Skip to main content

Molecular and biological functions of gingerol as a natural effective therapeutic drug for cervical cancer


Cervical cancer is one of the most common and important gynecological cancers, which has a global concern with an increasing number of patients and mortality rates. Today, most women in the world who suffer from cervical cancer are developing advanced stages of the disease. Smoking and even exposure to secondhand smoke, infections caused by the human papillomavirus, immune system dysfunction and high-risk individual-social behaviors are among the most important predisposing factors for this type of cancer. In addition, papilloma virus infection plays a more prominent role in cervical cancer. Surgery, chemotherapy or radical hysterectomy, and radiotherapy are effective treatments for this condition, the side effects of these methods endanger a person’s quality of life and cause other problems in other parts of the body. Studies show that herbal medicines, including taxol, camptothecin and combretastatins, have been shown to be effective in treating cervical cancer. Ginger (Zingiber officinale, Zingiberaceae) is one of the plants with valuable compounds such as gingerols, paradols and shogoals, which is a rich source of antioxidants, anti-cancer and anti-inflammatory agents. Numerous studies have reported the therapeutic effects of this plant through various pathways in cervical cancer. In this article, we look at the signaling mechanisms and pathways in which ginger is used to treat cervical cancer.


Cervical cancer is one of the most important cancers in women, causing death. Worldwide, this type of cancer ranks fourth in terms of cancer in women. Nearly 85% of cervical cancer deaths are reported in underdeveloped or developing countries. Reports also show that in economically weak or middle-income countries, cervical cancer mortality is about 18% higher than in rich countries. Central and South America, as well as South Asia, are geographically more prone to cervical cancer. In 2016, about 12,990 people were diagnosed with cervical cancer in the United States, of which 4120 died [1]. The average age of these people at the time of diagnosis was reported to be 47 years and half of the diagnoses occur in women under the age of 35 [1, 2]. Smoking, human papillomavirus infection, and immune system dysfunction are risk factors for cervical cancer [3,4,5,6,7,8,9]. The results of a cohort study of more than 300,000 women in Europe show that smoking is a major risk factor for cervical cancer [2].

The disease is treatable in its early stages, if diagnosed. Of course, in the long run, the effects of treatment on these people cause other health problems for the person [6]. The choice of cervical cancer treatment depends on the stage of the disease and the location of the tumor. Therapies for this disease include chemotherapy or radical hysterectomy, which may be used in combination. In the early stages of diagnosis and low-risk disease, the person is usually operated on to maintain fertility [2]. In general, chemotherapy is one of the major treatments for cervical cancer today, and vaccination against human papillomavirus (HPV) is one of the preventive measures against this disease [10, 11]. The International Federation of Obstetricians and Gynecologists divides cervical cancer into five stages (I, II, III, IVA and IVB) based on physical examinations and biopsies. In the stage I, although the cancer penetrates from the cervix to the inner layers, it is limited to the uterine tissue itself. The stage II, which is limited to the pelvis, cancer cells are also found in nearby tissues such as the vagina. In the stage III, tumor cells are also found in the lower parts of the vagina and the cancer spreads to the pelvic wall. At this stage, the tumor causes hydronephrosis by affecting the kidney. In the stage IVA, the bladder and rectum are also involved, but the cancer does not affect other parts of the body. In the stage IVB, the cancer spreads to other tissues in the body [12]. Some studies have suggested a combination of chemotherapy, surgery, and radiotherapy to treat cervical cancer. However, treating patients with this method, especially in the advanced stages of the disease, faces some obstacles, including the toxicity of chemotherapeutic drugs, weakness and therapeutic failure [13,14,15,16]. Moreover, patients may develop drug resistance which is mostly related to cancer stem-like features, such as diverse receptors and transmembrane proteins (e.g. c-Kit, located on these cells [17]. Therefore, it is very important to adopt alternative therapies with the least amount of side effects for the treatment of cervical cancer and to improve the quality of life of these patients, which requires various studies.

Today, the use of natural ingredients such as herbs and spices are increasing due to their beneficial properties for maintaining human health and their anti-cancer effects. Among the factors that cause various pathological disorders such as neurological, heart and cancer diseases in the body, we can mention the production of oxygen free radicals such as superoxide radical (O2 -), hydrogen peroxide (H2O2). These active oxygen species can also have destructive effects on cells and tissues in the body’s natural metabolism [18, 19]. Medicinal plants and spices are valuable sources of antioxidant compounds due to their phenolic, carotenoid and ascorbic acid factors [18, 20]. Anacardium occidentale in hepatoma, Asparagus racemosus in human epidermoid carcinoma, Boswellia serrata in human epidermal carcinoma of the nasopharynx, Erythrina suberosa in sarcoma, Euphorbia hirta in Freund virus leukemia, Gynandropsis pentaphylla in hepatoma, Nigella sativa in Lewis lung carcinoma, Paederia foetida in human epidermoid carcinoma of the nasopharynx, picrorhiza kurroa in hepatic cancers, and Withania somnifera in various tumors are herbal examples which have anticancer activity [21, 22]. Reports indicate that the use of these plants in the daily diet in South East Asian countries reduces the incidence of breast, prostate, intestinal and other cancers [18, 23]. Studies show that herbal medicines, including taxol, camptothecin and combretastatins, have been shown to be effective in treating cervical cancer [24,25,26].

Ginger (Zingiber officinale, Zingiberaceae) is one of the oldest herbs used to treat diseases such as colds, coughs, arthritis, digestive disorders, dyspepsia, vomiting, diarrhoea, gastritis, and nausea during pregnancy asthma, inflammation, nervous disease, hepatotoxicity, migraine, diabetes, hypercholesterolaemia, helminthiasis and schistosomiasis. This plant has antibacterial and antifungal properties and is effective in preventing or treating diseases such as cancer due to its antioxidant properties [18, 27,28,29,30,31,32,33,34]. So far, according to the ancient history of the use of ginger in diet, various studies have been conducted on the healing properties of this medicinal plant in a variety of cancers, including cervical, colorectal, pancreatic and breast cancer. In addition to anti-tumor properties, the anti-inflammatory and antioxidant potential of ginger has also been reported in these studies [35,36,37,38,39,40,41,42,43]. Furthermore, different supplements and gingerol are reported to affect the metabolic profiles [44,45,46,47,48]. In the study of Ansari et al. [18] the successful effects of antioxidant and anti-cancer properties of ginger in controlling cervical cancer and breast cancer has been confirmed [18]. Ginger has active phenolic compounds such as gingerol, paradol and shogoal that show anti-cancer, antioxidant, anti-angiogenic, anti-atherosclerotic and anti-inflammatory potentials [40, 49,50,51,52,53]. Therefore, the prevalence and mortality rate of this cancer is representative of its importance and the need for new diagnostic and therapeutic methods. This article is an attempt to show the therapeutic potential of ginger extract as a natural and herbal compound in the treatment of cervical cancer. This paper also describes the mechanisms of action of ginger compounds in the prevention and treatment of this type of cancer.

Cervical cancer: prevalence, pathogenesis, and diagnosis

In 2018, with the death of 311,365 women due to cervical cancer, the disease became a global concern [54]. Cervical cancer usually occurs in women with human papillomavirus infection. Studies show that types 16 and 18 of the virus are among the most important risk factors for cervical cancer due to their carcinogenic properties, such as cell gene degradation, increased uncontrollable cell division, and disruption of cell cycle regulation [55]. One of the cases of intrauterine changes is cervical neoplasia, which usually takes several years after the onset to become invasive. Therefore, cervical exfoliation cytology is used to identify intrauterine cervical neoplasia. This procedure can also be used to prevent the development of cervical cancer. As HPV infection became one of the risk factors for developing cervical cancer, preventive vaccination began in the 1990s [1]. So today, vaccination against (HPV) is one of the preventive methods of cervical cancer [10, 11]. Cervical cancer is usually divided into two types of squamous cell carcinoma and adenocarcinoma based on the origin of malignancy [56]. Common screening tests to detect human papillomavirus infection include examination, colposcopy, biopsy, and Papanikolaou smear, which are also used to diagnose cervical cancer [54, 57, 58]. Screening tests such as cytology or Pap smear can be used to identify primary lesions of cervical cancer and to diagnose it early [56, 59]. Due to the wide prevalence of this disease and the complications of the usual treatment methods of this disease that affect patients’ quality of life in the long run, in addition to finding effective biological markers for early diagnosis, finding new and safe treatment methods with the least number of complications. It is very important to improve the effectiveness of treatment and the outcome of the disease.

