The Potential of Chinese Herbal Medicines in the Treatment of Cervical Cancer

Abstract

Cervical cancer is a global health issue and places a considerable economic and medical burden on society. Thus, a concerted effort to improve the treatment of cervical cancer is warranted. Although several treatment options are currently available for treating patients with cervical cancer, such as chemoradiation and neoadjuvant or adjuvant chemotherapy, more aggressive systemic therapies and newer therapeutic agents are under investigation. Medicinal herbs have long been used to treat diseases. In this review, we summarize studies analyzing the antitumor effects and underlying mechanisms of Chinese herbal medicines, including the effects of crude extracts and compounds in vitro or in animal models for inducing apoptosis and inhibiting invasion or metastasis. Chinese herbal medicines with therapeutic targeting, such as those that interfere with tumor growth and progression in cervical cancer, have been widely investigated. To apply Chinese herbal medicine in the treatment of cervical cancer, adequate clinical studies are required to confirm its clinical safety and efficiency. Further investigations focused on the purification, pharmacokinetics, and identification of compounds from Chinese herbal medicines in cervical cancer treatment are necessary to achieve the aforementioned treatment goals.

Keywords

cervical cancer medicinal herb Chinese herbal medicine cancer treatment apoptosis

Introduction

Cervical cancer is a pertinent global health issue as it is the fourth most common cancer in women worldwide and causes more than one quarter of a million deaths per year.¹ Such cancer confers an economic and medical burden on society. Thus, a concerted global effort to improve the treatment of cervical cancer is warranted. The treatment of cervical cancer is based on the International Federation of Gynecology and Obstetrics staging system.² Cervical cancer stages range from I to IV. Patients with locally advanced or early-stage cervical cancer have access to conventional treatments, including surgery, chemotherapy, and radiotherapy. However, no standard therapy is available for patients with metastatic cervical cancer.³ Treatment options might be insufficient and have associated side effects. In addition to several treatment options being available to treat cervical cancer, such as chemoradiation and neoadjuvant or adjuvant chemotherapy, more aggressive systemic therapies and newer therapeutic agents are under investigation.⁴

Cancer is characterized by a multistep development of considerable complexity, including uncontrolled cell proliferation, invasion, migration, and metastasis.⁵ Antitumor therapies for human cancer tend to be based on administering apoptosis-inducing drugs that inhibit proliferation, invasion, and metastasis. Medicinal herbs have long been used to treat many diseases, including cancer.⁶

In this review, we summarize studies analyzing the antitumor effects and underlying mechanisms of Chinese herbal medicines, including the effects of crude extracts and compounds in vitro or in animal models for inducing apoptosis and inhibiting invasion or metastasis.

Effects of Chinese Herbal Medicines on Cervical Cancer Cells

Crude Extracts of Chinese Herbal Medicines With Anti-Cervical Cancer Effects

Antrodia cinnamomea

Antrodia cinnamomea, also called Antrodia camphorata, is a food source used in traditional Chinese medicine.⁷ Crude extracts of A camphorata exhibit a wide range of biological activities, with several studies having focused on its anticancer effects. The hepatoprotective activities⁸ and activities against liver injury⁹ of A camphorata have also been reported. By using the lyophilized powder of A camphorata mycelium with distilled water, A camphorata was revealed to be nontoxic. Furthermore, the researchers involved in that study demonstrated the effects of A camphorata extracts, including its dose-dependent antioxidant and antimutagenic effects on 4NQNO and its DNA-protective activities against hydroxyl radical–induced damage.¹⁰ Pharmacological studies of A camphorata have mostly been in vitro or in vivo experiments on animals.¹¹ Few clinical trials analyzing the effects of A camphorata extracts on humans have been reported. Clinical studies are required to confirm the therapeutic effects of such extracts. The effects of ethyl acetate extract from A camphorata fruiting bodies on hepatocellular carcinoma cell lines Hep G2 and PLC/PRF/5 have been investigated,¹² finding that cell growth decreased and apoptosis was induced in both Hep G2 and PLC/PRF/5.¹² The antiproliferative effects of methanol extracts from A camphorata mycelia were investigated, with the findings suggesting that apoptosis of human hepatoma HepG2 cells could be achieved through regulation of the Fas pathway.¹³ The effect of a fermented culture broth of A camphorata was shown to inhibit growth and have antiproliferative effects on MCF-7 cells through apoptosis induction.¹⁴ Furthermore, the induction of phase G(2)M arrest and the antimetastatic effects of A camphorata extracts on urinary bladder cancer have been demonstrated.¹⁵ A study also found that a fermented culture broth of A camphorata induced cell cycle arrest of MDA-MB-231 cells and apoptosis in an in vivo breast cancer model involving athymic nude mice.¹⁶ Extracts of A camphorata fruiting bodies induced leukemia HL 60 cell apoptosis and could be a potential chemotherapeutic adjuvant.¹⁷

The apoptotic effect of the crude extract of A camphorata on cervical cancer cells, HeLa and C-33A, has been reported.¹⁸ A camphorata extract increased the activity of caspase-3, -8, and -9 as well as the cytosolic level of cytochrome c in HeLa and C-33A cell lines. The expressions of Bad, Bak, and Bim were increased, and the expressions of Bcl-2 family proteins were decreased. The expressions of inhibitor of apoptosis proteins (IAPs) and X-linked IAP protein also decreased, as did cell survival. Thus, the cytotoxic effect of A camphorata extract on cervical cancer cells through both extrinsic and intrinsic apoptotic pathways was demonstrated.¹⁸

