Sage Journals: Discover world-class research

Abstract

Herbal drugs are continuously being developed and used as effective therapeutics for various cancers, such as cervical cancer (CC); however, their mechanisms of action at a systemic level have not been explored fully. To study such mechanisms, we conducted a network pharmacological investigation of the anti-CC mechanisms of FDY2004, an herbal drug consisting of Moutan Radicis Cortex, Persicae Semen, and Rhei Radix et Rhizoma. We found that FDY2004 inhibited the viability of human CC cells. By performing pharmacokinetic evaluation and network analysis of the phytochemical components of FDY2004, we identified 29 bioactive components and their 116 CC-associated pharmacological targets. Gene ontology enrichment analysis showed that the modulation of cellular functions, such as apoptosis, growth, proliferation, and survival, might be mediated through the FDY2004 targets. The therapeutic targets were also key components of CC-associated oncogenic and tumor-suppressive pathways, including PI3K-Akt, human papillomavirus infection, IL-17, MAPK, TNF, focal adhesion, and viral carcinogenesis pathways. In conclusion, our data present a comprehensive insight for the mechanisms of the anti-CC properties of FDY2004.

Keywords

herbal drug network pharmacology cervical cancer anticancer agents molecular mechanisms

Cervical cancer (CC), a malignant tumor that occurs owing to the abnormal control of the cellular behavior of cervical cells, is a highly incident gynecologic cancer possessing high mortality with more than 0.5 million cases and 0.3 million deaths per year worldwide.^1,2 Key molecular and pathway mechanisms for CC pathology include the dysregulation of multiple oncogenes and tumor suppressors, and their associated signaling and gene regulatory cascades.^3,4 Growing knowledge regarding the pathomechanisms of CC has advanced the design and development of chemotherapy, targeted therapy, and cancer immunotherapy, which are the most widely used CC therapies at present^5,6; however, they frequently cause resistance and side effects.⁷ Along with these concerns, substantial attention has been given to the development and usage of herbal drugs, the multiple component-multiple target polypharmacological agents with potent efficacy and safety, for cancer treatment.^8
-10 Herbal drugs elevate the clinical outcome and lower the toxicity of anticancer treatments, thereby improving the cancer-related symptoms and health status of cancer patients.¹¹

FDY2004 is an herbal drug consisting of Moutan Radicis Cortex (MRC), Persicae Semen (PS), and Rhei Radix et Rhizoma (RRR).¹² This herbal agent has demonstrated potent anticancer properties in breast and lung cancer cells.¹² However, its pharmacological activity against CC has not been examined.

Because herbal drugs show their therapeutic activities in a complex multiple phytochemical component-multiple targeted-manner, network pharmacology, a research concept that combines pharmacology, medicine, and network science and effectively facilitates the mechanistic investigation of polypharmacological drugs, is widely used to uncover the comprehensive mechanisms of herbal drugs.^9,13

-16 Network pharmacology analysis identifies the major bioactive phytochemical components and therapeutic targets that are important for the pharmacological action of herbal drugs, integrates herbal drug-associated comprehensive data into diverse types of networks, and investigates pharmacological mechanisms of herbal drugs by analyzing their network properties.^9,13

-16 Using this network pharmacology methodology, we studied the therapeutic activity of FDY2004¹² in CC treatment.

Materials and Methods

Preparation of FDY2004

Dried raw plant materials of MRC (6.67 g), PS (6.67 g), and RRR (6.67 g) were purchased from Green Myeong-poom Pharm. (Namyangju, South Korea). Then, they were ground and mixed, and further added to 200 ml of distilled water and boiled for 120 minutes at 100 °C. After filtration with a 1–μm-pore filter (Hyundai Micro, Seoul, South Korea), the herbal extract was lyophilized at −80 °C. The lyophilized samples were kept at −20 °C and dissolved in distilled water for experimental use.

Cell Culture

HeLa human CC cells were purchased from the Korean Cell Line Bank (Seoul, South Korea). The cells were cultured in Dulbecco’s modified Eagle’s medium (WELGENE, Daegu, South Korea) supplemented with 100 µg/mL streptomycin, 100 U/mL penicillin, and 10% fetal bovine serum (Thermo Fisher Scientific, Waltham, MA, USA) in a humidified atmosphere in 5% CO₂ at 37 °C.

Cell Viability Assay

The 3-(4,5-dimethyl-2-thiazolyl)−2,5-diphenyltetrazolium bromide (MTT; Sigma-Aldrich, St. Louis, MO, USA) assay was conducted to measure cell viability.¹⁷ Cells were seeded at 5.0 × 10⁴ cells per well in 48-well plates and treated with FDY2004 for 48 hours in 5% CO₂ at 37 °C. Cells were then incubated for 2 hours after adding 200 µL of MTT to the contents of each well. Afterwards, the MTT solution was removed and dimethyl sulfoxide was added to dissolve the formed formazan crystals. The absorbance was assessed using an Epoch 2 microplate reader (BioTek, Winooski, VT, USA) at 550 nm.

Determination of the Bioactive Phytochemical Components of FDY2004

The pharmacokinetic information (eg, oral bioavailability, drug-likeness, and Caco-2 permeability) of the phytochemical components of FDY2004 was investigated using the Traditional Chinese Medicine Systems Pharmacology ¹⁸, Traditional Chinese Medicine Integrated Database,¹⁸ Anticancer Herbs Database of Systems Pharmacology,¹⁹ and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine²⁰ databases. Then, bioactive phytochemical components were determined according to the following criteria, as previously described: oral bioavailability ≥30%, Caco-2 permeability ≥−0.4, and drug-likeness ≥0.18.¹⁴ Oral bioavailability refers to the quantitative proportion of the chemical components reaching the target sites (eg, tissues and organs) after oral administration; those with oral bioavailability ≥30% are expected to possess sufficient pharmacological absorption capability in the body.^21,22 Drug-likeness is a parameter indicating the qualitative assessment of chemical components to determine their suitability for drug usage based on their molecular information and Tanimoto coefficients^21,23; chemical components having drug-likeness ≥0.18 are considered to retain drug-like properties because the value of 0.18 is the average drug-likeness of available drugs.^21,23 Caco-2 permeability is a coefficient for evaluating the intestinal permeability, flux rate, and ability to transport chemical components using human Caco-2 intestinal cells; generally, those with Caco-2 permeability ≥−0.4 are considered to exhibit suitable permeability in the intestinal epithelium.^24,25

Targets of the Bioactive Phytochemical Components of FDY2004

The simplified molecular-input line-entry system (SMILES) notation of the phytochemical components of FDY2004 were extracted from the PubChem database,²⁶ and imported into the following databases to obtain the human molecular targets: Similarity Ensemble Approach,²⁷ SwissTargetPrediction,²⁸ Search Tool for Interactions of Chemicals 5,²⁹ and PharmMapper.³⁰ The targets associated with initiation, development, and progression of CC were collected from the following databases using “Uterine Cervical Neoplasms” (Medical Subject Headings Unique ID: D002583) as the search keyword: Therapeutic Target Database,³¹ Comparative Toxicogenomics Database,³² DrugBank,³³ Human Genome Epidemiology Navigator,³⁴ DisGeNET,³⁵ Online Mendelian Inheritance in Man,³⁶ GeneCards,³⁷ and Pharmacogenomics Knowledgebase.³⁸

Construction of the Herbal Drug-Related Networks

In network pharmacology, a network consists of nodes (eg, herbal medicines, bioactive phytochemical components, targets, or pathways), and edges (or links) representing interactions between them.³⁹ The number of edges connected to a node is called the degree.³⁹ Comprehensive data regarding the relationship between the herbal medicines and their bioactive phytochemical components and their components and therapeutic targets were merged into an herbal medicine-bioactive phytochemical component-target (H-C-T) network. The herbal medicine-bioactive phytochemical component-target-pathway (H-C-T-P) network was generated by linking the targets in the H-C-T network with their enriched pathways. A protein-protein interaction (PPI) network was created using the paired interaction between the targets with a confidence score ≥0.9 from the STRING database.⁴⁰ Nodes were considered as hubs if their degrees met the following criteria, ≥2 × average degree of all nodes in the PPI network, as previously described.^41,42 The constructed H-C-T, H-C-T-P, and PPI networks were visualized using Cytoscape software.⁴³

Survival Analysis

We used Kaplan-Meier Plotter⁴⁴ to perform the survival analysis of the FDY2004 targets.

Functional Analysis of the FDY2004 Targets

We used g:Profiler⁴⁵ and Kyoto Encyclopedia of Genes and Genomes⁴⁶ for the gene ontology (GO) and pathway enrichment analysis of the FDY2004 targets, respectively. Functional interaction analysis was conducted using GeneMANIA.⁴⁷

Molecular Docking Analysis

Information on the 3-dimensional structures of the bioactive phytochemical components and targets of FDY2004 was surveyed from the PubChem database²⁶ and the RCSB Protein Data Bank database,⁴⁸ respectively. Next, the molecular docking scores between them were evaluated by importing their structural information into Autodock Vina.⁴⁹ We considered the phytochemical component-target pairs with docking scores ≤ −5 to exhibit stable physicochemical binding affinities, as previously described.^50,51

Results

Effects of FDY2004 Treatment on Cervical Cancer Cells

To investigate the inhibitory effects of FDY2004 against CC, we treated HeLa cells with the herbal drug and observed their cell viability. The HeLa cells showed a significant reduction in their viability after FDY2004 treatment (Supplemental Figure S1), indicating the anticancer property of the herbal medicine against CC.