Ginger: components

Escape oils (1 to 3%) and oleoresin non-volatile fasteners are ginger compounds. Oleoresin contains a variety of active ingredients, including gingerols and shogaols. Gingerols are homologous compounds that have different non-branched alkyl chains. Shogaols are also homologues that are derived by gingerols dehydration at C4 and C5. These compounds are produced when long-term ginger is stored or heated [35, 36, 60,61,62]. Therefore, most of the fresh ginger compounds are Gingerols compounds, especially 6-gingerol. Shogaols are found largely in dried ginger [35, 60, 62, 63]. 6-gingerol, 8-gingerol, 10-gingerol and 6-shogaol are the most important and major compounds in Oleoresin [39, 64]. In general, gingerols are the most common compounds found in ginger, and reports indicate that these compounds have a variety of therapeutic potentials, including tumor prevention [39, 65,66,67,68,69], antipyretic [39], pain-reducing [70], and cardiotonic [71] effects. These compounds also have anti-inflammatory, anti-angiogenic, antibacterial and antifungal properties and reduce high blood cholesterol levels [35, 38, 72, 73]. Other compounds found in ginger include waxes, fats, vitamins, minerals and carbohydrates. Its rhizomes also produce a proteolytic enzyme called zingibain [40].

Ginger: pharmacokinetics

Numerous clinical studies to evaluate the pharmacological and therapeutic effects of ginger have not measured the amount of active ingredients in ginger extract. Therefore, different results from clinical trials can be generalized to the lack of use of the standard dose of ginger extract [35, 74].

Although extensive clinical trials have been conducted on the pharmacological effects of ginger, sufficient studies on the pharmacokinetics of ginger active compounds in human biological systems are not available. Therefore, concentrations of 6-, 8- and 10- gingerol and 6- shogaol for their effectiveness in the body have not yet been fully obtained.

Effects of ginger in cervical cancer (clinical studies)

Various studies have been conducted on the effects of ginger on a variety of cancers, including cervical cancer. The results of all research agree on the anti-cancer properties of this plant. Reports attribute the anti-cancer potential of ginger to its inhibitory effects on cell proliferation and induction of apoptosis [13, 18, 75, 76]. 6-gingerol as the most important functional component in ginger has a strong anti-cancer and anti-inflammatory potential [77]. 6-gingerol through inhibition of IkBα, nuclear translocation of NF-kB, suppression of Inducible nitric oxide synthase (iNOS), release of cytochrome c, increased expression of Apoptotic protease activating factor 1(Apaf-1), activation of caspase, stimulation of oxidative stress, induction of DNA damage, autophagy and increased protein activity of p53 and p21, causes apoptosis and thus prevents cancer progression and tumor growth [10, 78,79,80,81,82,83,84].

Another species of ginger that has been known for its thin white skin, fragrant juice, and crispness for more than a thousand years is known as Tongling White Ginger. This plant is welcomed as one of the best ginger species in China [85, 86]. The reports confirmed the valuable properties of another important ingredient in ginger extract called 10-gingerol, including anti-cancer, anti-inflammatory and antioxidant [85, 87, 88]. 6-Shogaol is another important biologically active ingredient in ginger that has anti-cancer properties. Various pathways including p38 mitogen-activated protein kinase, extracellular signal-regulate kinase 1/2 and c-Jun N-terminal Kinase 1/2, phosphatidylinositol 3-kinase/Akt and cell cycle checkpoint proteins cdk1 and cyclin B and cdc25C are involved in cell death induced by 6-Shogaol in cancer cells [16, 89, 90]. However, the pathways of apoptosis induction and cell signaling cascades that 6-Shogaol has in the removal of cervical cancer cells have not been fully investigated [16, 91]. Naturalness, antioxidant potential, easy access to the environment, easy metabolism and low cost of ginger have made this plant a natural remedy for effective chemotherapy in various cancers. However, there are not enough studies on its exact anti-cancer effects and its functional mechanism in improving cervical cancer. Therefore, in this part of the article, we summarize the mechanisms and signaling pathways of this highly effective medicinal plant in cervical malignancy. These signaling pathways are summarized in (Table 1).

Table 1 Experimental studies of gingrol in cervical cancer

6-gingerol improves cervical cancer caused by human papillomavirus by suppressing cell proliferation and stimulating cell apoptosis

The results of a study conducted by Rastogi et al. [10] in both in vivo on mice and in vitro on Hela cells show that the administration of 50 μM 6-gingerol, significantly inhibited the growth and proliferation of cervical cancer cells. Cellular and tissue studies show that ginger increases the percentage of apoptotic cells in both the initial stage of apoptosis and its final stage [10]. Therefore, ginger (6-gingerol) inhibits cell proliferation by inducing apoptosis cell death and can help control the progression of cancer.

6-gingerol improves cervical cancer by reactivating p53 without inhibiting HPV oncoprotein

Disabling the transcription of HPV oncoproteins (E6 and E7) inhibits the proliferation of cervical cancer cells. Many natural drug compounds demonstrate their anti-cancer potential by inhibiting these E6 and E7 proteins [10, 93, 94]. 6-gingerol stimulates both p53-dependent apoptosis and p53-independent apoptosis in cancer cells. P21 is the functional mediator of p53-dependent apoptosis pathways [10, 83]. Evaluations by Rastogi et al. [10] show that after administration of 6-gingerol, p21 mRNA expression levels in Hela cells increase significantly. These findings suggest that in these cells, the 6-gingerol-induced apoptosis is of the p53-dependent apoptosis type [10]. Therefore, it can be said that 6-gingerol reactivates p53 and increases the level of P21 with the onset of p53 activity. This process occurs under the influence of ginger without the need for suppression of E6 transcription in cervical cancer cells [10].

6-gingerol inhibits the progression of cervical cancer by suppressing proteasome and reactivating p53

In cervical cancer cells, p53 endogenous levels are low in the presence of human papillomavirus infection because in these cells the E6 and E6-AP proteins cause the rapid destruction of p53 by proteasomals [95]. In these cells, for the reactivation of p53, transcription and translation of the E6 protein must be inhibited or proteasome activity stopped using inhibitors. In this way, p53 levels and activity are indirectly restored [96,97,98]. In cervical cancer cells, 6-gingerol has not been reported to affect E6 and E7 mRNA levels, but it does increase p53 and p21 expression. Under these conditions, the level of apoptosis in cancer cells increases and their proliferation stops [10].

Studies show that in most human malignancies, including cervical cancer, the p53 tumor suppressor is inactivated. In cervical cancer, oncoprotein E6 inactivates p53. Oncoprotein E6 binds to E3 ubiquitin ligase E6-AP, thus inducing proteosomal degradation of P53 [10, 95]. Therefore, reactivation of p53 is one of the effective therapeutic goals in improving cervical cancer. Inhibition of proteosomal degradation of p53, suppression of viral protein expression or their inactivation are among the methods of reactivation of this tumor suppressor protein [10, 99, 100]. Proteasomes are involved in the non-lysosomal degradation of intracellular proteins [10, 101, 102]. Various cancers, including cervical cancer, can occur as a result of adverse activation of proteosomes [103, 104]. Some studies show that increased proteasome activity stimulates cancer progression by stimulating survival pathways and drug resistance in tumor cells [10, 102]. Therefore, the main strong anti-cell proliferation function of ginger in vivo is due to proteoosmal inhibition and reactivation of p53, which inhibits the growth and development of cervical cancer by inhibiting cell proliferation and stimulating apoptotic cell death.

6-gingerol in cancer cells, including cervical cancer, can cause DNA damage by producing ROS, which slows down the progression of cervical cancer by activating p53 in response to DNA damage

Reactive oxygen species (ROS) in cancer cells are caused by functional changes in cytochrome p450, iNOS, Nox NADPH oxidases, decreased antioxidant protein activity, or inhibition of mitochondrial respiratory complex I (MRC I) [10, 84]. Studies show that in cancer cells, including cervical cancer cells, 6-gingerol inhibits MRC I activity, thereby producing ROS. Accumulation of ROS in the cell activates multiple signaling pathways [10, 77, 84]. Thus, by suppressing MRC-I activity in cervical cancer cells, 6-gingerol increases the production of active oxygen species, which in turn causes oxidative stress and DNA damage. Therapies that produce reactive oxygen species are important factors in inducing apoptosis in cancer cells [84]. Studies show that proteasome inhibitors increase the level of ROS accumulation in cancer cells [105].

In Rastogi’s study, it was shown that in cervical cancer cells, 6-gingerol inhibits the activity of proteosomes by increasing the accumulation of reactive oxygen species and causes oxidative stress [10]. The occurrence of such processes causes further activity of p53 and p21, which responds to DNA damage [10, 106] and, by stopping the cell cycle, causes apoptosis of the cancer cell [10]. Harmful and irreversible DNA damage interrupts cell proliferation and causes the cell cycle to stop at S or G2 / M stages [10, 107]. Therefore, 6-gingerol stimulates the production of ROS, causing oxidative DNA damage in cancer cells in the cervix, which then stops the cell cycle in the G2 / M stage. In cancer cells, p21 is considered to be one of the important functional mediators of apoptosis related to p53 [108]. The results of this study also show that reactivation of p53 and apoptosis through proteasomal inhibition is one of the leading roles of 6-gingerol in cervical cancer cells caused by HPV, and stimulation of ROS production is a support mechanism in this cells [10]. In many studies, the process of producing reactive oxygen species has been confirmed as a natural mechanism supporting cancer cell death [10, 109, 110].