Terminalia catappa

Various phytoconstituents from the leaves, fruits, and seeds of Terminalia catappa have been identified.¹⁹ The antimicrobial, anti-inflammation, hepatoprotective, and anticancer activities of T catappa leaf extracts (TCEs) have been recognized.¹⁹ TCEs exhibited hepatoprotective effects on liver damage induced by D-galactosamine²⁰ and liver mitochondria damaged by carbon tetrachloride.²¹ Furthermore, the inhibitory effect of TCEs on lung cancer metastasis in vitro and in vivo was proven.²² The underlying molecular mechanisms of the antimetastatic effects of TCEs on hepatocellular carcinoma were demonstrated by a recent study.²³ The researchers found that TCEs exert antimetastatic effects through inhibiting the activities and expression of matrix metalloproteinase-9 (MMP-9) in hepatocellular carcinoma Huh7 cells.²³

The antitumor effect of TCEs against Ehrlich ascites carcinoma in an animal model has been reported.²⁴ Tumor-bearing animals, namely Swiss albino mice, were treated with ethanol extract of T catappa leaves. Decreasing levels of lipid peroxidation and glutathione and increasing levels of superoxide dismutase and catalase activity were detected. The researchers demonstrated the antitumor effect of TCEs by modulating lipid peroxidation and augmenting antioxidant defense systems.²⁴ The antimetastatic effect of ethanol extracts of T catappa on cervical cancer cells after treatment with 12-O-tetradecanoylphorbol-13-acetate was reported.²⁵ The results of that study revealed that TCE exerted antimetastatic effects on cervical cancer cells by inhibiting the expression of MMP-9 and mitogen-activated protein kinase (MAPK) pathways on such cells.²⁵

Chelidonium majus

Chelidonium majus, commonly known as greater celandine, has been shown to contain several isoquinoline alkaloids, such as sanguinarine, chelidonine, chelerythrine, berberine, and coptisisine, in the crude extract of its roots, shoots, and leaves.²⁶ Both C majus and its main alkaloid chelidonine have cytotoxic effects against cancer cells, such as leukemia,²⁷ PANC-1 (pancreatic cancer), and HT-29 (colon cancer) cells.²⁸ The effects of chelidonine isolated from the ethanolic extract of C majus on HeLa cells were demonstrated by Paul et al.²⁶ Chelidonine, isolated from the ethanolic extract of C majus, was reported to inhibit proliferation and induce apoptosis in HeLa cells through upregulating the expression of p38 and p53 and downregulating the expression of AKT, PI3K, JAK3, STAT3, E6, and E7.²⁶ The researchers of that study posited that these effects of chelidonine on cervical cancer cells were through the p38-p53 and AKT/PI3 kinase signaling pathways.²⁶

Lycopodium clavatum

The ethanolic extract of Lycopodium clavatum has been used as an alternative medicine for treating Alzheimer’s disease and liver ailments.²⁹ The protective potential of L clavatum extract on mice chronically fed hepatocarcinogens has also been shown.³⁰ The anticancer effects of lycopodine on cervical cancer were investigated by an in vitro study using HeLa cells.²⁹ Numerous activities of lycopodine were detected, including the induction of chromatin condensation, the enhancement of cell populations in the sub-G1 region, the fragmentation of internucleosomal DNA, and the activation of caspase-3.²⁹ The antiproliferative effect of lycopodine on HeLa cells was achieved through the induction of apoptosis via caspase-3 activation.²⁹

Diarylheptanoid-Myricanone

Myrica cerifera extract has been used as an anticancer drug, with hepatoprotective and apoptosis-promoting abilities also reported.³¹ The mechanism has been investigated by applying myricanone from the crude ethanolic extract of M cerifera in human hepatocellular carcinoma (HepG2) and normal liver (WRL-68) cell lines.³¹ The extract of M cerifera exhibited anticancer potential for inducing apoptosis in HepG2 cells through the generation of reactive oxygen species (ROS) and the depolarization of the mitochondrial membrane.³¹ Myricanone triggered apoptotic effects through ROS generation and mitochondrial membrane depolarization, elevating mitochondria-dependent caspase activity to induce apoptosis in HepG2 cells. The anticancer effect of diarylheptanoid-myricanone isolated from the ethanolic extract of M cerifera on HeLa cells has been investigated and was found to have a greater cytotoxic effect and promote G0/G1 arrest.³² The researchers demonstrated that myricanone induced apoptosis by triggering caspase activation and downregulating NF-κB and STAT3 signaling cascades³² (Table 1).

Table 1.

Functions of the Crude Extracts of Chinese Herbal Medicines in Uterine Cervical Cancer.

	Chinese Herbal Medicine	Cell Lines/Animal Models	Action	References
1	Antrodia camphorata	HeLa and C-33A cells	Cytotoxic to cervical cancer cells through both extrinsic and intrinsic apoptotic mechanisms	Yang et al¹⁸
2	Terminalia catappa	HeLa and SiHa cells	Antimetastatic effects through the inhibition of matrix metalloprotein-9 and MAPK pathway	Lee et al²⁵
3	Chelidonium majus	HeLa cells	Promoting apoptosis in HeLa cells through p38-p53 and PI3K/AKT signaling pathways	Paul et al²⁶
4	Lycopodium clavatum	HeLa cells	Inhibiting proliferation of HeLa cells through induction of apoptosis via caspase-3 activation	Mandal et al²⁹
5	Myrica cerifera	HeLa and PC3 cells	Inducing apoptosis in cancer cells by triggering caspase activation	Paul et al³²

Bioactive Compounds From Chinese Herbal Medicines in Uterine Cervical Cancer

Butein

Butein can be isolated from various plants, including Semecarpus anacardium, Toxicodendron vernicifluum, and Dalbergia odorifera, and it exhibits anti-allergic anti-inflammatory activities,³³ selectively inhibits NF-κB in activated human mast cells,³⁴ and suppresses MMP-9 expression and vascular endothelial growth factor in prostate cancer cells.³⁵ The effects of butein on cervical cancer cell growth, apoptosis, migration, and invasion have been investigated, with researchers finding that butein induced HeLa cell cycle at the G2/M stage and cell apoptosis through the PI3K/AKT/mTOR pathway.³⁶ Induction of apoptosis of human cervical cancer cells by butein has been reported recently.³⁷ The researchers found that butein disturbed mitochondrial transmembrane potential and caspase activities in C-33A and SiHa cells; moreover, they demonstrated butein’s proapoptotic effect, including inhibition of IAPs and activation of both extrinsic and intrinsic proapoptotic pathways.³⁷