Bioactive Phytochemical Components of FDY2004 and Their Targets

Among the phytochemical components of FDY2004 investigated from herbal medicine-associated databases (Supplemental Table S1), we screened the bioactive components among those using the criteria mentioned earlier (see Materials and Methods).^52,53 In addition, some phytochemical components that unsatisfied the criteria but are present in large quantities in the herbal medicines and possess effective therapeutic activity were also regarded as bioactive components. Consequently, we identified 35 bioactive components for FDY2004 (Supplemental Table S2). Thereafter, using various databases for the investigation of protein-chemical interactions and disease-associated genes and proteins, we obtained 212 targets (116 CC-associated and 96 non-CC-associated) for the 29 bioactive phytochemical components (Supplemental Table S3).

Network-Perspective Analysis of the Mechanism of FDY2004

The FDY2004-related detailed information was integrated into the H-C-T network with 148 nodes (3 herbal medicines, 29 bioactive phytochemical components, and 116 CC-related targets) and 271 links between them (Figure 1 and Supplemental Table S3). Quercetin and kaempferol were the bioactive components with the largest number of targets (Figure 1, Supplemental Table S3), suggesting their crucial pharmacological roles. Furthermore, 93.10% (27 out of 29) of the phytochemical components shared one or more target, and 77.59% (90 out of 116) of the CC-associated targets interacted with2 or more herbal medicines (Figure 1), indicating the multiple component-multiple target effects of FDY2004.

Figure 1

Herbal medicine-bioactive phytochemical component-target network of FDY2004. Green nodes, herbal medicines; red nodes, bioactive phytochemical components, blue nodes, targets.

To gain insight into the interactions between the CC-associated FDY2004 targets, we investigated the topological features of the PPI network (92 nodes and 231 links) in which the targets serve as nodes and their interactions as links (Figure 2). In the network analysis, we identified the high-degree hub nodes that have important biological functions and potential as key therapeutic targets (see Materials and Methods).^54,55 As a result, the nodes AKT1, EGFR, ESR1, HSP90AA1, JUN, PTK2, TNF, TP53, and VEGFA were determined as hubs, indicating that they are the major targets for the therapeutic activities of FDY2004 against CC (Figure 2). Furthermore, the expression levels of these nodes correlated with the survival outcome of patients with CC (Figure 3), which indicates their clinical significance. In addition, GeneMANIA analysis indicated the biological mechanisms underlying the interaction between the hubs, including the physical interaction, co-expression, and genetic interaction (Supplemental Figure S2). Altogether, the results demonstrate the network-perspective characteristics underlying the pharmacological activity of FDY2004 for CC treatment.

Figure 2

Protein-protein interaction network for cervical cancer-associated targets of FDY2004. Pink nodes, hub cervical cancer-associated targets; blue nodes, non-hub cervical cancer-associated targets that interact with a single hub node; purple nodes, non-hub cervical cancer-associated targets that interact with 2 or more hub nodes; orange nodes, non-hub cervical cancer-associated targets that do not interact with hub nodes.

Figure 3

Survival analysis of the cervical cancer-related targets of FDY2004. Kaplan-Meier curves for the survival of patients with cervical cancer having high or low expression levels of the indicated targets.

Investigation of Functional Enrichment of FDY2004 Networks

To dissect the biological mechanisms of the anti-CC activity of FDY2004, we analyzed the GO terms enriched for its targets. We found that the modulation of cellular behaviors, such as apoptosis, growth, proliferation, and survival, may be mediated by the FDY2004 targets (Supplemental Figure S3), thus demonstrating the molecular mechanisms of FDY2004.

Aberrant activation and/or inactivation of various signaling pathways is the key mechanism of cancer pathology.⁵⁶ By analyzing the pathway enrichment for the FDY2004 targets, we found that the targets were major components of the following CC-associated pathways: “Apoptosis,” “Cellular senescence,” “ErbB signaling pathway,” “Estrogen signaling pathway,” “Focal adhesion,” “HIF-1 signaling pathway,” “Human papillomavirus infection,” “IL-17 signaling pathway,” “MAPK signaling pathway,” “NF-kappa B signaling pathway,” “p53 signaling pathway,” “Pathways in cancer,” “PD-L1 expression and PD-1 checkpoint pathway in cancer,” “PI3K-Akt signaling pathway,” “Platinum drug resistance,” “Prolactin signaling pathway,” “Ras signaling pathway,” “TNF signaling pathway,” “VEGF signaling pathway,” and “Viral carcinogenesis” (Figure 4 and Supplemental Figure S3).

Figure 4

Herbal medicine-bioactive phytochemical component-target-pathway network of FDY2004. Green nodes, herbal medicines; red nodes, bioactive phytochemical components; blue nodes, targets; orange nodes, pathways.

The overall functional enrichment analysis suggests the pharmacological regulatory properties of FDY2004 for CC treatment at the molecular and pathway levels.

Molecular Docking Analysis

Using in silico molecular docking techniques, we examined the binding affinities of the chemical constituents and their CC-associated targets. The interactions between the bioactive phytochemical components and their hub targets showed molecular docking scores ≤ −5.0 (Figure 5), which suggests the potential binding capacities between them and further confirms the results of the network pharmacological analysis.

Figure 5

Molecular docking analysis for the bioactive phytochemical components of FDY2004 and their hub targets. (A) Aloe-emodin-HSP90AA1 (score = −7.2). (B) Aloe-emodin-TP53 (score = −7.1). (C) Emodin-ESR1 (score = −7.8). (D) Emodin-TNF (score = −6.8). (E) Emodin-TP53 (score = −7.3). (F) Emodin-VEGFA (score = −7.0). (G) Gallic acid-JUN (score = −5.1). (H) Pentagalloylglucose-EGFR (score = −8.9). (I) Pentagalloylglucose-ESR1 (score = −7.0). (J) Quercetin-AKT1 (score = −6.4). (K) Quercetin-EGFR (score = −7.9). (L) Quercetin-PTK2 (score = −6.1). (M) Rhein-VEGFA (score = −7.1).

Discussion

Globally, CC is among the most incident, prevalent, and fatal malignant cancer affecting women.¹ Herbal drugs are increasingly being considered as effective cancer therapeutics for their pharmacological efficacy and reduced toxicity.^8,9 Using a network pharmacology-based methodology, we investigated the therapeutic activity of FDY2004 against CC. We found that FDY2004 exerted anticancer effects on CC cells. The overall analysis results identified 29 bioactive phytochemical components of FDY2004 that interact with 116 CC-related targets. GO enrichment investigation suggested that the targets may participate in the modulation of apoptosis, growth, proliferation, and survival. Diverse signaling associated with CC initiation and progression, including phosphoinositide 3-kinase (PI3K)-Akt, human papillomavirus (HPV) infection, interleukin (IL)−17, mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), focal adhesion, and viral carcinogenesis pathways, may confer the polypharmacological anti-CC effects of FDY2004.

The hub targets of FDY2004 may serve as key regulators underlying the pathological processes of CC and have druggable potential. AKT (encoded by AKT1), c-Jun (encoded by JUN), and epidermal growth factor receptor (EGFR; encoded by EGFR) are implicated in the modulation of various cellular processes in CC cells, such as growth, proliferation, migration, invasion, metastasis, angiogenesis, survival, and apoptosis, and they are radio- and chemo-sensitizers of anticancer therapies for CC.^{57

-70} The overexpression of Akt1 and EGFR is associated with the poor survival and clinical outcomes of patients with CC.^69,71 The oncogene JUN is upregulated in the CC tumor tissues compared to normal tissues, and lower JUN expression is related to higher survival among patients with CC.⁷² The estrogen receptor α (encoded by ESR1) is associated with the tumorigenesis, development, and persistence of CC.^73
-75 Its expression level is downregulated in CC tissues, which is correlated with decreased survival rate among patients with CC.⁷⁶ Heat shock protein 90-α (encoded by HSP90AA1) plays a role in the regulation of anti-tumor immunity, cancer cell growth, and epithelial-to-mesenchymal transition (EMT) of CC cells, and its higher expression and activity is seen in the CC tissues.^77,78 Focal adhesion kinase (encoded by PTK2) suppresses apoptosis but promotes growth, proliferation, survival, EMT, tumorigenesis, migration, and invasion of CC cells and its expression is positively correlated with the progression, metastasis, angiogenesis, and the poor prognosis and clinical outcomes of patients with CC.^79

-86 The expression and activity of TNF-α (encoded by TNF) is associated with the apoptosis, chemosensitivity, DNA damage response, necrosis, proliferation, invasion, and EMT of CC cells, and its polymorphisms are further correlated with the risk of development, progression, and malignancy in patients with CC.^{87

