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Overview of signaling pathways against cervical cancer. Overview of signaling pathways against cervical cancer.
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Cervical cancer is the second most common gynecological malignancy globally; it seriously endangers women’s health because of its high morbidity and mortality. Conventional treatments are prone to drug resistance, recurrence and metastasis. Therefore, there is an urgent need to develop new drugs with high efficacy and low side effects to prevent an...
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... the inhibition of telomerase activity and enhancement of immune function were not included [192]. Our study reviewed 30 natural products that have antitumor effects on cervical cancer, which showed possible benefits in treating patients with cervical cancer through mechanisms, such as induction of apoptosis, inhibition of cell proliferation and angiogenesis ( Figure 6). Therefore, the search for more readily available natural antitumor active ingredients and precursor drugs could provide effectively alternative or adjuvant treatment strategies for cancer patients. ...
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... the inhibition of telomerase activity and enhancement of immune function were not included [192]. Our study reviewed 30 natural products that have antitumor effects on cervical cancer, which showed possible benefits in treating patients with cervical cancer through mechanisms, such as induction of apoptosis, inhibition of cell proliferation and angiogenesis ( Figure 6). Therefore, the search for more readily available natural antitumor active ingredients and precursor drugs could provide effectively alternative or adjuvant treatment strategies for cancer patients. ...
Citations
... The geographical distribution of Luffa species is widely found in North America, South America, Africa, and the Indian region [4]. Natural products have become a new hope for treating a variety of symptoms from non-alcoholic steatohepatitis [5], Cancer [6,7], Obesity [8], antimicrobial resistance [9], and neurodegeneration [10,11]. Luffa cylindrica is used in traditional medicine to treat boils, asthma, tuberculosis, shingles, and generalized body pain. ...
The loofah/sponge gourd Luffa cylindrica (L.), a member of the Cucurbitaceae family, is one of the neglected medicinal plants. Traditionally, Luffa cylindrica is prescribed for inducing labor. It has a long history of use in China for the treatment of fever, diabetes, dyspnea, and dysentery. This study investigated the toxicity profile of the alkaloid-rich fraction of Luffa cylindrica (ARF-LC) for the first time in Sprague Dawley rats. A total of 80 rats (40 male and 40 female rats) aged 13 weeks old and weighing 200–220 g were selected for this study. In SD rats, sub-chronic oral toxicity was investigated at doses of 100, 200, and 400 mg/kg/d for a total of 90 days, followed by a 30-day recovery period. The results showed no variation in body weight among the three dose groups compared to the control group. Treatment-related adverse events, such as alterations in hematology and serum biochemistry parameters and the histology of the liver were sporadic in the high-dose rats but within the reference range. However, these changes disappeared after the doses were withdrawn during the recovery period. In conclusion, the “no observed adverse effect level” (NOAEL) of oral administration of ARF-LC in SD rats was considered 400 mg/kg/d and can be studied for its potential in further in vivo chronic investigations.
... Attempts have been made to overcome these limitations, particularly through the use of nano-based drug delivery systems (NDDS), which are a new approach to the clinical application of natural products [76]. Natural products can achieve anti-CC effects through various mechanisms, including the inhibition of tumor cell proliferation, induction of apoptosis, inhibition of angiogenesis and telomerase activity, enhancement of immunity, and reversal of multidrug resistance [77]. Flavonoids, alkaloids, polyphenols, terpenoids, and quinones can act as anticancer agents. ...