Nujiangexathone A

Many traditional Chinese herbal medicines contain active compounds and exhibit anticancer effects.³⁸ Nujiangexathone A (NJXA), a compound isolated from the leaves of Garcinia nujiangensis, exhibits cytotoxic effects against tumor cell lines.³⁹ NJXA has been proposed to inhibit the proliferation of several human cancer cell lines,⁴⁰ the mechanism of which has been previously investigated.^39,40

Ubiquitin proteasome–dependent degradation of hnRNPK accelerated the cell cycle arrest of cervical tumor cell growth delayed in a HeLa xenograft model.³⁹ The tumor-inhibitory effect of NJXA was achieved through downregulation of hnRNPK.³⁹ The apoptosis-inducing activities of NJXA on HeLa and SiHa cells and in vitro have been studied.⁴⁰ NJXA induced caspase-dependent apoptosis. Changes in the levels of Bcl-2 family proteins, caspase-3 activation, cytochrome c release, and chromosome fragmentation have been identified.⁴⁰ NJXA induced apoptosis by activating the ROS-mediated JNK signaling pathway.⁴⁰

APS-1d

APS-1d is a novel polysaccharide isolated from Angelica sinensis. The root of A sinensis is a well-studied Chinese herbal medicine and has been used as an anti-inflammatory and hematopoietic agent for thousands of years.⁴¹ Recent advances in phytochemistry indicate that the crude extracts and pure compounds of A sinensis have numerous pharmacological activities, including antispasmodic, antioxidant, cardiovascular, and cerebrovascular effects and neuroprotective action.⁴² A sinensis polysaccharides have various important biological activities.⁴¹ The proapoptotic effects of APS-1d in HeLa cells both in vitro and in vivo have been investigated,⁴³ with findings revealing that APS-1d inhibited the growth of HeLa cells, induced the apoptosis of such cells in vitro, and promoted the apoptosis of these cells in vivo.⁴³ Furthermore, increasing the levels of proapoptotic proteins Bax and Bak and decreased the levels of antiapoptotic proteins Bcl-2 and Bcl-XL in APS-1d–treated cells.⁴³ APS-1d can inhibit HeLa cell proliferation and induce apoptosis via the intrinsic mitochondrial pathway.⁴³

Lappaol F

The antitumor activity of lappaol F, extracted from Arctium lappa L, was investigated in vitro and in vivo.⁴⁴ The researchers demonstrated that lappaol F strongly inhibited HeLa cell growth in xenograft tumors in nude mice. In HeLa cells, lappaol F suppressed cell growth and induced G1 and G2 cell cycle arrest and cell death. Lappaol F suppressed tumor growth in nude mice bearing the xenograft tumors of HeLa cervical cancer cells. From these results, the researchers posited that p21 may play a crucial role in lappaol F–mediated regulation of cyclin B1 and CDK1 and G2 cell cycle arrest and upregulate p21 at the transcriptional level in a p53-independent model.⁴⁴

Elephantopus mollis 23

Elephantopus mollis 23 (EM23), a natural sesquiterpene lactone from E mollis, is a traditional herbal medicine with multiple pharmacological activities, such as apoptotic activity in myeloid leukemia cells K562 and HL-60⁴⁵ and cytotoxic activities against mouse neuroblastoma B104 cells.⁴⁶ The apoptotic effect of EM23 has been investigated in CaSki and SiHa human cervical cancer cell lines. EM23 exerts growth inhibitory effects and results in caspase 3 activation, mitochondrial dysfunction, ASK1/JNK signaling activation, and inhibition of the expression levels of Trx/TrxR. A study demonstrated that EM23 inhibits activity of TrxR in cell-free systems and can induce downregulation of Trx and TrxR in CaSki and SiHa cells.⁴⁷

Eupafolin

Eupafolin is a flavone isolated from Artemisia princeps Pampanini. Eupafolin has several biological effects, such as anti-inflammatory activity against TNF-α–induced lung inflammation,⁴⁸ antitumor and antiangiogenic activity in hepatocellular carcinoma,⁴⁹ and enhancement of TRAIL-mediated apoptosis in renal carcinoma Caki cells.⁵⁰ The proapoptotic and molecular activity involving eupafolin in cervical adenocarcinoma HeLa cells was investigated,⁵¹ with the researchers finding that eupafolin triggered the activation of caspases 3, 6, 7, 8, and 9, as well as induced apoptosis dependent on caspase activation. Eupafolin induced mitochondrial membrane depolarization, modulated the expression of Bcl-2 family proteins, and induced caspase-8 activation by eupafolin via a Bcl-2–dependent pathway. The apoptotic effect of eupafolin on HeLa cells was through caspase-dependent pathways, involving caspases 3, 9, and 8.⁵¹

Baicalein

Baicalein is the active ingredient extracted from the root of Scutellaria baicalensis, which is used in traditional Chinese medicine. It has multiple effects, such as anti-inflammatory, anti-allergic, antioxidative, and antitumorigenic activities.⁵² Baicalein is involved in inhibiting various cancers, such as breast, bladder, and ovarian cancers.⁵³

Recent studies have reported that baicalein inhibits prostate cancer cell growth and metastasis via the caveolin-1/AKT/mTOR pathway⁵⁴ and inhibits hepatocellular carcinoma cells through suppressing the expression of CD24.⁵⁵ Furthermore, the restraining effect of baicalein on human cervical cancer cell line HeLa has been demonstrated.⁵² Baicalein induced HeLa cell apoptosis and significantly inhibited HeLa cell migration.⁵² Baicalein markedly downregulated extracellular signal–regulated kinase 1/2, MMP-2, and MMP-9 levels both in mRNA and protein.⁵²