-100} The genetic or epigenetic malfunction of p53 (encoded by TP53), a key tumor suppressor that coordinates the cell cycle process, proliferation, apoptosis, DNA damage repair, and metabolism, can drive CC pathogenesis; therefore, the restoration of its expression or functional activity has been suggested as a potential strategy for treating CC.^101
-103 In addition, elevated expression and polymorphisms of TP53 are commonly observed in CC tissues compared to normal cervical tissues, and correlated with the poor clinical outcome of patients with CC.^104,105 Vascular endothelial growth factor-A (VEGF-A; encoded by VEGFA) is involved in the proliferation, metastasis, angiogenesis, and growth processes of CC cells,^106

-110 and it is upregulated in CC tissues.^109,111 Moreover, the complex interactions between these hub targets via various genetic and signaling mechanisms may modulate diverse CC-associated pathologic cellular processes, confer the pharmacological effects of anti-CC therapies, and contribute to the development of therapeutic resistance.^{60,85,112

-121}

The FDY2004-targeted pathways are the key signaling mechanisms mediating CC pathology and its therapeutic strategies. Dysregulation of erythroblastic leukemia viral oncogene homologue (ErbB), focal adhesion, hypoxia-inducible factor 1 (HIF-1), MAPK, PI3K-Akt, and Ras pathways are important for CC initiation, development, and progression.^{4,122

-127} Abnormal activity of the estrogen signaling pathway is one of the major drivers of CC, and high expression levels of its pathway components are related to the risk of CC.^73
-75,128 Viral infection with HPV is one of the most crucial contributors to CC carcinogenesis.¹²⁹ The key components of the IL-17 pathway play a role in the carcinogenesis of CC with viral infection, and their activity functions as a prognostic indicator for patients with CC.^130

-134 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling modulates the growth, cell cycle, migration, invasion, survival, apoptosis, immunomicroenvironment, autophagy, and the pathomechanisms associated with the viral infection of CC cells.^135

-141 The p53 pathway is a pharmacological mediator of anticancer therapy-induced intervention of the survival, migration, invasion, and proliferation of CC cells.^142
-144 The upregulated activity of programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is implicated in the decreased survival of patients with CC and targeting this pathway can elevate anti-tumor immunity.^145,146 The hyperactivation of the anti-apoptotic prolactin pathway may enhance the survival and proliferative capacity of CC cells.^147,148 The TNF pathway controls the pro-tumorigenic inflammatory processes of CC cells and is linked with HPV-associated CC progression.^91,149
-151 Dysregulated activation of the VEGF pathway promotes the metastasis and angiogenesis of tumors, which in turn promotes CC progression and advancement.^152,153

The bioactive phytochemical components of the herbal medicines comprising FDY2004 have been reported to exhibit pharmacological effects against CC, which supports the anti-CC activity of this herbal drug. Aloe-emodin inhibits cell cycle progression, proliferation, growth, and survival, but enhances the apoptosis and radiosensitivity of CC cells.^154
-156 The anticancer mechanisms of caffeic acid include the enhancement of apoptotic cell death, chemosensitivity, and cell cycle arrest and the blockage of the proliferation and EMT of CC cells; these pharmacological effects are exhibited via the modulation of transforming growth factor (TGF)-β, HIF-1, p53, mitochondrial, and adenosine monophosphate-activated protein kinase (AMPK) pathways.^157

-161 Catechins possess anticancer potential that may cause growth-suppression and apoptosis of CC cells mediated by caspase activation and induction of oxidative stress.^162,163 Chrysophanol, paeoniflorin, paeonol, and pentagalloylglucose can repress the survival and proliferation of CC cells while promoting cell cycle arrest and apoptosis.^164

-167 Emodin suppresses the migration, invasion, and proliferation, and causes the oxidative stress, DNA damage, and apoptosis of CC cells by modulating the PI3K-Akt, HIF-1, VEGF, TGF-β, mitochondrial, and death receptor signaling pathways.^168

-171 Gallic acid is an anticancer compound that modulates the activities of oncogenic ErbB, PI3K-Akt, MAPK, p53, caspase, and HPV signaling, which leads to the augmentation of apoptosis and necrosis and suppression of growth, proliferation, angiogenesis, and chemoresistance.^172
-174 The pro-apoptotic and anti-proliferative role of hederagenin is mediated by the modulation of signal transducer and activator of transcription (STAT)−3 pathway.¹⁷⁵ Kaempferol regulates the activities of PI3K-Akt and telomerase reverse transcriptase (hTERT) pathways to promote apoptotic cell death and suppress the growth and survival of CC cells.¹⁷⁶ Mairin (betulinic acid) stimulates anti-tumor processes such as apoptosis, oxidative stress, and antiproliferation of CC cells that are conferred through the HIF, VEGF, TNF, PI3K-Akt, caspase, reactive oxygen species (ROS)-mediated mitochondrial, and endoplasmic reticulum (ER) pathways.^177
-179 Rhein-induced growth repression and apoptosis of CC cells may occur through the caspase and calcium pathways.¹⁸⁰ The anticancer component quercetin inhibits cell cycle progression, proliferation, survival, viability, metastasis, migration, invasion, and EMT of CC cells by modulating diverse signaling mechanisms, including HPV, p53, ER stress, ROS, PI3K-Akt, mitochondrial, DNA damage response, epigenetic, p53, caspase, MAPK, HIF-1, Wnt, and NF-κB pathways.^{144,181

-186} β-Sitosterol controls the expression and activity of HPV E6 and p53, which induces the apoptosis and arrests the growth of CC cells.^187,188

Limitations of the current study include the lack of experiments that evaluate the anti-CC effects and toxicity of combined treatment of FDY2004 with other anticancer agents involved in chemotherapy, targeted therapy, and cancer immunotherapy. Further investigations are needed to expand the therapeutic application of herbal drugs as anticancer therapies.

In summary, the overall network pharmacology-based analysis demonstrated the anti-CC properties of FDY2004. Our study offers an in-depth and systematic understanding of the polypharmacological mechanisms of herbal drugs, which will contribute to the design and development of improved anticancer herbal agents.

Supplemental Material

Online supplementary file 1 - Supplemental material for A Comprehensive Understanding of the Anticancer Mechanisms of FDY2004 Against Cervical Cancer Based on Network Pharmacology

Supplemental material, Online supplementary file 1, for A Comprehensive Understanding of the Anticancer Mechanisms of FDY2004 Against Cervical Cancer Based on Network Pharmacology by Ho-Sung Lee, In-Hee Lee, Kyungrae Kang, Sang-In Park, Minho Jung, Seung Gu Yang, Tae-Wook Kwon and Dae-Yeon Lee in Natural Product Communications

Footnotes

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) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Dae-Yeon Lee

Supplemental Material

Supplemental material for this article is available online.

References

Siegel

RL.

Miller

KD.

Jemal

. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.doi:10.3322/caac.21551

30620402

Arbyn

Weiderpass

Bruni

et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob Health. 2020;8(2):e191-e203.doi:10.1016/S2214-109X(19)30482-6

31812369

Manzo-Merino

Contreras-Paredes

Vázquez-Ulloa

Rocha-Zavaleta

Fuentes-Gonzalez

AM.

Lizano

. The role of signaling pathways in cervical cancer and molecular therapeutic targets. Arch Med Res. 2014;45(7):525-539.doi:10.1016/j.arcmed.2014.10.008

25450584

Zhang

Ling

MT.

Zhao

K-N

. The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses. Mol Cancer. 2015;14:87 doi:10.1186/s12943-015-0361-x

26022660

Kumar

Harish

Malik

PS.

Khurana

. Chemotherapy and targeted therapy in the management of cervical cancer. Curr Probl Cancer. 2018;42(2):120-128.doi:10.1016/j.currproblcancer.2018.01.016

29530393

Menderes

Black

Schwab

CL.

Santin

. Immunotherapy and targeted therapy for cervical cancer: an update. Expert Rev Anticancer Ther. 2016;16(1):83-98.doi:10.1586/14737140.2016.1121108

26568261

Oun

Moussa

YE.

Wheate

. The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans. 2018;47(19):6645-6653.doi:10.1039/C8DT00838H

29632935

Ohnishi

Takeda

. Herbal medicines for the treatment of cancer chemotherapy-induced side effects. Front Pharmacol. 2015;6(Suppl. 5):14 doi:10.3389/fphar.2015.00014

Poornima

Kumar

JD.

Zhao

Blunder

Efferth

. Network pharmacology of cancer: from understanding of complex interactomes to the design of multi-target specific therapeutics from nature. Pharmacol Res. 2016;111:290-302.doi:10.1016/j.phrs.2016.06.018

27329331

10.

Yin

S-Y.

Wei

W-C.

Jian

F-Y.

Yang

N-S

. Therapeutic applications of herbal medicines for cancer patients. Evid Based Complement Alternat Med. 2013;2013:1-15.doi:10.1155/2013/302426

23956768

11.

Kim

MS.

Joo

JC.

Song

. Efficacy of herbal medicine as an adjunctive therapy of chemotherapy for cervical cancer: a systematic review and meta-analysis. J Physiol Pathol Korean Med. 2020;34(5):255-262.

12.

Lee

I-H.

Lee

H-S.

Kang

et al. Influence of decoction duration of FDY2004 on its physicochemical components and antioxidant and antiproliferative activities. Nat Prod Commun. 2020;15(10)doi:10.1177/1934578X20968437

13.

Lee

W-Y.

Lee

C-Y.

Kim

Y-S.