Ongoing research is gradually broadening the idea of cancer treatment, with attention being focused on nanoparticles to improve the stability, therapeutic efficacy, targeting, and other important metrics of conventional drugs and traditional drug delivery methods. Studies have demonstrated that drug delivery carriers based on biomaterials (e.g., protein nanoparticles and lipids) and inorganic materials (e.g., metal nanoparticles) have potential anticancer effects. Among these carriers, self-assembled proteins and peptides, which are highly biocompatible and easy to standardize and produce, are strong candidates for the preparation of anticancer drugs. Breast cancer (BC) and cervical cancer (CC) are two of the most common and deadly cancers in women. These cancers not only threaten lives globally but also put a heavy burden on the healthcare system. Despite advances in medical care, the incidence of these two cancers, particularly CC, which is almost entirely preventable, continues to rise, and the mortality rate remains steady. Therefore, there is still a need for in-depth research on these two cancers to develop more targeted, efficacious, and safe therapies. This paper reviews the types of self-assembling proteins and peptides (e.g., ferritin, albumin, and virus-like particles) and natural products (e.g., soy and paclitaxel) commonly used in the treatment of BC and CC and describes the types of drugs that can be delivered using self-assembling proteins and peptides as carriers (e.g., siRNAs, DNA, plasmids, and mRNAs). The mechanisms (including self-assembly) by which the natural products act on CC and BC are discussed. The mechanism of action of natural products on CC and BC and the mechanism of action of self-assembled proteins and peptides have many similarities (e.g., NF-KB and Wnt). Thus, natural products using self-assembled proteins and peptides as carriers show potential for the treatment of BC and CC.
... These treatments often cause life-threatening side effects in patients and often cause problems in other parts of the body (Wipperman et al., 2018). Currently, the natural components of plants have been proposed as effective anticancer agents without generating side effects (G€ okalp, 2021;He et al., 2021). ...
Cervical cancer (CC) is the most frequent cancer in the female population worldwide. Although there are treatments available, they are ineffective and cause adverse effects. 6-gingerol is an active component in ginger with anticancer activity. This research aims to discover the mechanism by which 6-gingerol act as an anticancer agent on CC through a pharmacological network using bioinformatics databases. From MalaCard, Swiss Target Prediction, Comparative Toxicogenomics Database, and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, we obtained the target genes for 6-gingerol and CC and matched them. We got 26 genes and analyzed them in ShinyGO-0.76.3 and DAVID-Bioinformatics Resources. Then, we generated a protein-protein interaction network in Cytoscape and obtained 12 hub genes. Hub genes were analyzed in Gene Expression Profiling Interactive Analysis and TISIDB. In addition, molecular docking studies were performed between target proteins with 6-gingerol using SwissDock database. Finally, molecular dynamics studies
for three proteins with the lowest interaction energy were implemented using Gromacs software. According to gene ontology results, 6-gingerol is involved in processes of apoptosis, cell cycle, and protein kinase complexes, affecting mitochondria and pathways related to HPV infection. CTNNB1 gene was negatively correlated with CD8þ infiltration but was not associated with a higher survival rate. Furthermore, the molecular docking study showed that 6-gingerol has a high binding to proteins, and the molecular dynamics showed a stable interaction of 6-gingerol to AKT1, CCNB1, and CTNNB1 proteins. Conclusion, our work helps to understand the anticancer activity of 6-gingerol in CC that should be studied experimentally
... Methyl jasmonate treatment significantly increased the total anthocyanin and phenol contents in blackberry fruits; inhibited cell proliferation in human lungs, A549 cells, and HL-60 leukemia cells; and induced the apoptosis of HL-60 cells [21]. Cyanidin 3-O-glucoside (C3G) may increase cisplatin's antitumor activity to reduce the adverse effects of chemotherapy in cervical cancer [22]. Several mechanisms have been proposed to mediate the anticancer properties of anthocyanins. ...
... Their results demonstrated that they inhibited growth and metastasis, induced apoptosis, and arrested the cell cycle of non-small cell lung cancer cells, such as A549 cells, in vitro [25]. He et al. reviewed 30 plant-derived products with antitumor effects on cervical cancer that showed possible benefits in treating patients through various mechanisms, such as apoptosis induction and inhibiting cell proliferation [22]. Li et al. found a combination of C3G and DDP significantly inhibited the activities of SOD, catalase, and glutathione peroxidase by modulating the nuclear factor E2-related factor 2 (Nrf2) signaling pathway to induce oxidative stress and apoptosis in HeLa cells [38]. ...