Arctiin

Arctiin is a major lignan constituent of Arctium lappa. Its anti-inflammatory and antitumor effects have been widely explored.⁵⁶ The anticancer effects of arctiin regarding in vitro or in vivo animal models were investigated, revealing findings such as remarkable antitumor effects on mouse skin tumors,⁵⁷ protective effects on heterocyclic amino-induced mammary carcinogenesis in rats,⁵⁸ and growth inhibition in prostate cancer PC-3 cells via the upregulation of the antiadhesion mucin MUC-1 gene.⁵⁹ The inhibitory mechanism of arctiin in cervical cancer cells was through the downregulation of cyclin D1 expression.⁶⁰ The growth inhibition induced by arctiin was correlated with the downregulation of cyclin D1.⁶⁰

Corosolic Acid

The biological activities of corosolic acid (CRA), which can be obtained from various herbs, have been investigated.^57,61,62 CRA, extracted from Lagerstroemia speciosa L, lowered postchallenge plasma glucose levels in vivo in humans.⁶¹ CRA, a constituent of banaba leaves, has been reported to prevent oxidative stress, inflammation, and hypertension in vivo in SHR/NDmcr-cp rats.⁶² CRA, isolated from the fruit of Crategus pinnatifida var psilosa, exhibited antagonistic activity against the phorbol ester–induced morphological modification of leukemic cells via the suppression of protein kinase C activity.⁵⁷ The antitumor effect of CRA isolated from Actinidia valvata Dunn on human cervix adenocarcinoma HeLa cells was investigated,⁶³ finding that CRA induced apoptosis through increasing Bax/Bcl-2 ratios by upregulating Bax expression, disrupting mitochondrial membrane potential, and triggering the activation of caspases 8, 9, and 3 in HeLa cells.⁶³ Based on these results, the researchers posited that the apoptotic effect of CRA on HeLa cells is achieved through the activation of caspases via a mitochondrial pathway.⁶³

Praeruptorin A

Praeruptorin A, from the dried root of Peucedanum praeruptorum Dunn, was revealed to have antimicrobial activity in a previous study.⁶⁴ The anti-inflammatory⁶⁵ and anticancer effects⁶⁶ of praeruptorin A have been reported. The activity of praeruptorin A against cervical cancer cells was investigated in a recent study.⁶⁷ In that study, praeruptorin A inhibited cervical cancer HeLa and SiHa cell proliferation and migration and invasion.⁶⁷ The expression of MMP-2 was reduced, the tissue-inhibiting expression of metalloproteinase-2 (TIMP-2) increased, and ERK1/2 activation was suppressed in the cervical cancer cells treated with praeruptorin A; moreover, praeruptorin A suppressed MMP-2 expression and ERK1/2 signaling in cervical cancer cells.⁶⁷

Fisetin

Fisetin, a naturally occurring flavonoid, is present in fruits and vegetables. Fisetin has been described as a health-promoting dietary supplement.⁶⁸ Its effect on the antimetastatic potential of cervical cancer cells was previously investigated.⁶⁹ Fisetin suppressed the tetradecanoylphorbol-13-acetate (TPA)–induced activation of p38 MAPK and uPA and inhibited TPA-enhanced migration and invasion. The involved mechanism was the downregulation of urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-κB signaling pathway.⁶⁹ Furthermore, the therapeutic molecular mechanism of inducing apoptosis was through the ERK1/2-mediated activation of the caspase-8/caspase-3–dependent pathways.⁷⁰

Deoxyelephantopin

Deoxyelephantopin, extracted and purified from Elephantopus scaber, inhibited the growth of SiHa cells and triggered apoptosis through multiple molecular signaling pathways.⁷¹ The molecular mechanisms of the antiproliferative and apoptosis-inducing properties of deoxyelephantopin were investigated.⁷¹ An increase in p53 and p21 levels and a decrease in the phosphosignal transducer and activator of transcription 3 (pSTAT3-Tyr705), cyclin-dependent kinase 1 (cdc2), and cyclin B1 were detected. Downregulation of antiapoptotic proteins (Bcl2 and Bcl-xL) and upregulation of apoptotic protein (Bax) was also identified.⁷¹

Beta-Elemene

Beta-elemene is an active component of the traditional Chinese medicinal herb Curcuma zedoaria. Beta-elemene exhibits antitumor effects in various cancer cell lines, including hepatoma,⁷² MCF-7 human breast cancer,⁷³ and non–small cell lung cancer⁷⁴ cell lines. The antitumor effect of β-elemene on cervical cancer SiHa cells has been investigated.⁷⁵ Beta-elemene may inhibit cell proliferation and invasion and induce apoptosis. The expression levels of p53 and Bax were enhanced, and the expression of Bcl2 was suppressed. Downregulation of MMP-2 and MMP-9 expression levels was also detected.⁷⁵ The therapeutic molecular mechanism was through attenuation of the Wnt/β-catenin signaling pathway.⁷⁵

Polydatin

Polydatin, also known as piceid, is a stilbene compound that can be extracted from Polygonum cuspidatum.⁷⁶ Studies have demonstrated the various effects of polydatin, including its cardioprotective effects against ischemia or reperfusion injury,⁷⁷ its beneficial effects on attenuating ventricular remodeling in pressure-overload rat models,⁷⁸ its inhibition of lung cancer cell growth by inducing apoptosis and causing cell cycle arrest,⁷⁹ and its promotion of apoptosis and inhibition of proliferation in osteosarcoma cells.⁸⁰ Polydatin inhibits cell proliferation and induces apoptosis in Hep-2 and laryngeal cancer cell AMC-HN-8 through the suppression of the PDGF/AKT signaling pathway.⁷⁶ A proliferation-inhibiting effect and the induction of the apoptosis of polydatin were also noted in cervical cancer HeLa cells.⁸¹ In the same study, researchers showed that the growth-inhibiting effect caused S-phase arrest for HeLa cells, decreased the mRNA and protein expression levels of PI3K, AKT, mTOR, and P70S6K, and promoted cell apoptosis.⁸¹ Polydatin induces human cervical cancer cell apoptosis via the PI3K/AKT/mTOR signaling pathway.