Kim

C-E

. The methodological trends of traditional herbal medicine employing network pharmacology. Biomolecules. 2019;9(8):362-15.doi:10.3390/biom9080362

31412658

14.

Lee

H-S.

Lee

I-H.

Park

S-I.

Lee

D-Y

. Network Pharmacology-Based investigation of the system-level molecular mechanisms of the hematopoietic activity of Samul-Tang, a traditional Korean herbal formula. Evid Based Complement Alternat Med. 2020;2020:1-17.doi:10.1155/2020/9048089

32104198

15.

Zhang

SQ.

HB.

Zhang

SJ.

. Identification of the active compounds and significant pathways of Artemisia annua in the treatment of non-small cell lung carcinoma based on network pharmacology. Med Sci Monit. 2020;26:e923624. doi:10.12659/MSM.923624

32474568

16.

6628641 Lee

H-S.

Lee

I-H.

Kang

Park

S-I.

Kwon

T-W.

Lee

D-Y

. An investigation of the molecular mechanisms underlying the analgesic effect of Jakyak-Gamcho decoction: a network pharmacology study. Evid Based Complement Alternat Med. 2020;2020-20.doi:10.1155/2020/6628641

33343676

17.

Lee

D-Y.

Lee

I-H

. FDY003 inhibits colon cancer in a COLO205 xenograft mouse model by decreasing oxidative stress. Pharmacogn Mag. 2019;15(65):675-681.doi:10.4103/pm.pm_650_18

18.

Huang

Xie

et al. TCMID 2.0: a comprehensive resource for TCM. Nucleic Acids Res. 2018;46(D1):D1117-D1120.doi:10.1093/nar/gkx1028

29106634

19.

Tao

Gao

et al. CancerHSP: anticancer herbs database of systems pharmacology. Sci Rep. 2015;5:11481. doi:10.1038/srep11481

26074488

20.

Liu

Guo

Wang

et al. BATMAN-TCM: a bioinformatics analysis tool for molecular mechANism of traditional Chinese medicine. Sci Rep. 2016;6:21146. doi:10.1038/srep21146

26879404

21.

Wang

et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014;6:13. doi:10.1186/1758-2946-6-13

24735618

22.

Wang

CK.

Craik

. Cyclic peptide oral bioavailability: lessons from the past. Biopolymers. 2016;106(6):901-909.doi:10.1002/bip.22878

27178381

23.

Lee

AY.

Park

Kang

T-W.

Cha

MH.

Chun

. Network pharmacology-based prediction of active compounds and molecular targets in Yijin-Tang acting on hyperlipidaemia and atherosclerosis. J Ethnopharmacol. 2018;221:151-159.doi:10.1016/j.jep.2018.04.027

29698773

24.

Zhang

et al. Systems pharmacology to decipher the combinational anti-migraine effects of Tianshu formula. J Ethnopharmacol. 2015;174:45-56.doi:10.1016/j.jep.2015.07.043

26231449

25.

Zhang

Chen

Pan

Zhang

Wang

. Systems pharmacology dissection of multi-scale mechanisms of action for herbal medicines in stroke treatment and prevention. PLoS One. 2014;9(8):e102506. doi:10.1371/journal.pone.0102506

25093322

26.

Kim

Chen

Cheng

et al. PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 2019;47(D1):D1102-D1109.doi:10.1093/nar/gky1033

30371825

27.

Keiser

MJ.

Roth

BL.

Armbruster

BN.

Ernsberger

Irwin

JJ.

Shoichet

. Relating protein pharmacology by ligand chemistry. Nat Biotechnol. 2007;25(2):197-206.doi:10.1038/nbt1284

17287757

28.

Daina

Michielin

Zoete

. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019;47(W1):W357-W364.doi:10.1093/nar/gkz382

31106366

29.

Szklarczyk

Santos

von Mering

Jensen

LJ.

Bork

Kuhn

. Stitch 5: augmenting protein-chemical interaction networks with tissue and affinity data. Nucleic Acids Res. 2016;44(D1):D380-D384.doi:10.1093/nar/gkv1277

26590256

30.

Wang

Shen

Wang

et al. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 2017;45(W1):W356-W360.doi:10.1093/nar/gkx374

28472422

31.

Zhu

Han

Kumar

et al. Update of TTD: therapeutic target database. Nucleic Acids Res. 2010;38(Database issue):D787-D791.doi:10.1093/nar/gkp1014

19933260

32.

Davis

AP.

Grondin

CJ.

Johnson

et al. The comparative toxicogenomics database: update 2019. Nucleic Acids Res. 2019;47(D1):D948-D954.doi:10.1093/nar/gky868

30247620

33.

Wishart

DS.

Feunang

YD.

Guo

et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074-D1082.doi:10.1093/nar/gkx1037

29126136

34.

Gwinn

Clyne

Yesupriya

Khoury

. A navigator for human genome epidemiology. Nat Genet. 2008;40(2):124-125.doi:10.1038/ng0208-124

18227866

35.

Piñero

Bravo

Àlex.

Queralt-Rosinach

et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 2017;45(D1):D833-D839.doi:10.1093/nar/gkw943

27924018

36.

Amberger

JS.

Bocchini

CA.

Schiettecatte

Scott

AF.

Hamosh

. OMIM.org: online Mendelian inheritance in man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 2015;43(Database issue):D789-D798.doi:10.1093/nar/gku1205

25428349

37.

Safran

Dalah

Alexander

et al. GeneCards version 3: the human gene integrator. Database. 2010;2010:baq020. doi:10.1093/database/baq020

20689021

38.

Whirl-Carrillo

McDonagh

EM.

Hebert

et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414-417.doi:10.1038/clpt.2012.96

22992668

39.

Barabási

A-L.

Oltvai

. Network biology: understanding the cell’s functional organization. Nat Rev Genet. 2004;5(2):101-113.doi:10.1038/nrg1272

14735121

40.

Szklarczyk

Gable

AL.

Lyon

et al. String v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607-D613.doi:10.1093/nar/gky1131

30476243

41.

Zhong

Liu

Zhou

. Synergic Anti-Pruritus mechanisms of action for the Radix sophorae Flavescentis and Fructus Cnidii herbal pair. Molecules. 2017;22(9):1-13.doi:10.3390/molecules22091465

42.

1056708 Zhu

Zhang

Pan

Zhong

Huang

. Systems Pharmacology-Based approach to comparatively study the independent and synergistic mechanisms of DanHong injection and Naoxintong capsule in ischemic stroke treatment. Evid Based Complement Alternat Med. 2019;2019-17.doi:10.1155/2019/1056708

30863452

43.

Shannon

et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498-2504.doi:10.1101/gr.1239303

44.

Nagy

Ádám.

Lánczky

Menyhárt

Győrffy

. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep. 2018;8(1):9227. doi:10.1038/s41598-018-27521-y

29907753

45.

Raudvere

Kolberg

Kuzmin

et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update. Nucleic Acids Res. 2019;47(W1):W191-W198.doi:10.1093/nar/gkz369

31066453

46.

Kanehisa

Goto

. Kegg: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27-30.doi:10.1093/nar/28.1.27

10592173

47.

Montojo

Zuberi

Rodriguez

Bader

GD.

Morris

. GeneMANIA: fast gene network construction and function prediction for Cytoscape. F1000Res. 2014;3:153.doi:10.12688/f1000research.4572.1

25254104

48.

Burley

SK.

Berman

HM.

Bhikadiya

et al. Rcsb protein data bank: biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy. Nucleic Acids Res. 2019;47(D1):D464-D474.doi:10.1093/nar/gky1004

30357411

49.

Trott

Olson

. Autodock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455-461.doi:10.1002/jcc.21334

19499576

50.

Zhuang

Wen

Zhang

et al. Can network pharmacology identify the anti-virus and anti- inflammatory activities of Shuanghuanglian oral liquid used in Chinese medicine for respiratory tract infection? Eur J Integr Med. 2020;37:101139. doi:10.1016/j.eujim.2020.101139

32501408

51.

Zhang

Yuan

Zhou

et al. Network pharmacology analysis of Chaihu Lizhong Tang treating non-alcoholic fatty liver disease. Comput Biol Chem. 2020;86:107248. doi:10.1016/j.compbiolchem.2020.107248

32208163

52.

Huang

Cheung

Tan

H-Y

et al. Identification of the active compounds and significant pathways of yinchenhao decoction based on network pharmacology. Mol Med Rep. 2017;16(4):4583-4592.doi:10.3892/mmr.2017.7149

28791364

53.

Yue

S-J.

Xin

L-T.

Fan

Y-C

et al. Herb pair Danggui-Honghua: mechanisms underlying blood stasis syndrome by system pharmacology approach. Sci Rep. 2017;7:40318. doi:10.1038/srep40318

28074863

54.

Cho

D-Y.

Kim

Y-A.

Przytycka

. Chapter 5: network biology approach to complex diseases. PLoS Comput Biol. 2012;8(12):e1002820. doi:10.1371/journal.pcbi.1002820

23300411

55.

Jeong

Mason

SP.

Barabási

AL.

Oltvai

. Lethality and centrality in protein networks. Nature. 2001;411(6833):41-42.doi:10.1038/35075138

11333967

56.

