, Turkey. EO was obtained from the herbal parts of the plant. The composition was determined by GC/MS; the main components were carvacrol (24.52%), thymol (15.66%), and linalool (50.53%).
O. vulgare L. is used in traditional medicine for treating colds, indigestion, and upset stomach. The plant was collected in Guatemala, and the yield of EO was 0.66% w/w. The IC 50 values of the EO against epithelial gastric adenocarcinoma, epithelial malignant melanoma, and epithelial squamous carcinoma were 0.18, 0.09, and 0.08 μL/mL, respectively [22].
The EO obtained from O. vulgare collected in Córdoba, Argentina, was analyzed by GC/MS. Analysis of the chemical composition showed carvacrol and thymol as the predominant compounds. The cytotoxicity activity was evaluated in cultured A549 cells, and this oil reduced the viability of the cells (IC 50 of 2.25 μg/mL) [35].
Ajuga chamaepitys L. Schreb grows in the Mediterranean region and is used as a diuretic and emmenagogue. This plant was collected in Rocca Mattei, Italy, and the composition of the EO isolated from the aerial parts was determined by GC and GC/MS. Ethyl linoleate (13.7%), germacrene D (13.4%), kaurene (8.4%), β-pinene (6.8%), and phytol (5.3%) were the major components. The EO had moderate cytotoxic activity against the MDA-MB-231 cell line (IC 50 of 36.88 μg/mL) and an IC 50 value of 60.48 μg/mL against the human colon carcinoma cell line (HCT116) [38].
Ziziphora tenuior L. is used in Jordan for the treatment of stomachache, dysentery, and fever. The EO was obtained in 0.72% yield, and the composition was determined using GC/MS; pulegone (46.8%) and p-menth-3-en-8-ol (12.5%) were the major compounds. The EO was tested against HepG2 cell line, and cytotoxicity was determined using MTT assay. The IC 50 value obtained for the EO was 1.25 μL/mL [39].
Stachys annua L. is a perennial herb and small shrub. In the folk medicine of central Italy, its aerial parts have been used as anticatarrhal, antipyretic, tonic, and vulnerary (wound healing) agents. The EO isolated from its aerial parts was analyzed by GC/MS, and the major components were phytol (9.8%), germacrene D (9.2%), spathulenol (8.5%), and bicyclogermacrene (5.8%). The cytotoxic activity of the EO was determined by MTT assay. Analysis of the cytotoxicity against the HCT116, A375, and MDA-MB-231 cell lines showed IC 50 values of 23.5, 37.2, and 41.5 μg/mL, respectively [41].
Plectranthus amboinicus Lour Spreng is cultivated in home gardens and is used in India for the treatment of cough, chronic asthma, and hiccough. The leaves of P. amboinicus were collected from a medicinal plant garden in Tamil, India. The cytotoxic activity of the EO was tested using MTT assay against the MCF-7 and HT-29 cell lines, and the IC 50 values were 53 and 87 μg/mL, respectively [42].
Cedronella canariensis L. Webb & Berthel. (syn. Dracocephalum canariense L.) is present in the Canary Islands. It is a perennial herb, sometimes shrubby. The plant is used in traditional medicine as an anticatarrhal, tonic, antimicrobial, analgesic, carminative, diuretic, hypoglycemiant, hypotensive, and anti-inflammatory agent and decongestant of the respiratory tract. The EO was obtained from the aerial parts of C. canariensis collected in El Monte de las Mercedes, Canary Islands, Spain, in 2013 (yield of 2.5%). The EO was analyzed by GC/FID and GC/MS; pinocarvone (58.0%) and α-pinene (10.8%) were the main constituents. The cytotoxicity of the EO was evaluated against A345 (IC 50 of 4.3 μg/mL), MDA-MB-231 (IC 50 of 7.3 μg/ mL), and HCT 116 (IC 50 of 11.4 μg/mL) cell lines by MTT assay [44].
Rosmarinus officinalis L. EO is used as an antibacterial, cytotoxic, antimutagenic, antioxidant, antiphlogistic, and chemopreventive agent. The EO (yield of 0.23% w/w) was extracted from the plant collected in Guatemala. The IC 50 values of the EO against AGS, A375, and A431 cell lines were 0.21, 0.24, and 0.41 μL/mL, respectively [22].
The National Cancer Institute of the USA (NCI) has screened approximately 100,000 compounds and 50,000 natural product extracts for potential anticancer agents [47]. The NCI considers a compound or an extract to have potential anticancer activity if it has an IC 50 value of 4 or 30 μg/mL, respectively. Therefore, according to the NCI, the EOs described in this review with remarkable cytotoxic activity are those obtained from O. basilicum, S. sahandica, O. vulgare, N. rtanjensis, M. spicata, S. macrosiphon, Z. tenuior, C. canariensis, R. officinalis, and T. carmanicus (Figure 1).
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