Matrine

Matrine, an alkaloid isolated from Sophora flavescens, has been widely studied for its bioactivities and pharmacological effects, including anti-inflammatory, antimicrobial, antiviral, insecticidal, and anticancer activity.^82,83 Matrine has been shown to have antitumor effects for numerous types of cancer, such as breast,⁸⁴ lung,⁸⁵ and prostate⁸⁶ cancer. The molecular mechanisms of matrine in terms of its antitumor effects implicate the regulation of oncogene expression, the blockade of cell cycle progression, the inhibition of cytokine production, the induction of apoptosis, and the modulation of signaling pathways.^82,83 The antitumor effects of matrine on cervical cancer cells were evaluated in a recent study.⁸⁷ Matrine inhibited the cell growth and invasive and metastatic ability of HeLa and C33A cervical cancer cells in vitro; moreover, matrine inhibited tumor growth in vivo in a xenograft nude mouse model. Concerning the mechanism of matrine, induction of apoptosis, suppression of MMP-2 and MMP-9 expression, and inhibition of cervical cancer cell invasion were all achieved through the suppression of the p38 signaling pathway.⁸⁷

Conclusion and Future Prospects

Cervical cancer is a pertinent health concern for women worldwide. We reviewed the literature regarding the use of Chinese herbal medicines in the treatment of cervical cancer. These studies revealed that Chinese herbal medicines may be beneficial for treating patients with cervical cancer. The crude extracts or bioactive compounds from Chinese herbal medicines exhibit antiproliferative, apoptosis-inducing, anti-invasive, and static effects in uterine cervical cancer cell lines (HeLa, SiHa, or C33A cell lines) or animal models (BALB/c nude mice; Tables 1 and 2). These investigated drugs, with different molecular targets and modes of action, hold promising therapeutic potential and exhibited growth inhibition of xenograft tumors in nude mice. Cancer development and metastasis involve complex processes. Considerable advances in our understanding of invasion and metastasis have been achieved in recent years. The development of novel drugs with antitumor effects or for improving the quality of life of patients with cancer has been widely explored, with promising results.^88,89

Table 2.

Effects of Bioactive Compounds From Chinese Herbal Medicines on Uterine Cervical Cancer.

	Active Compound	Cell Lines/Animal Models	Function or Action	References
1	Butein	C33A and SiHa cells	Inducing apoptosis through activation of both extrinsic and intrinsic pathways	Yang et al³⁷
2	Nujiangex-athone A	HeLa and SiHa cells	Suppresses cervical cancer growth by targeting hnRNPK	Zhang et al³⁹
3	APS-1d	HeLa cells/BALB/c nude mice	Inducing apoptosis through an intrinsic apoptotic pathway	Cao et al⁴³
4	Lappaol F	HeLa cells/BALB/c nude mice	Growth suppression through inducing G1 and G2 cell cycle arrest	Sun et al⁴⁴
5	Elephantopus mollis 23	CaSki and SiHa cells	Induced cell apoptosis and cell cycle arrest	Shao et al⁴⁷
6	Eupafolin	HeLa cells	Induced apoptosis mediated by caspase-dependent pathways	Chung et al⁵¹
7	Baicalein	HeLa cells	Downregulated MMP-2 and MMP-9 levels	Ye et al⁵²
8	Arctiin	HeLa cells	Anti-proliferative effect downregulation of cyclin D1 expression	Matsuzaki et al⁶⁰
9	Corosolic acid	HeLa cells	Apoptosis through mitochondrial pathway and caspase activation	Xu et al⁶³
10	Praeruptorin A	HeLa and SiHa cells	Inhibits cell growth and invasion by suppressing MMP-2 expression	Wu et al⁶⁷
11	Fisetin	SiHa and CaSki cells/	Antimetastatic by downregulating urokinase plasminogen activator	Chou et al⁶⁹
11	Fisetin	HeLa cells	Apoptosis through caspase 8/3–dependent pathway	Ying et al⁷⁰
12	Deoxyelephantopin	SiHa cells	Impairs growth of cervical carcinoma SiHa cells and induces apoptosis	Farha et al⁷¹
13	β-elemene	SiHa cells	Induced apoptosis by enhancing the expression of p53 and Bax, and suppressing the expression of Bcl-2	Wang et al⁷⁵
14	Polydatin	HeLa cells	Inhibits cell proliferation and induces apoptosis via suppression of the PDGF/AKT signaling pathway	Li et al⁷⁶
15	Matrine	HeLa and C33A cells	Antimetastasis via downregulating the p38 signaling pathway	Wu et al⁸⁷

Prospects

Chinese herbal medicines with therapeutic targeting, such as interference with tumor growth and progression in cervical cancer cells and in nude mice, have been widely investigated. However, the effectiveness of Chinese herbal medicines in the treatment of cervical cancer is still unconfirmed. To apply Chinese herbal medicine in the treatment of cervical cancer, adequate clinical studies are required to confirm its clinical safety and efficiency. Further investigations focused on the purification, pharmacokinetics, and identification of compounds from Chinese herbal medicines in cervical cancer treatment are necessary to achieve this goal.

Footnotes

Authors’ Note

The funding source was not involved in study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the article for publication.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by research grants from Changhua Christian Hospital Research Foundation (106-CCH-IRP-109).

ORCID iD

Shun-Fa Yang

References

Small

Jr Bacon

Bajaj

et al . Cervical cancer: a global health crisis. Cancer. 2017;123:2404-2412.

Tsikouras

Zervoudis

Manav

et al . Cervical cancer: screening, diagnosis and staging. J BUON. 2016;21:320-325.