Kolch

Halasz

Granovskaya

Kholodenko

. The dynamic control of signal transduction networks in cancer cells. Nat Rev Cancer. 2015;15(9):515-527.doi:10.1038/nrc3983

26289315

57.

Liu

Ding

Bai

et al. Folate receptor alpha is associated with cervical carcinogenesis and regulates cervical cancer cells growth by activating ERK1/2/c-Fos/c-Jun. Biochem Biophys Res Commun. 2017;491(4):1083-1091.doi:10.1016/j.bbrc.2017.08.015

28782518

58.

Chen

Zheng

X-M.

Chen

M-L

. Experimental study on the apoptosis of cervical cancer HeLa cells induced by Juglone through c-Jun N-terminal kinase/c-Jun pathway. Asian Pac J Trop Med. 2017;10(6):572-575.doi:10.1016/j.apjtm.2017.06.005

28756921

59.

Xiong

Nie

Zou

et al. Twist1 enhances hypoxia induced radioresistance in cervical cancer cells by promoting nuclear EGFR localization. J Cancer. 2017;8(3):345-353.doi:10.7150/jca.16607

28261334

60.

Liu

Sun

Zhang

et al. Theanine from tea and its semi-synthetic derivative TBrC suppress human cervical cancer growth and migration by inhibiting EGFR/Met-Akt/NF-κB signaling. Eur J Pharmacol. 2016;791:297-307.doi:10.1016/j.ejphar.2016.09.007

27612630

61.

Guo

Zhu

et al. Genetic variations in the PI3K/Akt pathway predict platinum-based neoadjuvant chemotherapeutic sensitivity in squamous cervical cancer. Life Sci. 2015;143:217-224.doi:10.1016/j.lfs.2015.11.011

26585822

62.

Mao

Hua

et al. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Mol Med. 2015;7(11):1426-1449.doi:10.15252/emmm.201404976

26417066

63.

Bai

Mao

Wang

et al. Erk1/2 promoted proliferation and inhibited apoptosis of human cervical cancer cells and regulated the expression of c-fos and c-Jun proteins. Med Oncol. 2015;32(3):57.doi:10.1007/s12032-015-0490-5

25647783

64.

Shi

Y-H.

Tuokan

Lin

Chang

. Aquaporin 8 involvement in human cervical cancer SiHa migration via the EGFR-Erk1/2 pathway. Asian Pac J Cancer Prev. 2014;15(15):6391-6395.doi:10.7314/APJCP.2014.15.15.6391

25124631

65.

Rashmi

DeSelm

Helms

et al. Akt inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake. PLoS One. 2014;9(4):e92948. doi:10.1371/journal.pone.0092948

24705275

66.

Yung

MMH.

Chan

DW.

Liu

VWS.

Yao

K-M.

Ngan

HY-S

. Activation of AMPK inhibits cervical cancer cell growth through AKT/FOXO3a/FOXM1 signaling cascade. BMC Cancer. 2013;13:327. doi:10.1186/1471-2407-13-327

23819460

67.

Schwarz

JK.

Payton

JE.

Rashmi

et al. Pathway-specific analysis of gene expression data identifies the PI3K/Akt pathway as a novel therapeutic target in cervical cancer. Clin Cancer Res. 2012;18(5):1464-1471.doi:10.1158/1078-0432.CCR-11-2485

22235101

68.

Xia

Zhao

Zhang

. Activated PI3K/Akt/COX-2 pathway induces resistance to radiation in human cervical cancer HeLa cells. Cancer Biother Radiopharm. 2010;25(3):317-323.doi:10.1089/cbr.2009.0707

20578837

69.

Noordhuis

MG.

Eijsink

JJH.

Ten Hoor

et al. Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer. Clin Cancer Res. 2009;15(23):7389-7397.doi:10.1158/1078-0432.CCR-09-1149

19920104

70.

Prusty

BK.

Das

. Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin. Int J Cancer. 2005;113(6):951-960.doi:10.1002/ijc.20668

15514944

71.

Kurnia

IIN.

Siregar

Soetopo

et al. Correlation between Akt and p53 protein expression and chemoradiotherapy response in cervical cancer patients. Hayati. 2014;21(4):173-179.doi:10.4308/hjb.21.4.173

72.

Lai

Zhou

Tan

Wan

Zhang

. LINC00116 enhances cervical cancer tumorigenesis through miR-106a/c-Jun pathway. J Cell Biochem. 2020;121(3):2247-2257.doi:10.1002/jcb.29447

31693227

73.

Chung

S-H.

Franceschi

Lambert

PF.

Estrogen

LPF

. Estrogen and ERalpha: culprits in cervical cancer? Trends Endocrinol Metab. 2010;21(8):504-511.doi:10.1016/j.tem.2010.03.005

20456973

74.

Chung

S-H.

Wiedmeyer

Shai

Korach

KS.

Lambert

. Requirement for estrogen receptor alpha in a mouse model for human papillomavirus-associated cervical cancer. Cancer Res. 2008;68(23):9928-9934.doi:10.1158/0008-5472.CAN-08-2051

19047174

75.

Brake

Lambert

. Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proc Natl Acad Sci U S A. 2005;102(7):2490-2495.doi:10.1073/pnas.0409883102

15699322

76.

Dai

Chen

Wang

et al. Identification of candidate biomarkers correlated with the diagnosis and prognosis of cervical cancer via integrated bioinformatics analysis. Onco Targets Ther. 2019;12:4517-4532.doi:10.2147/OTT.S199615

31354287

77.

Song

K-H.

SJ.

Kim

et al. Hsp90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors. Nat Commun. 2020;11(1):562. doi:10.1038/s41467-019-14259-y

31992715

78.

Dong

Xiong

et al. MicroRNA-361-Mediated inhibition of Hsp90 expression and EMT in cervical cancer is counteracted by oncogenic lncRNA NEAT1. Cells. 2020;9(3):1-20.doi:10.3390/cells9030632

32151082

79.

Chen

Suo

Cheng

Zheng

. Vascular endothelial growth factor C enhances cervical cancer migration and invasion via activation of focal adhesion kinase. Gynecol Endocrinol. 2013;29(1):20-24.doi:10.3109/09513590.2012.705387

22817694

80.

Chen

Wang

Liu

. SASH1 inhibits cervical cancer cell proliferation and invasion by suppressing the FAK pathway. Mol Med Rep. 2016;13(4):3613-3618.doi:10.3892/mmr.2016.4946

26935246

81.

Chen

Yang

. Clinical significance of focal adhesion kinase (FAK) in cervical cancer progression and metastasis. Int J Clin Exp Pathol. 2020;13(10):2586-2592.33165433

82.

Wang

Liu

et al. High expression of integrin α3 predicts poor prognosis and promotes tumor metastasis and angiogenesis by activating the c-Src/Extracellular signal-regulated protein Kinase/Focal adhesion kinase signaling pathway in cervical cancer. Front Oncol. 2020;10:36. doi:10.3389/fonc.2020.00036

32117712

83.

Gabriel

zur Hausen

Stickeler

et al. Weak expression of focal adhesion kinase (pp125FAK) in patients with cervical cancer is associated with poor disease outcome. Clin Cancer Res. 2006;12(8):2476-2483.doi:10.1158/1078-0432.CCR-05-1867

16638855

84.

Zhang

Liu

Liang

Hypoxia

. Hypoxia and TGF-β1 induced PLOD2 expression improve the migration and invasion of cervical cancer cells by promoting epithelial-to-mesenchymal transition (EMT) and focal adhesion formation. Cancer Cell Int. 2017;17:54 doi:10.1186/s12935-017-0420-z

28507454

85.

Zhu

Chen

Liu

. MicroRNA‑433 inhibits cell growth and induces apoptosis in human cervical cancer through PI3K/Akt signaling by targeting FAK. Oncol Rep. 2018;40(6):3469-3478.doi:10.3892/or.2018.6718

30272334

86.

Zhou

Shu

Huang

. Fibronectin promotes cervical cancer tumorigenesis through activating FAK signaling pathway. J Cell Biochem. 2019:10988-10997.doi:10.1002/jcb.28282

30977220

87.

Barbisan

Pérez

LO.

Contreras

Golijow

. TNF-α and IL-10 promoter polymorphisms, HPV infection, and cervical cancer risk. Tumour Biol. 2012;33(5):1549-1556.doi:10.1007/s13277-012-0408-1

22592655

88.

Jin

Qiu

Shao

Zheng

. Fucoxanthin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically promotes apoptosis of human cervical cancer cells by targeting PI3K/Akt/NF-κB signaling pathway. Med Sci Monit. 2018;24:11-18.doi:10.12659/MSM.905360

29291370

89.

Liu

. The correlation between TNF-α-308 gene polymorphism and susceptibility to cervical cancer. Oncol Lett. 2018;15(5):7163-7167.doi:10.3892/ol.2018.8246

29725439

90.

Yin

et al. The correlation between TNF-α promoter gene polymorphism and genetic susceptibility to cervical cancer. Technol Cancer Res Treat. 2018;17:153303381878279.doi:10.1177/1533033818782793

29940817

91.

Liu

Yang

Chen

et al. Association between TNF-α polymorphisms and cervical cancer risk: a meta-analysis. Mol Biol Rep. 2012;39(3):2683-2688.doi:10.1007/s11033-011-1022-9

21670964

92.