6-gingerol supports the inhibitory effects of cisplatin on cell proliferation

One of the most effective and practical chemotherapy drugs in the treatment of various cancers, including cervical cancer, is cisplatin. The effects of this drug are shown by prescribing high doses, which causes severe and undesirable side effects in the patient [10, 111, 112]. Numerous studies on HeLa cells have shown that combination therapy with natural agents and cisplatin can reduce the dose of this drug with the same effects as before [10, 113]. In Rastogi’s study, after using a combination of 6-gingerol and cisplatin on cervical cancer cells, the level of production of reactive oxygen species was examined [10]. The results show that such combination therapy further increases the levels of ROS production in these cells. Under these conditions, the levels of oxidative stress applied to the cancer cells also increases. On the other hand, an assessment of H2AX (H2A histone family member X) phosphorylation levels shows that DNA damage is further enhanced by this combination therapy, and the cell cycle in most cells stops at the G2 / M stage [10]. The study also found that in vivo the Ki67 cell proliferation marker in cervical cancer cells was significantly reduced by the combined treatment of 6-gingerol and cisplatin compared with their single use. These cells are also more prone to apoptotic TUNEL formation [10]. Therefore, it can be found that combining ginger with cisplatin by increasing oxidative stress, DNA damage, and stimulating cell death in cervical cancer cells supports the anti-cell proliferation effect of cisplatin.

6-shogaol inhibits the progression of cervical cancer by stimulating apoptosis and stopping the cell cycle at G2/M stage through mitochondrial pathways and endoplasmic reticulum stress

6-shogaol stimulates apoptosis cell death through mitochondrial pathways and endoplasmic reticulum (ER) stress and stops the cell cycle in G2 / M stage. In this condition, the potential of mitochondrial membrane of cervical cancer cells is disturbed and progression of cervical cancer is prevented [16]. Liu et al. [16] to investigate the effect of 6-shogaol,ginger composition, on cell death in human cervical cancer cells in culture medium, mitochondrial apoptosis-related proteins levels such as pro caspase-3, poly ADP ribose polymerase (PARP), and apoptosis regulator Bax, as well as endoplasmic reticulum stress-related proteins levels., including protein kinase RNA-like endoplasmic reticulum kinase (PERK), CHOP, ARF5, and HSP60, were evaluated [16]. The results show that 6-shogaol reduces the expression of PERK and ARF5 proteins but increases the expression of HSP60. 6-Shogaol does not alter the expression of CHOP. Therefore, in cervical cancer cells, ER stress due to administration ginger plays an important role in the apoptosis of these cells [16].

The role of Bcl-2 family members is crucial in regulating the process of apoptosis [16, 114]. Bax protein is a member of this family [114], and studies show that the expression of this protein increases under the influence of 6-shogaol [16]. Caspase proteins play an important role in initiating the process of apoptosis. Caspase-3 is the most important executive protein of apoptosis, which is activated by caspase-9, the upper caspase inhibitor, during the internal path of apoptosis. Reportedly, 6-shogaol increases the activity of caspase-3. The PARP enzyme, which is a DNA repair enzyme, is the downstream target of caspase-3 and 7. The gap that PARP creates depends on the type of apoptotic responses [16, 115]. Studies show that 6-shogaol causes a breakdown in the structure of the PARP enzyme and inactivates it [16]. Thus, in cervical cancer cells 6-shogaol stops the cell cycle in the G2 / M stage and significantly inhibits the growth of these malignant cells by pushing the cells toward cell death and apoptosis. It also activates various signaling cascades in the apoptosis pathway by activating Bax, caspase-3 proteins and destroying the structure of PARP enzyme, and ultimately destroys the potential of mitochondrial membrane.

1′S-1′-acetoxychavicol acetate (ACA) in ginger stimulates apoptosis in cervical cancer cells by inhibiting miR-629 expression and increasing RSU-1 expression

1′S-1′-acetoxychavicol acetate or ACA is another compound found in wild ginger Alpinia conchigera. Studies show that this compound is effective in eliminating cancer cells such as cervical cancer [13, 116, 117]. MicroRNAs are small non-coding molecules that are responsible for regulating genes after transcription [118]. Studies show that in many cancers, the activity of these molecules is disrupted, affecting the regulation of cellular mechanisms such as apoptosis, cell proliferation, metastasis, and sensitivity to chemical reagents [13, 119,120,121,122,123]. MiR-629 is a member of miRNAs that is expressed in a variety of cancers, including breast, cervical, lung, bladder, kidney, and uterine cancers [124]. Studies show that lung and gastric cancer can be detected by assessing the increased levels of this molecule in the bloodstream [13, 125, 126].

Clinical reports indicate that in cervical cancer cells, the level of expression of miR-629 decreases with the presence of ACA. By inhibiting this molecule, cell proliferation is suppressed and the cells are directed to apoptosis [13, 127]. In cervical cancer cells infected with the human papillomavirus, the level of miR-629 expression is very high. The reason for the high level of this molecule is attributed to the expression of E6 / E7 in these cells [13, 128,129,130]. The miR-629 can be directly connected to the Ras suppressor-1 (RSU-1) and adjust the negative level of its expression so that increasing the miR-629 reduces the level of the RSU-1 and vice versa [13]. The findings are confirmed in a study by Phuah et al. [13] on cervical cancer cells. In their study, they found that MiR-629 expression was inhibited by ACA (a compound in ginger) prescription. As a result, the level of RSU-1, which is involved in inhibiting cell proliferation and stimulating apoptosis, increases. Therefore, ginger through the above pathway can inhibit the growth of cervical cancer cells and destroy them. Further expression of RSU-1 enhances the properties of ACA in inhibiting cell growth and stimulating cell death [13].

Ginger prevents the proliferation of cancer cells by inhibiting the production of prostaglandins and improves cervical cancer

Prostanoids are involved in processes such as the proliferation and differentiation of cancer cells, suppression of apoptosis, and the development of malignancies. Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), prostaglandin F2 (PGF2), prostaglandin I2 (PGI2) and thromboxane A2 are the most important types of prostanoids [131, 132]. Prostaglandins are important factors involved in the progression of cancer and malignancy and the process of angiogenesis. Prostaglandin E2 has been shown to play an important role in signaling pathways that stimulate angiogenesis, metastasis, tumor cell growth, and inhibition of apoptosis [133]. Prostaglandins are derived from arachidonic acid by the activity of the enzyme Cyclooxygenase (COX). These molecules are involved in causing cancer, inflammation and other pathophysiological processes. The COX2 enzyme is activated in response to inflammation and cell growth regulation. Therefore, it can be said that the use of natural medicinal plants that can inhibit the production of PGE2 can prevent cancer and inflammation [92]. Jaiaree and colleagues [92] in the study of cervical cancer cells found that herbal compounds, including Zingiber cassumunar Roxb, Zingiber officinale Roscoe and Zingiber zerumbet (Linn) Smith, used in Thai traditional medicine, reduce the level of Prostanoids such as PGE2, thereby showing their anti-cancer and anti-inflammatory effects, and improve cervical cancer [92].

Ginger with its antioxidant and cytotoxic properties prevents and treats cervical cancer

In the human body, free radicals such as reactive oxygen species (ROS), are produced by aerobic respiration and oxidative compounds, leading to oxidative stress. Reports indicate that these compounds are involved in diseases such as diabetes, cancer, Parkinson’s, Alzheimer’s, aging, and atherosclerosis [18, 76, 134,135,136,137,138]. Studies show that in normal cells, the concentration of active oxygen species causes gene mutations and disrupts cell signaling pathways and the balance of transcription factors. As a result, the cells are severely damaged and lead to cancer [18, 139]. Other external factors, such as lifestyle and diet, increase the production of free radicals in the human body, in which case the body’s natural antioxidant systems will not be able to clear active species. Under these conditions, important cellular molecules, including phospholipids, carbohydrates, DNA and proteins, are severely damaged and destroyed by oxidative stress. By stimulating the activity of the body’s endogenous antioxidant enzymes and using natural antioxidant compounds, it is possible to move towards reducing oxidative stress [18, 76, 140,141,142]. Today, a number of studies have focused on the valuable antioxidant properties of natural phenolic compounds, which has led researchers to explore and study different types of these plant-derived compounds.