Cheng

. Advances in diagnosis and treatment of metastatic cervical cancer. J Gynecol Oncol. 2016;27:e43.

Gurram

Chopra

Mahantshetty

. The management of locally advanced cervical cancer. Curr Opin Oncol. 2018;30:323-329.

Hanahan

Weinberg

. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.

Graham

Quinn

Fabricant

Farnsworth

. Plants used against cancer—an extension of the work of Jonathan Hartwell. J Ethnopharmacol. 2000;73:347-377.

Zhang

Huang

Chen

. Current advances on the structure, bioactivity, synthesis, and metabolic regulation of novel ubiquinone derivatives in the edible and medicinal mushroom Antrodia cinnamomea. J Agric Food Chem. 2017;65:10395-10405.

Yue

Wong

Tsoi

Leung

. Current evidence for the hepatoprotective activities of the medicinal mushroom Antrodia cinnamomea. Chin Med. 2013;8(1):21.

Liu

Sheen

. Protective effects of Antrodia cinnamomea against liver injury. J Tradit Complement Med. 2012;2:284-294.

10.

Hsieh

Fang

Hwang

. Effects of Antrodia camphorata extracts on anti-oxidation, anti-mutagenesis and protection of DNA against hydroxyl radical damage. BMC Complement Altern Med. 2015;15:237.

11.

Geethangili

Tzeng

. Review of pharmacological effects of Antrodia camphorata and its bioactive compounds. Evid Based Complement Alternat Med. 2011;2011:212641.

12.

Hsu

Kuo

Lin

. Apoptotic effects of extract from Antrodia camphorata fruiting bodies in human hepatocellular carcinoma cell lines. Cancer Lett. 2005;221:77-89.

13.

Song

Hsu

Yeh

Yen

. Mycelia from Antrodia camphorata in submerged culture induce apoptosis of human hepatoma HepG2 cells possibly through regulation of Fas pathway. J Agric Food Chem. 2005;53:5559-5564.

14.

Yang

Chen

Chang

et al . Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by Antrodia camphorata. Cancer Lett. 2006;231:215-227.

15.

Peng

Chen

Peng

Hsieh-Li

. Human urinary bladder cancer T24 cells are susceptible to the Antrodia camphorata extracts. Cancer Lett. 2006;243:109-119.

16.

Hseu

Chen

Liao

Yang

. Antrodia camphorata inhibits proliferation of human breast cancer cells in vitro and in vivo. Food Chem Toxicol. 2008;46:2680-2688.

17.

Chuu

et al . Active extracts of wild fruiting bodies of Antrodia camphorata (EEAC) induce leukemia HL 60 cells apoptosis partially through histone hypoacetylation and synergistically promote anticancer effect of trichostatin A. Arch Toxicol. 2009;83:121-129.

18.

Yang

Liu

. Cytotoxic effect and induction of apoptosis in human cervical cancer cells by Antrodia camphorata. Am J Chin Med. 2013;41:1169-1180.

19.

Anand

Divya

Kotti

. An updated review of Terminalia catappa. Pharmacogn Rev. 2015;9:93-98.

20.

Tang

Gao

et al . Mechanisms of hepatoprotection of Terminalia catappa L extract on D-galactosamine-induced liver damage. Am J Chin Med. 2004;32:509-519.

21.

Tang

Gao

Wang

et al . Effective protection of Terminalia catappa L leaves from damage induced by carbon tetrachloride in liver mitochondria. J Nutr Biochem. 2006;17:177-182.

22.

Chu

Yang

Liu

Kuo

Chang

Hsieh

. In vitro and in vivo antimetastatic effects of Terminalia catappa L leaves on lung cancer cells. Food Chem Toxicol. 2007;45:1194-1201.

23.

Yeh

Hsieh

et al . Terminalia catappa exerts antimetastatic effects on hepatocellular carcinoma through transcriptional inhibition of matrix metalloproteinase-9 by modulating NF-κB and AP-1 activity. Evid Based Complement Alternat Med. 2012;2012:595292.

24.

Pandya

Tigari

Dupadahalli

Kamurthy

Nadendla

. Antitumor and antioxidant status of Terminalia catappa against Ehrlich ascites carcinoma in Swiss albino mice. Indian J Pharmacol. 2013;45:464-469.

25.

Lee

Yang

Wang

et al . Antimetastatic effects of Terminalia catappa leaf extracts on cervical cancer through the inhibition of matrix metalloprotein-9 and MAPK pathway. Environ Toxicol. 2019;34:60-66.

26.

Paul

Bishayee

Ghosh

et al . Chelidonine isolated from ethanolic extract of Chelidonium majus promotes apoptosis in HeLa cells through p38-p53 and PI3K/AKT signalling pathways. Zhong Xi Yi Jie He Xue Bao. 2012;10:1025-1038.

27.

El-Readi

Eid

Ashour

Tahrani

Wink

. Modulation of multidrug resistance in cancer cells by chelidonine and Chelidonium majus alkaloids. Phytomedicine. 2013;20:282-294.

28.

Capistrano

Wouters

Lardon

Gravekamp

Apers

Pieters

. In vitro and in vivo investigations on the antitumour activity of Chelidonium majus. Phytomedicine. 2015;22:1279-1287.

29.

Mandal

Biswas

Bhattacharyya

et al . Lycopodine from Lycopodium clavatum extract inhibits proliferation of HeLa cells through induction of apoptosis via caspase-3 activation. Eur J Pharmacol. 2010;626:115-122.

30.

Pathak

Banerjee

Paul

Khuda-Bukhsh

. Protective potentials of a plant extract (Lycopodium clavatum) on mice chronically fed hepato-carcinogens. Indian J Exp Biol. 2009;47:602-607.

31.

Paul

Das

Samadder

Khuda-Bukhsh

. Anticancer potential of myricanone, a major bioactive component of Myrica cerifera: novel signaling cascade for accomplishing apoptosis. J Acupunct Meridian Stud. 2013;6:188-198.