JN.

Lee

WS.

Yun

et al. Anthocyanins from Vitis coignetiae Pulliat inhibit cancer invasion and epithelial-mesenchymal transition, but these effects can be attenuated by tumor necrosis factor in human uterine cervical cancer HeLa cells. Evid Based Complement Alternat Med. 2013;2013:503043. doi:10.1155/2013/503043

23864892

93.

Managit

Sakurai

Saiki

. Ethanolic extract of Thevetia peruviana flowers enhances TNF-α and TRAIL-induced apoptosis of human cervical cancer cells via intrinsic and extrinsic pathways. Oncol Lett. 2017;13(4):2791-2798.doi:10.3892/ol.2017.5748

28454468

94.

Pan

Tian

C-S

et al. Association of TNF-α-308 and -238 polymorphisms with risk of cervical cancer: a meta-analysis. Asian Pac J Cancer Prev. 2012;13(11):5777-5783.doi:10.7314/APJCP.2012.13.11.5777

23317256

95.

Roszak

Misztal

Sowińska

Jagodziński

. TNF-α -308 G/A as a risk marker of cervical cancer progression in the Polish population. Mol Diagn Ther. 2015;19(1):53-57.doi:10.1007/s40291-015-0130-y

25614219

96.

Suk

Chang

Kim

et al. Interferon gamma (IFNgamma) and tumor necrosis factor alpha synergism in ME-180 cervical cancer cell apoptosis and necrosis. IFNgamma inhibits cytoprotective NF-kappa B through STAT1/IRF-1 pathways. J Biol Chem. 2001;276(16):13153-13159.doi:10.1074/jbc.M007646200

11278357

97.

Sun

Cui

Wang

Guo

Zhang

. Tumor necrosis factor-related apoptosis inducing ligand overexpression and taxol treatment suppresses the growth of cervical cancer cells in vitro and in vivo . Oncol Lett. 2018;15(4):5744-5750.doi:10.3892/ol.2018.8071

29556305

98.

Wang

Yang

Huang

Tian

. Tumor necrosis factor-α polymorphisms and cervical cancer: evidence from a meta-analysis. Gynecol Obstet Invest. 2020;85(2):153-158.doi:10.1159/000502955

31825934

99.

Zhang

. Microrna-21 regulates the proliferation and apoptosis of cervical cancer cells via tumor necrosis factor-α. Mol Med Rep. 2017;16(4):4659-4663.doi:10.3892/mmr.2017.7143

28765959

100.

Zhao

Wang

Cui

. Melatonin enhances TNF-α-mediated cervical cancer HeLa cells death via suppressing CaMKII/Parkin/mitophagy axis. Cancer Cell Int. 2019;19:58. doi:10.1186/s12935-019-0777-2

30923460

101.

Węsierska-Gądek

. Targeting p53 as a promising therapeutic option for cancer by re-activating the WT or mutant p53’s tumor suppression. Future Med Chem. 2018;10(7):755-777.doi:10.4155/fmc-2017-0175

29569948

102.

Hietanen

Lain

Krausz

Blattner

Lane

. Activation of p53 in cervical carcinoma cells by small molecules. Proc Natl Acad Sci U S A. 2000;97(15):8501-8506.doi:10.1073/pnas.97.15.8501

10900010

103.

Sun

Zhao

Guo

. P53 introduction enhances chemotherapy-induced apoptosis in HeLa cells. Transl Cancer Res. 2018;7(4):1103-1111.doi:10.21037/tcr.2018.08.25

104.

Klug

SJ.

Ressing

Koenig

et al. Tp53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies. Lancet Oncol. 2009;10(8):772-784.doi:10.1016/S1470-2045(09)70187-1

19625214

105.

Lin

Wang

Xue

. The prognostic values of the expression of vimentin, TP53, and podoplanin in patients with cervical cancer. Cancer Cell Int. 2017;17:80. doi:10.1186/s12935-017-0450-6

28912668

106.

Tao

Wen

Yang

Zhang

. miR-144 inhibits growth and metastasis of cervical cancer cells by targeting VEGFA and VEGFC. Exp Ther Med. 2018;15(1):562-568.doi:10.3892/etm.2017.5392

29387205

107.

Chen

Zhang

Dong

Guo

. Molecular regulation of cervical cancer growth and invasion by VEGFA. Tumour Biol. 2014;35(11):11587-11593.doi:10.1007/s13277-014-2463-2

25135429

108.

Braicu

EI.

Gasimli

Richter

et al. Role of serum VEGFA, TIMP2, MMP2 and MMP9 in monitoring response to adjuvant radiochemotherapy in patients with primary cervical cancer–results of a companion protocol of the randomized NOGGO-AGO phase III clinical trial. Anticancer Res. 2014;34(1):385-391.24403492

109.

Zhu

Mao

et al. miR-203 suppresses tumor growth and angiogenesis by targeting VEGFA in cervical cancer. Cell Physiol Biochem. 2013;32(1):64-73.doi:10.1159/000350125

23867971

110.

Chen

Qiu

et al. Ly6K promotes cervical cancer growth, invasion and migration through regulating VEGFA. Int J Clin Exp Pathol. 2016;9(11):10981-10991.

111.

Guo

Chen

Mao

Zhou

. Hsa_circ_0023404 enhances cervical cancer metastasis and chemoresistance through VEGFA and autophagy signaling by sponging miR-5047. Biomed Pharmacother. 2019;115:108957. doi:10.1016/j.biopha.2019.108957

31082770

112.

Bhushan

Malik

Kumar

et al. Activation of p53/p21/PUMA alliance and disruption of PI-3/Akt in multimodal targeting of apoptotic signaling cascades in cervical cancer cells by a pentacyclic triterpenediol from Boswellia serrata. Mol Carcinog. 2009;48(12):1093-1108.doi:10.1002/mc.20559

19544329

113.

Cao

Wang

Ren

Tian

Yang

Cheng

. miR-125a-5p post-transcriptionally suppresses GALNT7 to inhibit proliferation and invasion in cervical cancer cells via the EGFR/PI3K/AKT pathway. Cancer Cell Int. 2020;20:117. doi:10.1186/s12935-020-01209-8

32308562

114.

Chen

H-H.

Chen

S-P.

Zheng

Q-L

et al. Genistein promotes proliferation of human cervical cancer cells through estrogen receptor-mediated PI3K/Akt-NF-κB pathway. J Cancer. 2018;9(2):288-295.doi:10.7150/jca.20499

29344275

115.

Chen

Y-H.

Yang

S-F.

Yang

C-K

et al. Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/Akt signaling in human cervical cancer cells. Mol Med Rep. 2021;23(1):1-11.doi:10.3892/mmr.2020.11725

33236135

116.

de Almeida

VH.

de Melo

AC.

Meira

et al. Radiotherapy modulates expression of EGFR, ERCC1 and p53 in cervical cancer. Braz J Med Biol Res. 2017;51(1):e6822. doi:10.1590/1414-431x20176822

29160417

117.

Hakimee

Hutamekalin

Tanasawet

Chonpathompikunlert

Tipmanee

Sukketsiri

. Metformin inhibit cervical cancer migration by suppressing the FAK/Akt signaling pathway. Asian Pac J Cancer Prev. 2019;20(12):3539-3545.doi:10.31557/APJCP.2019.20.12.3539

31870092

118.

Wang

Chen

et al. Hsp90 inhibitor SNX-2112 enhances TRAIL-induced apoptosis of human cervical cancer cells via the ROS-mediated JNK-p53-Autophagy-DR5 pathway. Oxid Med Cell Longev. 2019;2019:1-26.doi:10.1155/2019/9675450

31019655

119.

Liu

Xue

Bai

Zhang

. F-Box protein FBXO31 modulates apoptosis and epithelial-mesenchymal transition of cervical cancer via inactivation of the PI3K/AKT-mediated MDM2/p53 axis. Life Sci. 2020;259:118277. doi:10.1016/j.lfs.2020.118277

32800832

120.

Muñoz

JP.

Carrillo-Beltrán

Aedo-Aguilera

et al. Tobacco exposure enhances human papillomavirus 16 oncogene expression via EGFR/PI3K/Akt/c-Jun signaling pathway in cervical cancer cells. Front Microbiol. 2018;9:3022. doi:10.3389/fmicb.2018.03022

30619121

121.

Yamashita

Murakami

Asari

Okuma

Ohtomo

Nakagawa

. Correlation among six biologic factors (p53, p21(WAF1), MIB-1, EGFR, HER2, and Bcl-2) and clinical outcomes after curative chemoradiation therapy in squamous cell cervical cancer. Int J Radiat Oncol Biol Phys. 2009;74(4):1165-1172.doi:10.1016/j.ijrobp.2008.09.005

19101092

122.

Bossler

Hoppe-Seyler

. Pi3K/Akt/mTOR signaling regulates the Virus/Host cell crosstalk in HPV-positive cervical cancer cells. Int J Mol Sci. 2019;20(9):1-13.doi:10.3390/ijms20092188

31058807

123.

Shi

Wang

Lei

Cong

Tan

Zhou

. Research progress on the PI3K/Akt signaling pathway in gynecological cancer (review). Mol Med Rep. 2019;19(6):4529-4535.doi:10.3892/mmr.2019.10121

30942405

124.