Various studies on Alpinia pahangensis and Zingiber officinale Roscoe from the ginger family have shown that these plants have antioxidant potential in addition to their antibacterial, antifungal and other properties [18, 76]. Alpinia pahangensis is a rare wild species of ginger found in Pahang and Malaysia [76]. In a study of cervical cancer cells, Phang et al. [76] concluded that treating normal healthy cells with Alpinia pahangensis prevents cancer. They found that methanol and ethyl acetate extracts in this plant are natural sources rich in antioxidants. On the other hand, Phang and his [76] studied the effect of Alpinia pahangensis on cervical cancer cells and found that this plant with its cytotoxic and antioxidant properties can cause the death of these cancer cells [76]. In another study by Ansari et al. [18] on the effect of Zingiber officinale on breast cancer and cervical cancer cells, they found that the plant’s methanolic extract, with its anti-cancer and antioxidant potential, prevents cell proliferation and cell colonization. The results of their study show that in addition to directing the cells to apoptosis, the methanolic extract in this plant also changes the nucleus morphology of these cells, which destroys the cells. Therefore, this plant can be used to prevent, manage and treat cervical and breast cancer [18].

10-gingerol inhibits cervical cancer by altering cell morphology

Morphological study of cervical cancer cells after treatment with 10- gingerol shows that this combination reduces the number of cells and the cells go out of their normal state and lose their connections with other cells. Also, the apoptotic bodies are observed and in the cytoplasm of these cells, after treatment with 10- gingerol, many vacuoles appear. All these findings show that this combination eliminates cervical cancer cells by making changes in the morphology and shape of these cells [85].

10. Gingerol stops the progression of cervical cancer by stopping the cell cycle in stage G0/G1

Reportedly, 10-gingerol suppresses the cell cycle in G0/G1. Examination of the expression of several important genes related to the cell cycle, including CDK-1, CDK-2, CDK- 4, CDK-6, cyclin A, cyclin B1, cyclin D1, cyclin E1, GSK-3β, β-catenin, and p15, p16, p21, p27 shows that the expression of CDK-2, CDK-4, CDK-6, cyclin A, cyclin D1, cyclin E1, p15 and p21 mRNA significantly decreases in the presence of 10-gingerol [85]. A slight decrease in expression of CDK-1, GSK-3β, β-catenin, and p16 and p27 mRNA is also seen. Cyclin A and cyclin D1 are the most important markers of the G0 / G1 stage of the cell cycle [85]. A study by Zhang et al. [85] shows that 10-gingerol significantly reduces the level of expression of these markers. Thus, 10-gingerol controls the progression of cervical cancer by affecting the expression of cell cycle-related marker genes at both transcription levels and after transcription [85].

10-gingerol inhibits cervical cancer through apoptosis

Apoptosis is a regulated biological process of cell death that has two main pathways: the outer and inner pathways [85, 143]. At the cell membrane surface, there are cell death receptors 3 and 5 (DR3 and DR5) as receptors for tumor necrosis factor. These receptors mediate the process of apoptosis and differentiation [85, 144]. 10-gingrol significantly increases the expression levels of apoptotic proteins (DR3 and DR5). As the expression of these proteins increases, apoptotic indicators, such as caspases − 3, − 8, and − 9, are activated and trigger the caspases cascading. By launching these cascades, 10-gingrol induces apoptosis in cervical cells, and thus can play an important role in the treatment of cervical cancer [85]. Other studies have confirmed the increase in caspase-3 expression by 10-gingrol in cervical cancer cells [145]. To investigate the effect of ginger on the mitochondrial pathway, Zhang and his colleagues [85] evaluated the expression of, Bad, Bid, Bax, Bcl-2 and cytochrome c. They found that the expression of these proteins, except Bcl-2, increased in the presence of 10-gingrol. With a slight decrease in Bid, the level of Bcl-2 decreased significantly, which eventually led to the activation of Bax. Therefore, 10-gingrol activates apoptosis signaling pathways and causes mitochondrial dysfunction in cervical cancer cells, causing cell death and inhibiting cervical cancer [85].

10-gingrol inhibits the proliferation of cervical cancer cells by inhibiting the PI3K / Akt pathway

PI3K/Akt pathway, which is upstream signaling pathway of the mTOR, is one of the most important factors in regulating cancer progression. The proteins in this pathway are activated by phosphorylation at specific sites [85, 146]. Zhang and his colleagues [85] showed in their study that signaling the PI3K/Akt pathway is another case in which 10-gingrol could affect its anti-cancer potential. Suppression of PI3K/Akt signaling can stop the cell cycle and prevent cell proliferation in cervical cancer cells [85]. The results of this study also show that PI3K causes changes in protein kinase Cε (PKCε) expression and decreases nuclear factor-Kappa B (NF-kB) expression [85, 147]. By stimulating AMPK activity, 10-gingrol reduces the level of phosphorylation of the mTOR pathway and inactivates it [85]. Thus, by inhibiting cell proliferation, 10-gingrol induces cell death in cervical cancer cells.

Signaling pathways that may be involved in ginger effects on cervical cancer

As we mentioned before, ginger plays a variety of anti-tumor roles in different cancers. There are some studies on cancers other than cervical cancer that deal with ginger effects on certain signaling pathways. Although currently there is no study investigating these signaling pathways in cervical cancer, they may be involved in ginger effects on this cancer.

The Nuclear Factor Kappa B (NF-kB) family is consisted of transcription factors involved in inflammation and immune responses [148]. Studies have shown that NF-kB plays different roles in initiation of cancers as well as their progression and drug-resistance. This signaling pathway that is stimulated by HPV infection exerts important roles in cervical cancer. NF-kB induces the transcription of genes involved in proliferation (e.g. c-myc and cyclin D1), VEGF-dependant angiogenesis, metastasis, and telomerase-dependent cell immortality. Furthermore, activation of NF-kB leads to the expression of cytodine deaminase and APOBEC proteins, leading to cervical cancer’s mutagenic properties [148]. [6]-gingerol treatment leads to the downregulation of the extracellular signal-regulated kinase (ERK) pathway in human pancreatic duct cell-derived cancer cell line PANC-1 [149]. Subsequently, NF- κ B/Snail nuclear translocation is suppressed. Also, it is concluded that [6]-gingerol treatment suppresses invasion and metastasis through NF- κ B/Snail inhibition [149]. Ginger extract is reported to significantly inhibit the activation of NF-κB in ovarian cancer cell lines, CaOV3 and SKOV3 [150]. Activator protein 1 (AP-1) is a transcription factor involved in HPV-mediated cervical carcinogenesis and chemo-radio-resistance. Besides, AP-1 activity and expression loss has been associated with a reduction in the viability and proliferation of UV-irradiated non-stem cervical cancer cells [151]. Oral administration of [6]-Shogaol inhibits phosphorylation of IκB, c-jun and c-fos; leading to the suppression of p65, NF-κB, and AP-1. Consequently, suppressing the activation of NF-κB and AP-1 leads to the inhibition of inflammation and cell proliferation in hamster buccal pouch carcinogenesis [152]. Ling et al. [153] has also reported that 6-shogaol reduces the transcriptional activity of NF-κB in MDA-MB-231 breast cancer cells. Furthermore, they indicated that 6-shogaol inhibits the activation of JNK without reducing the transcriptional activity of AP-1 [153]. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in cellular proliferation, survival and differentiation. STAT3 has attracted a lot of attention as a cancer therapeutic target in several cancers, such as ovarian cancer, neck squamous cell carcinoma, and cervical cancer [154]. In hepatocellular carcinoma HepG2 cells, 10-gingerol inhibits the activation of Src and STAT3 and suppress proliferation [155]. A study on colorectal cancer has also demonstrated that 8-gingerol inhibits epidermal growth factor receptor (EGFR) signaling. Moreover, it suppresses proliferation and migration by EGFR/STAT/ERK axis [156].


Cervical cancer is one of the most common and important gynecological cancers, which has become a global concern with an increasing number of patients and mortality rates. Although surgery, chemotherapy or radical hysterectomy, and radiotherapy are effective treatments for this disease, the side effects of these methods endanger a person’s quality of life and cause other problems in other parts of the body. In this regard, the establishment of new methods with fewer side effects seems to be necessary. Ginger is one of the plants with valuable compounds such as gingerols, paradols and shogoals, which is a rich source of antioxidants, anti-cancer and anti-inflammatory agents. Studies show that ginger by participating in various signaling pathways, can play a significant role in the prevention and treatment of cervical cancer (Fig. 1). Apoptosis, cell proliferation, altered cell morphology, suppressing proteasome and reactivating p53, DNA damage, redox potential regulation, and the production of free radicals are examples of pathways that ginger uses to treat cervical cancer.

Fig. 1

Schematic representation of gingerol applications on signaling pathway in cervical cancer

Induction of apoptosis and inhibition of cell proliferation are the main routes through which ginger restricts the progression of cervical cancer and can cure it. Also, inhibiting miR-629 expression and inhibiting the production of prostaglandins and inhibiting the PI3K/Akt pathway are other ways in which ginger extract improves cervical cancer. After all, it seems that ginger can be a safe natural treatment for cervical cancer. On the other hand, by combining ginger with other treatments such as the use of chemotherapy drugs, more effective treatment with fewer side effects can be achieved. Since there are not enough studies to determine the appropriate and effective dose of this plant, more clinical studies inside the body and in the laboratory, it is necessary for the therapeutic purposes of this plant. For instance, the effect of gingerol on cancer stem cells which are responsible for many tumor features such as drug resistance is not investigated.