32.

Paul

Das

et al . Diarylheptanoid-myricanone isolated from ethanolic extract of Myrica cerifera shows anticancer effects on HeLa and PC3 cell lines: signalling pathway and drug-DNA interaction. J Integr Med. 2013;11:405-415.

33.

Chan

Chang

Wang

Chen

Kuo

. Three new flavonoids and antiallergic, anti-inflammatory constituents from the heartwood of Dalbergia odorifera. Planta Med. 1998;64:153-158.

34.

Rasheed

Akhtar

Khan

Haqqi

. Butrin, isobutrin, and butein from medicinal plant Butea monosperma selectively inhibit nuclear factor-kappaB in activated human mast cells: suppression of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8. J Pharmacol Exp Ther. 2010;333:354-363.

35.

Moon

Choi

Moon

Kim

. Butein suppresses the expression of nuclear factor-kappa B-mediated matrix metalloproteinase-9 and vascular endothelial growth factor in prostate cancer cells. Toxicol In Vitro. 2010;24:1927-1934.

36.

Bai

Zhang

. Butein suppresses cervical cancer growth through the PI3K/AKT/mTOR pathway. Oncol Rep. 2015;33:3085-3092.

37.

Yang

Kao

Lin

Liu

. Butein induces apoptotic cell death of human cervical cancer cells. Oncol Lett. 2018;16:6615-6623.

38.

Man

Gao

Wei

Liu

. Anticancer drugs from traditional toxic Chinese medicines. Phytother Res. 2012;26:1449-1465.

39.

Zhang

Feng

Kong

et al . Nujiangexathone A, a novel compound from Garcinia nujiangensis, suppresses cervical cancer growth by targeting hnRNPK. Cancer Lett. 2016;380:447-456.

40.

Zhang

Kong

Zheng

et al . Nujiangexathone A, a novel compound derived from Garcinia nujiangensis, induces caspase-dependent apoptosis in cervical cancer through the ROS/JNK pathway. Molecules. 2016;21:E1360.

41.

Jin

Zhao

Huang

Shang

. Isolation, structure and bioactivities of the polysaccharides from Angelica sinensis (Oliv) Diels: a review. Carbohydr Polym. 2012;89:713-722.

42.

Wei

Zeng

Huang

. Angelica sinensis in China—a review of botanical profile, ethnopharmacology, phytochemistry and chemical analysis. J Ethnopharmacol. 2016;190:116-141.

43.

Cao

Wang

et al . A novel polysaccharide, isolated from Angelica sinensis (Oliv) Diels induces the apoptosis of cervical cancer HeLa cells through an intrinsic apoptotic pathway. Phytomedicine. 2010;17:598-605.

44.

Sun

Liu

Shen

et al . Lappaol F, a novel anticancer agent isolated from plant arctium Lappa L. Mol Cancer Ther. 2014;13:49-59.

45.

Wang

et al . EM23, a natural sesquiterpene lactone from Elephantopus mollis, induces apoptosis in human myeloid leukemia cells through thioredoxin- and reactive oxygen species–mediated signaling pathways. Front Pharmacol. 2016;7:77.

46.

Tabopda

Ngoupayo

Liu

et al . Further cytotoxic sesquiterpene lactones from Elephantopus mollis KUNTH. Chem Pharm Bull (Tokyo). 2008;56:231-233.

47.

Shao

Wang

et al . EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells. Oncotarget. 2016;7:6790-6808.

48.

Sung

Liang

Lee

et al . The protective effect of eupafolin against TNF-α-induced lung inflammation via the reduction of intercellular cell adhesion molecule-1 expression. J Ethnopharmacol. 2015;170:136-147.

49.

Jiang

et al . Eupafolin exhibits potent anti-angiogenic and antitumor activity in hepatocellular carcinoma. Int J Biol Sci. 2017;13:701-711.

50.

Liu

Park

Chen

et al . Eupafolin suppresses prostate cancer by targeting phosphatidylinositol 3-kinase-mediated Akt signaling. Mol Carcinog. 2015;54:751-760.

51.

Chung

Choi

Back

et al . Eupafolin, a flavonoid isolated from Artemisia princeps, induced apoptosis in human cervical adenocarcinoma HeLa cells. Mol Nutr Food Res. 2010;54:1318-1328.

52.

Zhang

Wang

Xia

Mao

. The restraining effect of baicalein and U0126 on human cervical cancer cell line HeLa. Mol Med Rep. 2017;16:957-963.

53.

Liu

Dong

Gao

et al . The fascinating effects of baicalein on cancer: a review. Int J Mol Sci. 2016;17:E1681.

54.

Guo

Xing

et al . Baicalein inhibits prostate cancer cell growth and metastasis via the caveolin-1/AKT/mTOR pathway. Mol Cell Biochem. 2015;406:111-119.

55.

Han

Zhu

Han

Wang

Zheng

. Baicalein inhibits hepatocellular carcinoma cells through suppressing the expression of CD24. Int Immunopharmacol. 2015;29:416-422.

56.

Gao

Yang

Zuo

. Overview of the anti-inflammatory effects, pharmacokinetic properties and clinical efficacies of arctigenin and arctiin from Arctium lappa L. Acta Pharmacol Sin. 2018;39:787-801.

57.

Ahn

Hahm

Park

Lee

Kim

. Corosolic acid isolated from the fruit of Crataegus pinnatifida var psilosa is a protein kinase C inhibitor as well as a cytotoxic agent. Planta Med. 1998;64:468-470.

58.

Hirose

Nishikawa

Shibutani

Imai

Shirai

. Chemoprevention of heterocyclic amine-induced mammary carcinogenesis in rats. Environ Mol Mutagen. 2002;39:271-278.

59.

Huang

Guh

Chueh

Teng

. Modulation of anti-adhesion molecule MUC-1 is associated with arctiin-induced growth inhibition in PC-3 cells. Prostate. 2004;59:260-267.