Yang

Nie

Wei

Peng

Wei

. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019;18(1):26. doi:10.1186/s12943-019-0954-x

30782187

125.

McLean

GW.

Carragher

NO.

Avizienyte

Evans

Brunton

VG.

Frame

. The role of focal-adhesion kinase in cancer - a new therapeutic opportunity. Nat Rev Cancer. 2005;5(7):505-515.doi:10.1038/nrc1647

16069815

126.

Semenza

. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721-732.doi:10.1038/nrc1187

13130303

127.

del Campo

JM.

Prat

Gil-Moreno

Pérez

Parera

. Update on novel therapeutic agents for cervical cancer. Gynecol Oncol. 2008;110(3):S72-S76.doi:10.1016/j.ygyno.2008.04.016

18544460

128.

Rinaldi

Plummer

Biessy

et al. Endogenous sex steroids and risk of cervical carcinoma: results from the EPIC study. Cancer Epidemiol Biomarkers Prev. 2011;20(12):2532-2540.doi:10.1158/1055-9965.EPI-11-0753

21994406

129.

Schiffman

Castle

PE.

Jeronimo

Rodriguez

AC.

Wacholder

. Human papillomavirus and cervical cancer. Lancet. 2007;370(9590):890-907.doi:10.1016/S0140-6736(07)61416-0

17826171

130.

Punt

Fleuren

GJ.

Kritikou

et al. Angels and demons: Th17 cells represent a beneficial response, while neutrophil IL-17 is associated with poor prognosis in squamous cervical cancer. Oncoimmunology. 2015;4(1):e984539. doi:10.4161/2162402X.2014.984539

25949866

131.

Punt

van Vliet

ME.

Spaans

et al. FoxP3(+) and IL-17(+) cells are correlated with improved prognosis in cervical adenocarcinoma. Cancer Immunol Immunother. 2015;64(6):745-753.doi:10.1007/s00262-015-1678-4

25795131

132.

Sun

LX.

Wang

XB.

Huang

. Association analysis of rs2275913G>A and rs763780T>C interleukin 17 polymorphisms in Chinese women with cervical cancer. Genet Mol Res. 2015;14(4):13612-13617.doi:10.4238/2015.October.28.22

26535675

133.

Tartour

Fossiez

Joyeux

et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res. 1999;59(15):3698-3704.10446984

134.

Xue

Wang

Chen

Zhu

. Effects of Th17 cells and IL-17 in the progression of cervical carcinogenesis with high-risk human papillomavirus infection. Cancer Med. 2018;7(2):297-306.doi:10.1002/cam4.1279

29277958

135.

Cai

Yan

Liu

Cai

. Ifi16 promotes cervical cancer progression by upregulating PD-L1 in immunomicroenvironment through STING-TBK1-NF-kB pathway. Biomed Pharmacother. 2020;123:109790. doi:10.1016/j.biopha.2019.109790

31896065

136.

Meng

Liu

Cao

Sun

. Ovatodiolide exerts anticancer effects on human cervical cancer cells via mitotic catastrophe, apoptosis and inhibition of NF-kB pathway. J Buon. 2020;25(1):87-92.32277618

137.

Vandermark

ER.

Deluca

KA.

Gardner

et al. Human papillomavirus type 16 E6 and E 7 proteins alter NF-kB in cultured cervical epithelial cells and inhibition of NF-kB promotes cell growth and immortalization. Virology. 2012;425(1):53-60.doi:10.1016/j.virol.2011.12.023

22284893

138.

Sun

. Bismahanine exerts anticancer effects on human cervical cancer cells by inhibition of growth, migration and invasion via suppression of NF-kB signalling pathway. J Buon. 2020;25(1):93-98.32277619

139.

Zhang

Chinnathambi

Alharbi

SA.

Veeraraghavan

VP.

Mohan

SK.

Zhang

. Punicalagin promotes the apoptosis in human cervical cancer (ME-180) cells through mitochondrial pathway and by inhibiting the NF-kB signaling pathway. Saudi J Biol Sci. 2020;27(4):1100-1106.doi:10.1016/j.sjbs.2020.02.015

32256171

140.

Zhang

. Inhibition of human cervical cancer cell growth by Salviolone is mediated via autophagy induction, cell migration and cell invasion suppression, G2/M cell cycle arrest and downregulation of Nf-kB/m-TOR/PI3K/AKT pathway. J Buon. 2018;23(6):1739-1744.30610802

141.

Zhang

Zhao

Ran

Guo

Cui

Liu

. Alantolactone exhibits selective antitumor effects in HeLa human cervical cancer cells by inhibiting cell migration and invasion, G2/M cell cycle arrest, mitochondrial mediated apoptosis and targeting NF-kB signalling pathway. J Buon. 2019;24(6):2310-2315.31983099

142.

Qiu

R-L.

Lin

et al. Resveratrol suppresses human cervical carcinoma cell proliferation and elevates apoptosis via the mitochondrial and p53 signaling pathways. Oncol Lett. 2018;15(6):9845-9851.doi:10.3892/ol.2018.8571

29928358

143.

Xiao

Zhou

et al. Fra-1 is downregulated in cervical cancer tissues and promotes cervical cancer cell apoptosis by p53 signaling pathway in vitro. Int J Oncol. 2015;46(4):1677-1684.doi:10.3892/ijo.2015.2873

25651840

144.

Vidya Priyadarsini

Senthil Murugan

Maitreyi

Ramalingam

Karunagaran

Nagini

. The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-κB inhibition. Eur J Pharmacol. 2010;649(1-3):84-91.doi:10.1016/j.ejphar.2010.09.020

20858478

145.

Mezache

Paniccia

Nyinawabera

Nuovo

. Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers. Mod Pathol. 2015;28(12):1594-1602.doi:10.1038/modpathol.2015.108

26403783

146.

Lipson

EJ.

Forde

PM.

Hammers

H-J.

Emens

LA.

Taube

JM.

Topalian

. Antagonists of PD-1 and PD-L1 in cancer treatment. Semin Oncol. 2015;42(4):587-600.doi:10.1053/j.seminoncol.2015.05.013

26320063

147.

Ascencio-Cedillo

López-Pulido

EI.

Muñoz-Valle

et al. Prolactin and prolactin receptor expression in cervical intraepithelial neoplasia and cancer. Pathol Oncol Res. 2015;21(2):241-246.doi:10.1007/s12253-014-9814-6

24990775

148.

Lopez-Pulido

EI.

Muñoz-Valle

JF.

Del Toro-Arreola

et al. High expression of prolactin receptor is associated with cell survival in cervical cancer cells. Cancer Cell Int. 2013;13(1):103. doi:10.1186/1475-2867-13-103

24148306

149.

Fernandes

JV.

DE Medeiros Fernandes

TAA.

DE Azevedo

JCV

et al. Link between chronic inflammation and human papillomavirus-induced carcinogenesis (review). Oncol Lett. 2015;9(3):1015-1026.doi:10.3892/ol.2015.2884

25663851

150.

Deivendran

Marzook

KH.

Radhakrishna Pillai

. The role of inflammation in cervical cancer. Adv Exp Med Biol. 2014;816:377-399.doi:10.1007/978-3-0348-0837-8_15

24818731

151.

Parida

Mandal

. Inflammation induced by human papillomavirus in cervical cancer and its implication in prevention. Eur J Cancer Prev. 2014;23(5):432-448.doi:10.1097/CEJ.0000000000000023

24787377

152.

Epstein

. Vegf signaling inhibitors: more pro-apoptotic than anti-angiogenic. Cancer Metastasis Rev. 2007;26(3-4):443-452.doi:10.1007/s10555-007-9071-1

17786538

153.

Wei

L-H.

Kuo

M-L.

Chen

C-A

et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 2003;22(10):1517-1527.doi:10.1038/sj.onc.1206226

12629515

154.

Guo

J-ming.

Xiao

B-xiu.

Liu

Zhang

Liu

D-hai.

Gong

Z-hui

. Anticancer effect of aloe-emodin on cervical cancer cells involves G2/M arrest and induction of differentiation. Acta Pharmacol Sin. 2007;28(12):1991-1995.doi:10.1111/j.1745-7254.2007.00707.x

18031614

155.

Luo

Yuan

Chang

Liu

. Combination of aloe-emodin with radiation enhances radiation effects and improves differentiation in human cervical cancer cells. Mol Med Rep. 2014;10(2):731-736.doi:10.3892/mmr.2014.2318

24920336

156.

Trybus

Król

Trybus

Stachurska

Kopacz-Bednarska

Król

. Induction of mitotic catastrophe in human cervical cancer cells after administration of aloe-emodin. Anticancer Res. 2018;38(4):2037-2044.doi:10.21873/anticanres.12443

29599321

157.

Koraneekit

Limpaiboon

Sangka

Boonsiri

Daduang

. Synergistic effects of cisplatin-caffeic acid induces apoptosis in human cervical cancer cells via the mitochondrial pathways. Oncol Lett. 2018;15(5):7397-7402.doi:10.3892/ol.2018.8256

29731891

158.