Blackberries have high nutritional value and strong biological activities, such as antiproliferative activity. Anthocyanins are important functional components in blackberries. We collected 25 kinds (lines) of blackberries from our nursery to investigate antiproliferative agents in natural foods. Among them, the Shuofeng variety had the highest anthocyanin content, with 2.54 mg/g of fresh fruit, which increased to 357.75 mg/g of dried powder through ultrasound-assisted solvent extraction and macroporous resin adsorption. Additional experiments showed that Shuofeng’s anthocyanin content had high anti-HepG2 activity in vitro and in vivo, as well as activity against Hela (68.62 μg/mL), HepG2 (55.85 μg/mL), MCF-7 (181.21 μg/mL), and A549 cells (82.01 μg/mL), as determined by MTT assay. It also had no apparent toxic effects. The combination of DDP and DOX significantly enhanced the antiproliferative activity of the four cell lines. The IC50 value of Shuofeng’s anthocyanin content combined with DOX in HepG2 cells was the lowest at only 0.08 μg/mL, indicating that the combination of drugs had additive and synergistic effects. Shuofeng’s anthocyanin content might intercalate into DNA and alter or destroy DNA, causing apoptosis and inhibiting cell proliferation. Our results show that blackberry anthocyanins can inhibit the proliferation of cancer cells and their possible mechanisms. However, we must study the deeper mechanism and explore its targeting effects in the future.
... Natural products have attracted much attention as cancer treatments because of their strong potency and low toxicity, and several products have shown efficacy in cancer control and treatment [5,6]. Ginsenoside Rh2 (GRh2) is the natural extract of Panax ginseng C.A. Meyer (ginseng) and exhibits biological activities in inhibiting cell proliferation and inducing cell apoptosis in oral cancer, colon cancer, and prostate cancer [7][8][9]. ...
Cervical cancer is a common gynecological malignancy afflicting women all over the world. Ginsenoside Rh2 (GRh2), especially 20(S)-GRh2, is a biologically active component in the natural plant ginseng, which can exhibit anticancer effects. Here, we aimed to investigate the effect of 20(S)-GRh2 on cervical cancer and elucidate the underlying mechanism through RNA-seq. In this study, the CCK-8 assay showed that 20(S)-GRh2 inhibited HeLa cell viability in a time- and dose-dependent manner. Caspase 3 activity and Annexin V staining results showed that 20(S)-GRh2 induced apoptosis of HeLa cells. Gene function enrichment analysis revealed that the biological process gene ontology (GO) terms were associated with the apoptotic signaling pathway. Biological process GO terms’ similarity network indicated that apoptosis might be from endoplasmic reticulum stress (ERs). Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that 20(S)-GRh2 primarily modulates apoptosis pathway genes. Combined protein–protein interaction network, hub gene screening, and qPCR validation data showed that ERs-related genes (ATF4 and DDIT3) and the downstream apoptotic genes (JUN, FOS, BBC3, and PMAIP1) were potential novel targets of 20(S)-GRh2-inducing cervical cancer cell apoptosis. Differential transcript usage analysis indicated that DDIT3 is also a differential transcript and its usage of the isoform (ENST00000552740.5) was reduced by 20(S)-GRh2. Molecular docking suggested that 20(S)-GRh2 binds to the targets (ATF4, DDIT3, JUN, FOS, BBC3, and PMAIP1) with high affinity. In conclusion, our findings indicated that 20(S)-GRh2 might promote ERs-related apoptosis of cervical cancer cells by regulating the DDIT3-based targets’ signal pathway. The role of 20(S)-GRh2 at the transcriptome level provides novel targets and evidence for the treatment of cervical cancer.
... Among its numerous effects [15], it has been shown that resveratrol inhibits the progression of cervical cancer by suppressing the expression of HPV E6 and E7 genes [16], decreases angiogenic activity by inhibiting the expression of HIF-1α and VEGF through blocking ERK1/2 and PI3K/Akt signaling pathways [17] and inhibits the migration of HeLa cells by suppression of NF-kB and AP-1-mediated MM9 expression [18]. The involvement of natural polyphenols, including resveratrol, in the chemoprevention of cervical cancer was recently reviewed [19,20]. ...