We suggest that also using nanotechnology for enhancing the effects of gingerol, improving bio viability, monitoring its release, lowering its side effects, and finally providing a more personalized treatment should be considered by future researches. Additionally, despite the advantages of herbal medicine there are some limitations for using these products against cancer. For instance, all of the data on the efficacy of herbal compounds might not be true due to some impurities which have their own biological activity. This means that still more precise investigations are required for approving the effects of these compounds and their safeness. Moreover, in spite of the general belief, herbal medication is not completely safe and has also some side effects including nephrotoxicity [157]. In this regard, the following measurements are needed before using herbal medication in clinics: detection and characterization of every bioactive ingredient of the intended herbal compound and the standardization of these extracts.

Availability of data and materials

Not applicable.



human papillomavirus


Inducible nitric oxide synthase


Apoptotic protease activating factor 1


Mitochondrial respiratory complex I


H2A histone family member X.


Endoplasmic reticulum


Poly ADP ribose polymerase


Protein kinase RNA-like endoplasmic reticulum kinase


Ras suppressor-1


Prostaglandin D2


Prostaglandin E2


Prostaglandin F2


Prostaglandin I2




Reactive oxygen species


Death receptors 3


Death receptors 5


Protein kinase Cε


Nuclear factor-Kappa B


  1. 1.

    Small W Jr, Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM, et al. Cervical cancer: a global health crisis. Cancer. 2017;123:2404–12.

    PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Cohen PA, Jhingran A, Oaknin A, Denny L. Seminar Cervical cancer. 2019.

  3. 3.

    Slattery ML, Robison LM, Schuman KL, French TK, Abbott TM, Overall JC, et al. Cigarette smoking and exposure to passive smoke are risk factors for cervical cancer. Jama. 1989;261:1593–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Daly SF, Doyle M, English J, Turner M, Clinch J, Prendiville W. Can the number of cigarettes smoked predict high-grade cervical intraepithelial neoplasia among women with mildly abnormal cervical smears? Am J Obstet Gynecol. 1998;179:399–402.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Kjellberg L, Hallmans G, Åhren A, Johansson R, Bergman F, Wadell G, et al. Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection. Br J Cancer. 2000;82:1332–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Waggoner SE. Cervical cancer. Lancet. 2003;361:2217–25.

    PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Ngelange C, Munoz N, Bosch FX, Festin MR, Deacon J, Jacobs MV, et al. Causes of cervical cancer in the Philippines: a case-control study. JNCI. 1998;90:43–9.

    Article  Google Scholar 

  8. 8.

    Chichareon S, Herrero R, Munoz N, Bosch FX, Jacobs MV, Deacon J, et al. Risk factors for cervical cancer in Thailand: a case-control study. JNCI. 1998;90:50–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Bosch FX, Manos MM, Muñoz N, Sherman M, Jansen AM, Peto J, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. JNCI. 1995;87:796–802.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Rastogi N, Duggal S, Singh SK, Porwal K, Srivastava VK, Maurya R, et al. Proteasome inhibition mediates p53 reactivation and anticancer activity of 6-Gingerol in cervical cancer cells. Oncotarget. 2015;6:43310–25.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Das BC, Hussain S, Nasare V, Bharadwaj M. Prospects and prejudices of human papillomavirus vaccines in India. Vaccine. 2008;26:2669–79.

    PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Bhatla N, Berek JS, Fredes MC, Denny LA, Grenman S, Karunaratne K, et al. Revised FIGO staging for carcinoma of the cervix uteri 2019;145:129–35.

  13. 13.

    Phuah NH, Azmi MN, Awang K, Nagoor NH. Suppression of microRNA-629 enhances sensitivity of cervical cancer cells to 1′S-1′-acetoxychavicol acetate via regulating RSU1. OncoTargets and Therapy. 2017;10:1695–705.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Crafton SM, Salani R. Beyond chemotherapy: an overview and review of targeted therapy in cervical cancer. Clin Ther. 2016;38:449–58.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Liu Q, Peng YB, Qi LW, Cheng XL, Xu XJ, Liu LL, et al. The cytotoxicity mechanism of 6-shogaol-treated HeLa human cervical cancer cells revealed by label-free shotgun proteomics and bioinformatics analysis. Evid Based Complement Alternat Med. 2012:2012.

  17. 17.

    Huang R, Rofstad EK. Cancer stem cells (CSCs), cervical CSCs and targeted therapies. Oncotarget. 2017;8:35351–67.

    PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Ansari JA, Ahmad MK, Khan AR, Fatima N, Khan HJ, Rastogi N, et al. Anticancer and antioxidant activity of Zingiber officinale roscoe rhizome. Indian J Exp Biol. 2016;54:767–73.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Astley SB. Dietary antioxidants: past, present and future? Trends in food science & technology (Regular ed). 2003;14:93–8.

    CAS  Article  Google Scholar 

  20. 20.

    Zheng W, Wang SY. Antioxidant activity and phenolic compounds in selected herbs. J Agric Food Chem. 2001;49:5165–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Hassan BJMPUPTD. Plants and Cancer Treatment. 2019:1–11.

  22. 22.

    Desai AG, Qazi GN, Ganju RK, El-Tamer M, Singh J, Saxena AK, et al. Medicinal plants and cancer chemoprevention 2008;9:581–91.

  23. 23.

    Dorai T, Aggarwal BB. Role of chemopreventive agents in cancer therapy. Cancer Lett. 2004;215:129–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Wang SJ, Zheng CJ, Peng C, Zhang H, Jiang YP, Han T, et al. Plants and cervical cancer: an overview. Expert Opin Investig Drugs. 2013;22:1133–56.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  25. 25.

    Peng B, Hu Q, Liu X, Wang L, Chang Q, Li J, et al. Duchesnea phenolic fraction inhibits in vitro and in vivo growth of cervical cancer through induction of apoptosis and cell cycle arrest. Exp Biol Med. 2009;234:74–83.

    CAS  Article  Google Scholar 

  26. 26.

    Yong Y, Shin SY, Lee YH, Lim Y. Antitumor activity of deoxypodophyllotoxin isolated from Anthriscus sylvestris: induction of G2/M cell cycle arrest and caspase-dependent apoptosis. Bioorg Med Chem Lett. 2009;19:4367–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Choudhury D, Das A, Bhattacharya A, Chakrabarti G. Aqueous extract of ginger shows antiproliferative activity through disruption of microtubule network of cancer cells. Food Chem Toxicol. 2010;48:2872–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    White B. Ginger: an overview. Am Fam Physician. 2007;75:1689–91.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Mathew M, Subramanian S. In vitro evaluation of anti-Alzheimer effects of dry ginger (Zingiber officinale roscoe) extract. 2014.

  30. 30.

    Langmead L, Rampton D. Herbal treatment in gastrointestinal and liver disease—benefits and dangers. Aliment Pharmacol Ther. 2001;15:1239–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Iqbal Z, Lateef M, Akhtar MS, Ghayur MN, Gilani AH. In vivo anthelmintic activity of ginger against gastrointestinal nematodes of sheep. J Ethnopharmacol. 2006;106:285–7.

    PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Islam MS, Choi H. Comparative effects of dietary ginger (Zingiber officinale) and garlic (Allium sativum) investigated in a type 2 diabetes model of rats. J Med Food. 2008;11:152–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Iwami M, Shiina T, Hirayama H, Shima T, Takewaki T, Shimizu Y. Inhibitory effects of zingerone, a pungent component of Zingiber officinale roscoe, on colonic motility in rats. J Nat Med. 2011;65:89–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Lin R-J, Chen C-Y, Chung L-Y, Yen C-M. Larvicidal activities of ginger (Zingiber officinale) against Angiostrongylus cantonensis. Acta Trop. 2010;115:69–76.

    PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Yu Y, Zick S, Li X, Zou P, Wright B, Sun D. Examination of the pharmacokinetics of active ingredients of ginger in humans. AAPS J. 2011;13:417.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Zick SM, Djuric Z, Ruffin MT, Litzinger AJ, Normolle DP, Alrawi S, et al. Pharmacokinetics of 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol and conjugate metabolites in healthy human subjects. Cancer Epidemiology and Prevention Biomarkers. 2008;17:1930–6.

    CAS  Article  Google Scholar 

  37. 37.

    Kawai T, Kinoshita K, Koyama K, Takahashi K. Anti-emetic principles of Magnolia obovata bark and Zingiber officinale rhizome. Planta Med. 1994;60:17–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Surh Y-J. Anti-tumor promoting potential of selected spice ingredients with antioxidative and anti-inflammatory activities: a short review. Food Chem Toxicol. 2002;40:1091–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Wang W, Li C-Y, Wen X-D, Li P, Qi L-W. Simultaneous determination of 6-gingerol, 8-gingerol, 10-gingerol and 6-shogaol in rat plasma by liquid chromatography–mass spectrometry: application to pharmacokinetics. J Chromatogr B. 2009;877:671–9.