Tyszka-Czochara

Bukowska-Strakova

Kocemba-Pilarczyk

Majka

. Caffeic acid targets AMPK signaling and regulates tricarboxylic acid cycle anaplerosis while metformin downregulates HIF-1α-Induced glycolytic enzymes in human cervical squamous cell carcinoma lines. Nutrients. 2018;10(7):1-21.doi:10.3390/nu10070841

29958416

159.

Tyszka-Czochara

Bukowska-Strakova

Majka

. Metformin and caffeic acid regulate metabolic reprogramming in human cervical carcinoma SiHa/HTB-35 cells and augment anticancer activity of Cisplatin via cell cycle regulation. Food Chem Toxicol. 2017;106(Pt A):260-272.doi:10.1016/j.fct.2017.05.065

28576465

160.

Tyszka-Czochara

Konieczny

Majka

. Caffeic acid expands anti-tumor effect of metformin in human metastatic cervical carcinoma HTB-34 cells: implications of AMPK activation and impairment of fatty acids de novo biosynthesis. Int J Mol Sci. 2017;18(2):1-16.doi:10.3390/ijms18020462

28230778

161.

Tyszka-Czochara

Lasota

Majka

. Caffeic acid and metformin inhibit invasive phenotype induced by TGF-β1 in C-4I and HTB-35/SiHa human cervical squamous carcinoma cells by acting on different molecular targets. Int J Mol Sci. 2018;19(1):1-19.doi:10.3390/ijms19010266

29337896

162.

Al-Hazzani

AA.

Alshatwi

. Catechin hydrate inhibits proliferation and mediates apoptosis of SiHa human cervical cancer cells. Food Chem Toxicol. 2011;49(12):3281-3286.doi:10.1016/j.fct.2011.09.023

21967781

163.

Horie

Hirabayashi

Takahashi

Miyauchi

Taguchi

Takeishi

. Synergistic effect of green tea catechins on cell growth and apoptosis induction in gastric carcinoma cells. Biol Pharm Bull. 2005;28(4):574-579.doi:10.1248/bpb.28.574

15802789

164.

Trybus

Król

Trybus

Stachurska

Król

. The potential antitumor effect of chrysophanol in relation to cervical cancer cells. J Cell Biochem. 2021:1-14.doi:10.1002/jcb.29891

33417255

165.

Taiwo

BJ.

Popoola

TD.

van Heerden

FR.

Fatokun

AA.

Pentagalloylglucose

FAA

. Pentagalloylglucose, isolated from the leaf extract of Anacardium occidentale L., could elicit rapid and selective cytotoxicity in cancer cells. BMC Complement Med Ther. 2020;20(1):287.doi:10.1186/s12906-020-03075-3

32957961

166.

Sun

GP.

Wang

Shen

YX.

. Inhibitory effects of paeonol on the proliferation of four tumor cell lines. Anhui Med Pharm J. 2004;8:85-86.

167.

Zhang

. Modulating Bcl-2 family proteins and caspase-3 in induction of apoptosis by paeoniflorin in human cervical cancer cells. Phytother Res. 2011;25(10):1551-1557.doi:10.1002/ptr.3534

21698669

168.

Moreira

TF.

Sorbo

JM.

Souza

FdeO

et al. Emodin, Physcion, and Crude Extract of Rhamnus sphaerosperma var. pubescens Induce Mixed Cell Death, Increase in Oxidative Stress, DNA Damage, and Inhibition of AKT in Cervical and Oral Squamous Carcinoma Cell Lines. Oxid Med Cell Longev. 2018;2018:1-18.doi:10.1155/2018/2390234

30057674

169.

Srinivas

Anto

RJ.

Srinivas

Vidhyalakshmi

Senan

VP.

Karunagaran

. Emodin induces apoptosis of human cervical cancer cells through poly(ADP-ribose) polymerase cleavage and activation of caspase-9. Eur J Pharmacol. 2003;473(2-3):117-125.doi:10.1016/S0014-2999(03)01976-9

12892828

170.

Thacker

PC.

Karunagaran

. Curcumin and emodin down-regulate TGF-β signaling pathway in human cervical cancer cells. PLoS One. 2015;10(3):e0120045. doi:10.1371/journal.pone.0120045

25786122

171.

Yaoxian

Hui

Yunyan

Yanqin

Xin

Xiaoke

. Emodin induces apoptosis of human cervical cancer HeLa cells via intrinsic mitochondrial and extrinsic death receptor pathway. Cancer Cell Int. 2013;13(1):71. doi:10.1186/1475-2867-13-71

23866157

172.

Aborehab

NM.

Osama

. Effect of gallic acid in potentiating chemotherapeutic effect of paclitaxel in HeLa cervical cancer cells. Cancer Cell Int. 2019;19:154. doi:10.1186/s12935-019-0868-0

31171918

173.

Shi

Lei

Srivastava

Qin

Chen

. Gallic acid induces apoptosis in human cervical epithelial cells containing human papillomavirus type 16 episomes. J Med Virol. 2016;88(1):127-134.doi:10.1002/jmv.24291

26059022

174.

Zhao

. Gallic acid reduces cell viability, proliferation, invasion and angiogenesis in human cervical cancer cells. Oncol Lett. 2013;6(6):1749-1755.doi:10.3892/ol.2013.1632

24843386

175.

Fang

Liu

Cai

. Hederagenin inhibits proliferation and promotes apoptosis of cervical cancer CaSki cells by blocking STAT3 pathway. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2019;35(2):140-145.30975278

176.

Kashafi

Moradzadeh

Mohamadkhani

Erfanian

. Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/Akt and telomerase pathways. Biomed Pharmacother. 2017;89:573-577.doi:10.1016/j.biopha.2017.02.061

28258039

177.

Kim

H-J.

Cho

H-S.

Ban

HS.

Nakamura

. Suppression of HIF-1α accumulation by betulinic acid through proteasome activation in hypoxic cervical cancer. Biochem Biophys Res Commun. 2020;523(3):726-732.doi:10.1016/j.bbrc.2020.01.031

31948750

178.

Pang

Wang

Yan

. Betulinic acid induces apoptosis by regulating PI3K/Akt signaling and mitochondrial pathways in human cervical cancer cells. Int J Mol Med. 2017;40(6):1669-1678.doi:10.3892/ijmm.2017.3163

29039440

179.

Pang

Zhou

et al. Proteomic investigation into betulinic acid-induced apoptosis of human cervical cancer HeLa cells. PLoS One. 2014;9(8):e105768. doi:10.1371/journal.pone.0105768

25148076

180.

S-W.

Weng

Y-S.

Lin

S-Y

et al. The role of Ca+2 on rhein-induced apoptosis in human cervical cancer Ca Ski cells. Anticancer Res. 2007;27(1A):379-389.17352257

181.

Bishayee

Ghosh

Mukherjee

Sadhukhan

Mondal

Khuda-Bukhsh

. Quercetin induces cytochrome-c release and ROS accumulation to promote apoptosis and arrest the cell cycle in G2/M, in cervical carcinoma: signal cascade and drug-DNA interaction. Cell Prolif. 2013;46(2):153-163.doi:10.1111/cpr.12017

23510470

182.

Clemente-Soto

AF.

Salas-Vidal

Milan-Pacheco

Sánchez-Carranza

JN.

Peralta-Zaragoza

González-Maya

. Quercetin induces G2 phase arrest and apoptosis with the activation of p53 in an E6 expression‑independent manner in HPV‑positive human cervical cancer‑derived cells. Mol Med Rep. 2019;19(3):2097-2106.doi:10.3892/mmr.2019.9850

30664221

183.

Kedhari Sundaram

Hussain

Haque

Raina

Afroze

. Quercetin modifies 5’CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells. J Cell Biochem. 2019;120(10):18357-18369.doi:10.1002/jcb.29147

31172592

184.

Kedhari Sundaram

Raina

Afroze

et al. Quercetin modulates signaling pathways and induces apoptosis in cervical cancer cells. Biosci Rep. 2019;39(8):1-17.doi:10.1042/BSR20190720

31366565

185.

X-M.

Liu

Pan

F-F.

Shi

D-D.

Wen

Z-G.

Yang

P-L

. Quercetin and aconitine synergistically induces the human cervical carcinoma HeLa cell apoptosis via endoplasmic reticulum (ER) stress pathway. PLoS One. 2018;13(1):e0191062. doi:10.1371/journal.pone.0191062

29324796

186.

Lin

T-H.

Hsu

W-H.

Tsai

P-H

et al. Dietary flavonoids, luteolin and quercetin, inhibit invasion of cervical cancer by reduction of UBE2S through epithelial-mesenchymal transition signaling. Food Funct. 2017;8(4):1558-1568.doi:10.1039/C6FO00551A

28277581

187.

Alvarez-Sala

Attanzio

Tesoriere

Garcia-Llatas

Barberá

Cilla

. Apoptotic effect of a phytosterol-ingredient and its main phytosterol (β-sitosterol) in human cancer cell lines. Int J Food Sci Nutr. 2019;70(3):323-334.doi:10.1080/09637486.2018.1511689

30192685

188.

Cheng

Guo

Zhang

. Effect of β-sitosterol on the expression of HPV E6 and p53 in cervical carcinoma cells. Contemp Oncol. 2015;1(1):36-42.doi:10.5114/wo.2015.50011

26199569

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

1.12 MB