human colon cancer cells, such as HCT116 and LoVo, by inducing apoptosis and
triggering cell cycle arrest at the G2/M phase. It reduced the expression levels of
matrix metalloprotease-2 (MMP-2), MMP-9, and cyclin B1. It also downregulated
the expression levels of Bcl-2 and upregulated the expression levels of Bax. Apart
from this, it decreased the expression levels of phosphorylated protein kinase B
(p-Akt) associated with the activation of the PI3K/Akt signaling pathway. In
association with the activation of the MAPK signaling pathway, there is a decrease
in the expression levels of phosphorylated extracellular signal-regulated kinases
(p-ERK) and an increase in the expression levels of phosphorylated c-Jun
N-terminal kinase (p-JNK) (Fan et al. 2015). The mitochondrial membrane
potential was impaired by carvacrol treatment in choriocarcinoma cell lines, such as
JAR and JEG3 cells. The antiproliferative activity was associated with the induction
of apoptosis and cell cycle arrest at the sub G1 phase. There was a decrease in
cytosolic calcium level in JAR and JEG3 cells. The MAPK and PI3K–AKT signaling pathway was affected similarly in choriocarcinoma cells via regulation of the
phosphorylation of various proteins involved in the pathway (Lim et al. 2019).
Carvacrol inhibited the proliferation of human gastric adenocarcinoma cell line
(AGS cells) and normal human fibroblast (WA-1) by the apoptotic pathway in a
dose-dependent manner but the cytotoxicity towards cancer cells was more in
comparison to normal cells (Günes-Bayir et al. 2018a, b). Apart from the apoptotic
pathway, through autophagy mechanism, the carvacrol exhibited cytotoxic activity
against human cervical cancer cells (HeLa). The mTOR, phospho‐mTOR, and
phospho‐Akt protein expression levels were reduced in cancer treated cells
(Potočnjak et al. 2018). It exhibited its antiproliferative activity against prostate
cancer DU145 cells by inducing apoptosis and activation of caspase 3. Its induced
cell cycle arrest at the G0/G1 phase and loss of mitochondrial membrane potential
occurred in the cancer cells (Khan et al. 2017). Similar observation was reported by
Bhakkiyalakshmi et al. (2016) in which carvacrol showed cytotoxic activity against
human acute promyelocytic leukemia cell line (HL-60), and (immortalized human
T cell lymphocyte cell line (Jurkat). Carvacrol inhibited the PI3K/Akt and MAPK
signaling pathways in prostate cancer cell lines DU145 and PC3, by preventing the
proliferation, migration, and invasion of the cancer cells. It reduced the MMP-2,
p-Akt, and p-ERK1/2 protein expression levels in the prostate cancer cells (Luo
et al. 2016). Carvacrol reduced the production of interleukin-2 (IL-2) and interferon
(IFN-c) in the human Jurkat T cells through the inhibition of activator protein (AP)1 and nuclear factors of activated T cells (NFAT2) (Gholijani et al. 2015). It
inhibited the proliferation of human oral squamous cell carcinoma (Tca-8113) as
well as metastasis and invasion of the cells by inducing apoptosis. But it triggers a
cell cycle arrest at the G1/S stage. It reduces the expression level of cyclin D1 and
cyclin-dependent kinase (CDK4) (Dai et al. 2016). A similar mechanism of action
of carvacrol was reported in human hepatoma cells (HepG2) (Melušová et al.
2014). It reduced the tumor growth of murine melanoma cells B16(F10) (He et al.
1997) and displayed potent cytotoxicity at a higher dose against neuroblastoma
cells (N2a cells) (Aydin et al. 2014). Mitogen-activated protein kinase pathway is
altered by carvacrol on treating the HepG2 cell line apart from the apoptotic
13 Carvacrol (Origanum vulgare): Therapeutic Properties …
451
triggering cell cycle arrest at the G2/M phase. It reduced the expression levels of
matrix metalloprotease-2 (MMP-2), MMP-9, and cyclin B1. It also downregulated
the expression levels of Bcl-2 and upregulated the expression levels of Bax. Apart
from this, it decreased the expression levels of phosphorylated protein kinase B
(p-Akt) associated with the activation of the PI3K/Akt signaling pathway. In
association with the activation of the MAPK signaling pathway, there is a decrease
in the expression levels of phosphorylated extracellular signal-regulated kinases
(p-ERK) and an increase in the expression levels of phosphorylated c-Jun
N-terminal kinase (p-JNK) (Fan et al. 2015). The mitochondrial membrane
potential was impaired by carvacrol treatment in choriocarcinoma cell lines, such as
JAR and JEG3 cells. The antiproliferative activity was associated with the induction
of apoptosis and cell cycle arrest at the sub G1 phase. There was a decrease in
cytosolic calcium level in JAR and JEG3 cells. The MAPK and PI3K–AKT signaling pathway was affected similarly in choriocarcinoma cells via regulation of the
phosphorylation of various proteins involved in the pathway (Lim et al. 2019).
Carvacrol inhibited the proliferation of human gastric adenocarcinoma cell line
(AGS cells) and normal human fibroblast (WA-1) by the apoptotic pathway in a
dose-dependent manner but the cytotoxicity towards cancer cells was more in
comparison to normal cells (Günes-Bayir et al. 2018a, b). Apart from the apoptotic
pathway, through autophagy mechanism, the carvacrol exhibited cytotoxic activity
against human cervical cancer cells (HeLa). The mTOR, phospho‐mTOR, and
phospho‐Akt protein expression levels were reduced in cancer treated cells
(Potočnjak et al. 2018). It exhibited its antiproliferative activity against prostate
cancer DU145 cells by inducing apoptosis and activation of caspase 3. Its induced
cell cycle arrest at the G0/G1 phase and loss of mitochondrial membrane potential
occurred in the cancer cells (Khan et al. 2017). Similar observation was reported by
Bhakkiyalakshmi et al. (2016) in which carvacrol showed cytotoxic activity against
human acute promyelocytic leukemia cell line (HL-60), and (immortalized human
T cell lymphocyte cell line (Jurkat). Carvacrol inhibited the PI3K/Akt and MAPK
signaling pathways in prostate cancer cell lines DU145 and PC3, by preventing the
proliferation, migration, and invasion of the cancer cells. It reduced the MMP-2,
p-Akt, and p-ERK1/2 protein expression levels in the prostate cancer cells (Luo
et al. 2016). Carvacrol reduced the production of interleukin-2 (IL-2) and interferon
(IFN-c) in the human Jurkat T cells through the inhibition of activator protein (AP)1 and nuclear factors of activated T cells (NFAT2) (Gholijani et al. 2015). It
inhibited the proliferation of human oral squamous cell carcinoma (Tca-8113) as
well as metastasis and invasion of the cells by inducing apoptosis. But it triggers a
cell cycle arrest at the G1/S stage. It reduces the expression level of cyclin D1 and
cyclin-dependent kinase (CDK4) (Dai et al. 2016). A similar mechanism of action
of carvacrol was reported in human hepatoma cells (HepG2) (Melušová et al.
2014). It reduced the tumor growth of murine melanoma cells B16(F10) (He et al.
1997) and displayed potent cytotoxicity at a higher dose against neuroblastoma
cells (N2a cells) (Aydin et al. 2014). Mitogen-activated protein kinase pathway is
altered by carvacrol on treating the HepG2 cell line apart from the apoptotic
13 Carvacrol (Origanum vulgare): Therapeutic Properties …
451