    CAS  Article  Google Scholar 

  40. 40.

    Shukla Y, Singh M. Cancer preventive properties of ginger: a brief review. Food Chem Toxicol. 2007;45:683–90.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Lee SH, Cekanova M, Baek SJJMCPicwtUoTMACC. Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells 2008;47:197–208.

  42. 42.

    Park YJ, Wen J, Bang S, Park SW, Song SYJYMJ. [6]-Gingerol induces cell cycle arrest and cell death of mutant p53-expressing pancreatic cancer cells. 2006;47:688.

  43. 43.

    Al-Abbasi FA, Alghamdi EA, Baghdadi MA, Alamoudi AJ, El-Halawany AM, El-Bassossy HM, et al. Gingerol synergizes the cytotoxic effects of doxorubicin against liver cancer cells and protects from its vascular toxicity 2016;21:886.

  44. 44.

    Jiang H, Xie Z, Koo HJ, McLaughlin SP, Timmermann BN, Gang DR. Metabolic profiling and phylogenetic analysis of medicinal Zingiber species: tools for authentication of ginger (Zingiber officinale Rosc). Phytochemistry. 2006;67:1673–85.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Maharlouei N, Tabrizi R, Lankarani KB, Rezaianzadeh A, Akbari M, Kolahdooz F, et al. The effects of ginger intake on weight loss and metabolic profiles among overweight and obese subjects: a systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr. 2019;59:1753–66.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Raygan F, Ostadmohammadi V, Bahmani F, Reiter RJ, Asemi Z. Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: a randomized, double-blind, placebo-controlled trial. Clin Nutr. 2019;38:191–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Tajadadi-Ebrahimi M, Bahmani F, Shakeri H, Hadaegh H, Hijijafari M, Abedi F, et al. Effects of daily consumption of synbiotic bread on insulin metabolism and serum high-sensitivity C-reactive protein among diabetic patients: a double-blind, randomized, controlled clinical trial. Annals of nutrition & metabolism. 2014;65:34–41.

    CAS  Article  Google Scholar 

  48. 48.

    Jamilian M, Samimi M, Ebrahimi FA, Hashemi T, Taghizadeh M, Razavi M, et al. The effects of vitamin D and omega-3 fatty acid co-supplementation on glycemic control and lipid concentrations in patients with gestational diabetes. Journal of clinical lipidology. 2017;11:459–68.

    PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Habib SHM, Makpol S, Hamid NAA, Das S, Ngah WZW, Yusof YAM. Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-induced hepatoma rats. Clinics. 2008;63:807–13.

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Jeyakumar S, Nalini N, Menon VP. Antioxidant activity of ginger (Zingiber officinale Rosc) in rats fed a high fat diet. Medical science research. 1999;27:341–4.

    Google Scholar 

  51. 51.

    Hudson EA, Fox LH, Luckett JC, Manson MM. Ex vivo cancer chemoprevention research possibilities. Environ Toxicol Pharmacol. 2006;21:204–14.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Huang S, DeGuzman A, Bucana CD, Fidler IJ. Nuclear factor-κB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice. Clin Cancer Res. 2000;6:2573–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Coppola G, Novo S. Statins and peripheral arterial disease: effects on claudication, disease progression, and prevention of cardiovascular events. Arch Med Res. 2007;38:479–88.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet. 2019;393:169–82.

    PubMed  Article  Google Scholar 

  55. 55.

    Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. Lancet. 2013;382:889–99.

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Hosseini ES, Meryet-Figuiere M, Sabzalipoor H, Kashani HH, Nikzad H, Asemi Z. Dysregulated expression of long noncoding RNAs in gynecologic cancers. Mol Cancer. 2017;16:107.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Goodman A. HPV testing as a screen for cervical cancer. Bmj. 2015;350:h2372.

    PubMed  Article  Google Scholar 

  58. 58.

    Tsikouras P, Zervoudis S, Manav B, Tomara E, Iatrakis G, Romanidis C, et al. Cervical cancer: screening, diagnosis and staging. J buon. 2016;21:320–5.

    PubMed  Google Scholar 

  59. 59.

    Peirson L, Fitzpatrick-Lewis D, Ciliska D, Warren R. Screening for cervical cancer: a systematic review and meta-analysis. Systematic reviews. 2013;2:35.

    PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Govindarajan V, Connell D. Ginger—chemistry, technology, and quality evaluation: part 1. Critical Reviews in Food Science & Nutrition. 1983;17:1–96.

    Article  Google Scholar 

  61. 61.

    Sang S, Hong J, Wu H, Liu J, Yang CS, Pan M-H, et al. Increased growth inhibitory effects on human cancer cells and anti-inflammatory potency of shogaols from Zingiber officinale relative to gingerols. J Agric Food Chem. 2009;57:10645–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Govindarajan V, Connell D. Ginger—chemistry, technology, and quality evaluation: part 2. Critical Reviews in Food Science & Nutrition. 1983;17:189–258.

    Article  Google Scholar 

  63. 63.

    Wu H, Hsieh MC, Lo CY, Liu CB, Sang S, Ho CT, et al. 6-Shogaol is more effective than 6-gingerol and curcumin in inhibiting 12-O-tetradecanoylphorbol 13-acetate-induced tumor promotion in mice. Mol Nutr Food Res. 2010;54:1296–306.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Schwertner HA, Rios DC. High-performance liquid chromatographic analysis of 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol in ginger-containing dietary supplements, spices, teas, and beverages. J Chromatogr B. 2007;856:41–7.

    CAS  Article  Google Scholar 

  65. 65.

    Katiyar S, Agarwal R, Mukhtar H. Inhibition of 12-O-tetradecanoyl phorbal acetate caused tumor promotion in 7, 12, dimethyl benz (a) anthracene-initiated Sincar mouse by a polyphenol fraction. Cancer Res. 1996;56:1023–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Park K-K, Chun K-S, Lee J-M, Lee SS, Surh Y-J. Inhibitory effects of [6]-gingerol, a major pungent principle of ginger, on phorbol ester-induced inflammation, epidermal ornithine decarboxylase activity and skin tumor promotion in ICR mice. Cancer Lett. 1998;129:139–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol. 2006;71:1397–421.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Kim SO, Chun KS, Kundu JK, Surh YJ. Inhibitory effects of [6]-gingerol on PMA-induced COX-2 expression and activation of NF-κB and p38 MAPK in mouse skin. Biofactors. 2004;21:27–31.

    PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Sadzuka Y, Hatakeyama H, Daimon T, Sonobe T. Screening of biochemical modulator by tumor cell permeability of doxorubicin. Int J Pharm. 2008;354:63–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Young H-Y, Luo Y-L, Cheng H-Y, Hsieh W-C, Liao J-C, Peng W-H. Analgesic and anti-inflammatory activities of [6]-gingerol. J Ethnopharmacol. 2005;96:207–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    Shoji N, Iwasa A, Takemoto T, Ishida Y, Ohizumi Y. Cardiotonic principles of ginger (Zingiber officinale roscoe). J Pharm Sci. 1982;71:1174–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Park M, Bae J, Lee DS. Antibacterial activity of [10]-gingerol and [12]-gingerol isolated from ginger rhizome against periodontal bacteria. Phytotherapy Research. 2008;22:1446–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Mascolo N, Jain R, Jain S, Capasso F. Ethnopharmacologic investigation of ginger (Zingiber officinale). J Ethnopharmacol. 1989;27:129–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Schwertner HA, Rios DC, Pascoe JE. Variation in concentration and labeling of ginger root dietary supplements. Obstet Gynecol. 2006;107:1337–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Abdul AB, Abdelwahab SI, Al-Zubaira AS, Elhassan MM, Murali SM. Anticancer and antimicrobial activities of zerumbone from the rhizomes of Zingiber zerumbut. Int J Pharmacol. 2008;4:301–4.

    CAS  Article  Google Scholar 

  76. 76.

    Phang CW, Malek SNA, Ibrahim H. Antioxidant potential, cytotoxic activity and total phenolic content of Alpinia pahangensis rhizomes. BMC Complement Altern Med. 2013;13.

  77. 77.

    Oyagbemi AA, Saba AB, Azeez OI. Molecular targets of [6]-gingerol: its potential roles in cancer chemoprevention. Biofactors. 2010;36:169–78.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Liu Y, Whelan RJ, Pattnaik BR, Ludwig K, Subudhi E, Rowland H, et al. Terpenoids from Zingiber officinale (ginger) induce apoptosis in endometrial cancer cells through the activation of p53. PLoS One. 2012:7.

  79. 79.