60.

Matsuzaki

Koyama

Hitomi

et al . Arctiin induces cell growth inhibition through the down-regulation of cyclin D1 expression. Oncol Rep. 2008;19:721-727.

61.

Fukushima

Matsuyama

Ueda

et al . Effect of corosolic acid on postchallenge plasma glucose levels. Diabetes Res Clin Pract. 2006;73:174-177.

62.

Yamaguchi

Yamada

Yoshikawa

Nakamura

Haginaka

Kunitomo

. Corosolic acid prevents oxidative stress, inflammation and hypertension in SHR/NDmcr-cp rats, a model of metabolic syndrome. Life Sci. 2006;79:2474-2479.

63.

et al . Corosolic acid induces apoptosis through mitochondrial pathway and caspase activation in human cervix adenocarcinoma HeLa cells. Cancer Lett. 2009;284:229-237.

64.

Nicoletti

Battinelli

Mazzanti

. Isolation of praeruptorins A and B from Peucedanum praeruptorum Dunn and their general pharmacological evaluation in comparison with extracts of the drug. Farmaco. 2001;56:417-420.

65.

Wang

et al . Praeruptorin A inhibits lipopolysaccharide-induced inflammatory response in murine macrophages through inhibition of NF-κB pathway activation. Phytother Res. 2011;25:550-556.

66.

Liang

Yue

. Chemopreventive effects of Peucedanum praeruptorum DUNN and its major constituents on SGC7901 gastric cancer cells. Molecules. 2010;15:8060-8071.

67.

Lin

Chiou

et al . Praeruptorin A inhibits human cervical cancer cell growth and invasion by suppressing MMP-2 expression and ERK1/2 signaling. Int J Mol Sci. 2017;19:E10.

68.

Moon

Wang

Morris

. Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro. 2006;20:187-210.

69.

Chou

Hsieh

Huang

Hsieh

. Fisetin inhibits migration and invasion of human cervical cancer cells by down-regulating urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-κB signaling pathway. PLoS One. 2013;8:e71983.

70.

Ying

Yang

Tsai

et al . Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. Arch Toxicol. 2012;86:263-273.

71.

Farha

Dhanya

Mangalam

Geetha

Latha

Remani

. Deoxyelephantopin impairs growth of cervical carcinoma SiHa cells and induces apoptosis by targeting multiple molecular signaling pathways. Cell Biol Toxicol. 2014;30:331-343.

72.

Bao

Qiu

Zhang

. Potential role of beta-elemene on histone H1 in the H22 ascites hepatoma cell line. Mol Med Rep. 2012;6:185-190.

73.

Zhang

. β-Elemene decreases cell invasion by upregulating E-cadherin expression in MCF-7 human breast cancer cells. Oncol Rep. 2013;30:745-750.

74.

Wang

Huang

et al . Antitumor effect of beta-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death. Cell Mol Life Sci. 2005;62:881-893.

75.

Wang

Zhao

Guan

. Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells. Mol Med Rep. 2018;17:4299-4306.

76.

Shi

Yin

. Polydatin inhibits cell proliferation and induces apoptosis in laryngeal cancer and HeLa cells via suppression of the PDGF/AKT signaling pathway. J Biochem Mol Toxicol. 2017;31(7). doi:10.1002/jbt.21900

77.

Miao

Wang

Miao

Wang

Xie

Yang

. Cardioprotective effect of polydatin against ischemia/reperfusion injury: roles of protein kinase C and mito K(ATP) activation. Phytomedicine. 2011;19:8-12.

78.

Gao

Chen

Wang

Lü

. Effects of polydatin on attenuating ventricular remodeling in isoproterenol-induced mouse and pressure-overload rat models. Fitoterapia. 2010;81:953-960.

79.

Zhang

Zhuang

Meng

Jiao

Fan

. Polydatin inhibits growth of lung cancer cells by inducing apoptosis and causing cell cycle arrest. Oncol Lett. 2014;7:295-301.

80.

Kuang

Jiang

. Polydatin promotes apoptosis through upregulation the ratio of Bax/Bcl-2 and inhibits proliferation by attenuating the β-catenin signaling in human osteosarcoma cells. Am J Transl Res. 2016;8:922-931.

81.

Pan

Wang

Liu

Zhang

. Polydatin induces human cervical cancer cell apoptosis via PI3K/AKT/mTOR signaling pathway [in Chinese]. Zhongguo Zhong Yao Za Zhi. 2017;42:2345-2349.

82.

Yong

. Anticancer advances of matrine and its derivatives. Curr Pharm Des. 2015;21:3673-3680.

83.

Huang

. Matrine: bioactivities and structural modifications. Curr Top Med Chem. 2016;16:3365-3378.

84.

Shao

Yang

Wang

. Matrine effectively inhibits the proliferation of breast cancer cells through a mechanism related to the NF-κB signaling pathway. Oncol Lett. 2013;6:517-520.

85.

Zhang

et al . Effects of matrine against the growth of human lung cancer and hepatoma cells as well as lung cancer cell migration. Cytotechnology. 2009;59:191-200.

86.

Chen

Wang

Guo

. Inhibitory effect of matrine on the expression of PSA and AR in prostate cancer cell line LNCaP. J Huazhong Univ Sci Technolog Med Sci. 2008;28:697-699.

87.

Zhou

Cai

. Matrine inhibits the metastatic properties of human cervical cancer cells via downregulating the p38 signaling pathway. Oncol Rep. 2017;38:1312-1320.

88.

Ying

Zhang

Qiu

. The potential of herb medicines in the treatment of esophageal cancer. Biomed Pharmacother. 2018;103:381-390.

89.

Chen

Song

Hou

. Reactive oxygen species induced by icaritin promote DNA strand breaks and apoptosis in human cervical cancer cells. Oncol Rep. 2019;41:765-778.