    Chakraborty D, Bishayee K, Ghosh S, Biswas R, Mandal SK, Khuda-Bukhsh AR. [6]-Gingerol induces caspase 3 dependent apoptosis and autophagy in cancer cells: drug–DNA interaction and expression of certain signal genes in HeLa cells. Eur J Pharmacol. 2012;694:20–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Park YJ, Wen J, Bang S, Park SW, Song SY. [6]-Gingerol induces cell cycle arrest and cell death of mutant p53-expressing pancreatic cancer cells. Yonsei Med J. 2006;47:688–97.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Lin C-B, Lin C-C, Tsay GJ. 6-Gingerol inhibits growth of colon cancer cell LoVo via induction of G2/M arrest. Evid Based Complement Alternat Med. 2012;2012.

  82. 82.

    Kim E-C, Min J-K, Kim T-Y, Lee S-J, Yang H-O, Han S, et al. [6]-Gingerol, a pungent ingredient of ginger, inhibits angiogenesis in vitro and in vivo. Biochem Biophys Res Commun. 2005;335:300–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Lee SH, Cekanova M, Baek SJ. Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells. Molecular Carcinogenesis. 2008;47:197–208.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Rastogi N, Gara RK, Trivedi R, Singh A, Dixit P, Maurya R, et al. (6)-Gingerolinduced myeloid leukemia cell death is initiated by reactive oxygen species and activation of miR-27b expression. Free Radical Biology and Medicine. 2014;68:288–301.

  85. 85.

    Zhang F, Thakur K, Hu F, Zhang JG, Wei ZJ. 10-Gingerol, a phytochemical derivative from “Tongling White ginger”, inhibits cervical Cancer: insights into the molecular mechanism and inhibitory targets. J Agric Food Chem. 2017;65:2089–99.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Feng T, Su J, Ding Z-H, Zheng Y-T, Li Y, Leng Y, et al. Chemical constituents and their bioactivities of “Tongling White ginger”(Zingiber officinale). J Agric Food Chem. 2011;59:11690–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Dugasani S, Pichika MR, Nadarajah VD, Balijepalli MK, Tandra S, Korlakunta JN. Comparative antioxidant and anti-inflammatory effects of [6]-gingerol,[8]-gingerol,[10]-gingerol and [6]-shogaol. J Ethnopharmacol. 2010;127:515–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Ryu MJ, Chung HS. [10]-Gingerol induces mitochondrial apoptosis through activation of MAPK pathway in HCT116 human colon cancer cells. In Vitro Cellular & Developmental Biology-Animal. 2015;51:92–101.

    CAS  Article  Google Scholar 

  89. 89.

    Hung J-Y, Hsu Y-L, Li C-T, Ko Y-C, Ni W-C, Huang M-S, et al. 6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. J Agric Food Chem. 2009;57:9809–16.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Gan F-F, Nagle AA, Ang X, Ho OH, Tan S-H, Yang H, et al. Shogaols at proapoptotic concentrations induce G 2/M arrest and aberrant mitotic cell death associated with tubulin aggregation. Apoptosis. 2011;16:856–67.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91.

    Brusic V, Marina O, Wu CJ, Reinherz EL. Proteome informatics for cancer research: from molecules to clinic. Proteomics. 2007;7:976–91.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Jaiaree N, Itharat A, Ruangnoo S. Cytotoxic and anti-inflammatory activities of medicinal plants and women’s health remedy found in “Mahachotarat scripture” of Thai traditional medicine. J Med Assoc Thail. 2016;99:S211–S21.

    Google Scholar 

  93. 93.

    Munagala R, Kausar H, Munjal C, Gupta RC. Withaferin a induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis. 2011;32:1697–705.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 94.

    Tan S, GE de Vries E. GJ van der zee a, de Jong S. anticancer drugs aimed at E6 and E7 activity in HPV-positive cervical cancer. Curr Cancer Drug Targets. 2012;12:170–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993;75:495–505.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Kochetkov D, Il'Inskaia G, Komarov P, Strom E, Agapova L, Ivanov A, et al. Transcriptional inhibition of human papilloma virus in cervical carcinoma cells reactivates functions of the tumor suppressor p53. Mol Biol. 2007;41:515–23.

    CAS  Article  Google Scholar 

  97. 97.

    Saha B, Adhikary A, Ray P, Saha S, Chakraborty S, Mohanty S, et al. Restoration of tumor suppressor p53 by differentially regulating pro-and anti-p53 networks in HPV-18-infected cervical cancer cells. Oncogene. 2012;31:173–86.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98.

    Lin Z, Bazzaro M, Wang M-C, Chan KC, Peng S, Roden RB. Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin Cancer Res. 2009;15:570–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Zhao CY, Szekely L, Bao W, Selivanova G. Rescue of p53 function by small-molecule RITA in cervical carcinoma by blocking E6-mediated degradation. Cancer Res. 2010;70:3372–81.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  100. 100.

    Horner SM, DeFilippis RA, Manuelidis L, DiMaio D. Repression of the human papillomavirus E6 gene initiates p53-dependent, telomerase-independent senescence and apoptosis in HeLa cervical carcinoma cells. J Virol. 2004;78:4063–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Orlowski RZ, Kuhn DJ. Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res. 2008;14:1649–57.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102.

    Rastogi N, Mishra DP. Therapeutic targeting of cancer cell cycle using proteasome inhibitors. Cell Div. 2012;7:26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Bruning A, Vogel M, Mylonas I, Friese K, Burges A. Bortezomib targets the caspase-like proteasome activity in cervical cancer cells, triggering apoptosis that can be enhanced by nelfinavir. Curr Cancer Drug Targets. 2011;11:799–809.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. 104.

    Anchoori RK, Khan SR, Sueblinvong T, Felthauser A, Iizuka Y, Gavioli R, et al. Stressing the ubiquitin-proteasome system without 20S proteolytic inhibition selectively kills cervical cancer cells. PLoS One. 2011:6.

  105. 105.

    Hong YS, Hong S-W, Kim S-M, Jin D-H, Shin J-S, Yoon DH, et al. Bortezomib induces G2-M arrest in human colon cancer cells through ROS-inducible phosphorylation of ATM-CHK1. Int J Oncol. 2012;41:76–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Smits VA, Klompmaker R, Vallenius T, Rijksen G, Mäkelä TP, Medema RH. p21 inhibits Thr161 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint. J Biol Chem. 2000;275:30638–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Achanta G, Huang P. Role of p53 in sensing oxidative DNA damage in response to reactive oxygen species-generating agents. Cancer Res. 2004;64:6233–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Lv C, Hong Y, Miao L, Li C, Xu G, Wei S, et al. Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway. Cell death & disease. 2013;4:e952-e.

  109. 109.

    Wang Q, Zheng X-L, Yang L, Shi F, Gao L-B, Zhong Y-J, et al. Reactive oxygen species-mediated apoptosis contributes to chemosensitization effect of saikosaponins on cisplatin-induced cytotoxicity in cancer cells Journal of experimental & clinical cancer research 2010;29:159.

  110. 110.

    Sharma V, Joseph C, Ghosh S, Agarwal A, Mishra MK, Sen E. Kaempferol induces apoptosis in glioblastoma cells through oxidative stress. Mol Cancer Ther. 2007;6:2544–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Serkies K, Jassem J. Concurrent weekly cisplatin and radiotherapy in routine management of cervical cancer: a report on patient compliance and acute toxicity. Int J Radiat Oncol Biol Phys. 2004;60:814–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    Poveda A, Salazar R, Del Campo J, Mendiola C, Cassinello J, Ojeda B, et al. Update in the management of ovarian and cervical carcinoma. Clin Transl Oncol. 2007;9:443–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. 113.

    Singh M, Bhui K, Singh R, Shukla Y. RETRACTED: Teea polyphenols enhance cisplatin chemosensitivity in cervical cancer cells via induction of apoptosis. Elsevier; 2013.

  114. 114.

    Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009;122:437–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Riedl SJ, Salvesen GS. The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol. 2007;8:405–13.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Awang K, Azmi N, Nurul M, Aun IL, Lian LI, Nazif Aziz AN, et al. The apoptotic effect of 1′S-1′-Acetoxychavicol acetate from Alpinia conchigera on human cancer cells. Molecules. 2010;15:8048–59.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Phuah NH, In LL, Azmi MN, Ibrahim H, Awang K, Nagoor NH. Alterations of microRNA expression patterns in human cervical carcinoma cells (ca ski) toward 1′ S-1′-acetoxychavicol acetate and cisplatin. Reprod Sci. 2013;20:567–78.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294:853–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Yan B, Guo Q, Nan X-X, Wang Z, Yin Z, Yi L, et al. Micro-ribonucleic acid 29b inhibits cell proliferation and invasion and enhances cell apoptosis and chemotherapy effects of cisplatin via targeting of DNMT3b and AKT3 in prostate cancer. OncoTargets and therapy. 2015;8:557.

  121. 121.

    Othman N, In LL, Harikrishna JA, Hasima N. Bcl-xL silencing induces alterations in hsa-miR-608 expression and subsequent cell death in A549 and SK-LU1 human lung adenocarcinoma cells. PLoS One. 2013;8.

  122. 122.

    Liu J, Wang H, Wang Y, Li Z, Pan Y, Liu Q, et al. Repression of the miR-93-enhanced sensitivity of bladder carcinoma to chemotherapy involves the regulation of LASS2. OncoTargets and therapy. 2016;9:1813.

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Ho CS, Yap SH, Phuah NH, In L, Hasima N. MicroRNAs associated with tumour migration, invasion and angiogenic properties in A549 and SK-Lu1 human lung adenocarcinoma cells. Lung cancer (Amsterdam, Netherlands). 2014;83:154–62.

  124. 124.

    Liu Z, Zhang J, Yuan X, Liu B, Liu Y, Li A, et al. Detecting pan-cancer conserved microRNA modules from microRNA expression profiles across multiple cancers. Mol BioSyst. 2015;11:2227–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125.

    Cazzoli R, Buttitta F, Di Nicola M, Malatesta S, Marchetti A, Rom WN, et al. microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer. Journal of thoracic oncology. 2013;8:1156–62.

  126. 126.

    Shin VY, Ng EK, Chan VW, Kwong A, Chu K-M. A three-miRNA signature as promising non-invasive diagnostic marker for gastric cancer. Mol Cancer. 2015;14:202.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Honegger A, Schilling D, Bastian S, Sponagel J, Kuryshev V, Sültmann H, et al. Dependence of intracellular and exosomal microRNAs on viral E6/E7 oncogene expression in HPV-positive tumor cells. PLoS Pathog. 2015:11.

  128. 128.

    Cutler M, Bassin R, Zanoni L, Talbot N. Isolation of rsp-1, a novel cDNA capable of suppressing v-Ras transformation. Mol Cell Biol. 1992;12:3750–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Vasaturo F, Dougherty G, Cutler M. Ectopic expression of Rsu-1 results in elevation of p21 CIP and inhibits anchorage-independent growth of MCF7 breast cancer cells. Breast Cancer Res Treat. 2000;61:69–78.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. 130.

    Tsuda T, Marinetti MR, Masuelli L, Cutler ML. The Ras suppressor RSU-1 localizes to 10p13 and its expression in the U251 glioblastoma cell line correlates with a decrease in growth rate and tumorigenic potential. Oncogene. 1995;11:397–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Dietlmeier S, Ye Y, Kuhn C, Vattai A, Vilsmaier T, Schröder L, et al. The prostaglandin receptor EP2 determines prognosis in EP3-negative and galectin-3-high cervical cancer cases. Sci Rep. 2020;10:1–10.

    Article  CAS  Google Scholar 

  132. 132.

    Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999;79:1193–226.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    Amano H, Hayashi I, Endo H, Kitasato H, Yamashina S, Maruyama T, et al. Host prostaglandin E2-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med. 2003;197:221–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Paz-Elizur T, Sevilya Z, Leitner-Dagan Y, Elinger D, Roisman LC, Livneh Z. DNA repair of oxidative DNA damage in human carcinogenesis: potential application for cancer risk assessment and prevention. Cancer Lett. 2008;266:60–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Heinecke JW. Mechanisms of oxidative damage of low density lipoprotein in human atherosclerosis. Curr Opin Lipidol. 1997;8:268–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Liu J, Mori A. Oxidative damage hypothesis of stress-associated aging acceleration: neuroprotective effects of natural and nutritional antioxidants. RESEARCH COMMUNICATIONS IN BIOLOGICAL PSYCHOLOGY PSYCHIATRY AND NEUROSCIENCES. 2005;30:B103.

    Google Scholar 

  137. 137.

    Beal MF. Mitochondria, oxidative damage, and inflammation in Parkinson's disease. ANNALS-NEW YORK ACADEMY OF SCIENCES. 2003;991:120–31.

    CAS  Article  Google Scholar 

  138. 138.

    Jain SK. Superoxide dismutase overexpression and cellular oxidative damage in diabetes. Free Radic Biol Med. 2006;8:1187–90.

    Article  CAS  Google Scholar 

  139. 139.

    Noda N, Wakasugi H. Cancer and oxidative stress. Japan Medical Association Journal. 2001;44:535–9.

    Google Scholar 

  140. 140.

    Halliwell B. How to characterize a biological antioxidant. Free Radic Res Commun. 1990;9:1–32.

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Halliwell B. Antioxidants: the basics-what they are and how to evaluate them. Advances in pharmacology: Elsevier; 1996. p. 3–20.

  142. 142.

    Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. 143.

    Murugan K, Vanithakumari G, Sampathraj R. Biochemical changes in epididymis following treatment with combined extracts of Amaranthus spinosus roots and Dolichos biflorus seeds. Anc Sci Life. 1993;13:154.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Nishikii H, Kim B-S, Yokoyama Y, Chen Y, Baker J, Pierini A, et al. DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease. Blood, The Journeal of the American Society of Hematology 2016;s.

  145. 145.

    Adbul ABH, Al-Zubairi AS, Tailan ND, Wahab SIA, Zain ZNM, Rusley S, et al. Anticancer activity of natural compound (Zerumbone) extracted from Zingiber zerumbet in human HeLa cervical cancer cells. Int J Pharmacol. 2008;4:160–8.

    Article  Google Scholar 

  146. 146.

    Lin H-C, Lin M-H, Liao J-H, Wu T-H, Lee T-H, Mi F-L, et al. Antroquinonol, a ubiquinone derivative from the mushroom Antrodia camphorata, inhibits colon cancer stem cell-like properties: insights into the molecular mechanism and inhibitory targets. J Agric Food Chem. 2017;65:51–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  147. 147.

    Sharma C, Ahmed T, Sasidharan S, Ahmed M, Hussain A. Use of gemcitabine and ginger extract infusion may improve the efficiency of cervical cancer treatment. Afr J Biotechnol. 2009;8:7087–93.

    CAS  Google Scholar 

  148. 148.

    Tilborghs S, Corthouts J, Verhoeven Y, Arias D, Rolfo C, Trinh XB, et al. The role of nuclear factor-kappa B signaling in human cervical cancer. Crit Rev Oncol Hematol. 2017;120:141–50.

    PubMed  Article  PubMed Central  Google Scholar 

  149. 149.

    Kim SO, Kim MR. [6]-Gingerol prevents disassembly of cell junctions and activities of MMPs in invasive human pancreas Cancer cells through ERK/NF- κ B/snail signal transduction pathway. eCAM. 2013;761852:2013.

    Google Scholar 

  150. 150.

    Rhode J, Fogoros S, Zick S, Wahl H, Griffith KA, Huang J, et al. Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells. BMC Complement Altern Med. 2007;7:44.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. 151.

    Tyagi A, Vishnoi K, Kaur H, Srivastava Y, Roy BG, Das BC, et al. Cervical cancer stem cells manifest radioresistance: association with upregulated AP-1 activity. Sci Rep. 2017;7:4781.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  152. 152.

    Annamalai G, Suresh K. [6]-Shogaol attenuates inflammation, cell proliferation via modulate NF-κB and AP-1 oncogenic signaling in 7,12-dimethylbenz [a] anthracene induced oral carcinogenesis. Biomedicine & pharmacotherapy. 2018;98:484–90.

    CAS  Article  Google Scholar 

  153. 153.

    Ling H, Yang H, Tan SH, Chui WK, Chew EH. 6-Shogaol, an active constituent of ginger, inhibits breast cancer cell invasion by reducing matrix metalloproteinase-9 expression via blockade of nuclear factor-κB activation. Br J Pharmacol. 2010;161:1763–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Morgan EL, Macdonald A. Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Rac1-NFκB-IL-6 signalling axis. PLoS Pathog. 2019;15:e1007835.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Chen J, Wu Y, Li S, Wu H, Li L. 10-gingerol inhibits proliferation of hepatocellular carcinoma HepG2 cells via Src/STAT3 signaling pathway. Journal of Southern Medical University. 2018;38:1002–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Hu SM, Yao XH, Hao YH, Pan AH, Zhou XW. 8-Gingerol regulates colorectal cancer cell proliferation and migration through the EGFR/STAT/ERK pathway. Int J Oncol. 2020;56:390–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Yang B, Xie Y, Guo M, Rosner MH, Yang H, Ronco C. Nephrotoxicity and Chinese herbal medicine. CJASN. 2018;13:1605–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references


Not applicable.


Not applicable.

Author information




JH and ZA contributed in conception, design and drafting of the manuscript. PZ, PM-D, EN contributed in data collection and manuscript drafting. All authors approved the final version for submission. JH oversaw the study.

Corresponding author

Correspondence to Jamal Hallajzadeh.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zivarpour, P., Nikkhah, E., Maleki Dana, P. et al. Molecular and biological functions of gingerol as a natural effective therapeutic drug for cervical cancer. J Ovarian Res 14, 43 (2021).

Download citation


  • Cervical cancer
  • Gynecological cancers
  • Human papillomavirus
  • Ginger