... Resveratrol (3.5.40-trihydroxystilbene) is one of the most-studied plant-derived molecules in cancer biology and was recently reviewed [15,21,43]. Although it is proven that RSV possesses many in vitro beneficial effects, in vivo effects must be considered in the perspective of its low bioavailability. ...
Resveratrol is a well-studied plant-derived molecule in cancer biology, with a plethora of documented in vitro effects. However, its low bioavailability and toxicity risk hamper its wider use. In this study, vine shoots after pruning were used as a source of resveratrol (RSV). The activity of subcritical water extract (SWE) and dry extract (DE) is examined on three cell lines: HeLa, MCF-7 and MRC-5. The cytotoxic effect is assessed by the MTT test and EB/AO staining, levels of apoptosis are determined by Annexin V assay, autophagia by ULK-1 expression using Western blot and NF-kB activation by p65 ELISA. Our results show that both resveratrol-rich extracts (DE, SWE) have a preferential cytotoxic effect on malignant cell lines (HeLa, MCF-7), and low cytotoxicity on non-malignant cells in culture (MRC-5). Further experiments indicate that the investigated malignant cells undergo different cell death pathways. MCF-7 cells died preferentially by apoptosis, while the HeLa cells died most likely by necrosis (possibly ferroptosis). Protective autophagia is diminished upon treatment with DE in both HeLa and MCF-7 cells, while SWE does not influence the level of autophagia. The extracts are effective even at low concentrations (below IC50) in the activation of NF-kB (p65 translocation).
... Human astrocytoma U373MG cell culture In vitro [67] Attenuation of mitochondrial membrane potential rupture and release of CYT-C 5 Reducing caspase-9 and caspase-3 activity and increasing the BAX:BCL-2 ratio Rat PC12 cells; HeLa cell line In vitro [68] Epicatechin Protects neurons from programmed cell death induced by oxLDL 6 by inhibiting the activation of JNK, c-JUN and caspase-3 ...
Nutritional interventions may highly contribute to the maintenance or restoration of human health. Grapes (Vitis vinifera) are one of the oldest known beneficial nutritional components of the human diet. Their high polyphenol content has been proven to enhance human health beyond doubt in statistics-based public health studies, especially in the prevention of cardiovascular disease and cancer. The current review concentrates on presenting and classifying polyphenol bioactive molecules (resveratrol, quercetin, catechin/epicatechin, etc.) available in high quantities in Vitis vinifera grapes or their byproducts. The molecular pathways and cellular signaling cascades involved in the effects of these polyphenol molecules are also presented in this review, which summarizes currently available in vitro and in vivo experimental literature data on their biological activities mostly in easily accessible tabular form. New molecules for different therapeutic purposes can also be synthesized based on existing polyphenol compound classes available in high quantities in grape, wine, and grape marc. Therefore an overview of these molecular structures is provided. Novel possibilities as dendrimer nanobioconjugates are reviewed, too. Currently available in vitro and in vivo experimental literature data on polyphenol biological activities are presented in easily accessible tabular form. The scope of the review details the antidiabetic, anticarcinogenic, antiviral, vasoprotective, and neuroprotective roles of grape-origin flavonoids. The novelty of the study lies in the description of the processing of agricultural by-products (grape seeds and skins) of industrial relevance, and the detailed description of the molecular mechanisms of action. In addition, the review of the clinical therapeutic applications of polyphenols is unique as no summary study has yet been done.
... Determined Anthocyanins, Curcumin, Emodin, Epifriedelanol, Mitomycin C, and Piperine, induce apoptosis in cervical cancers [6,43]. Activation of apoptosis is used as an anticancer mechanism in cancer therapy research [6]. ...
Natural products are commonly used for developing anticancer drugs that are beneficial for various cancer types. The aim of this study is to apply Colchicum umbrosum Steven and Colchicum baytopiorum CD Brickell (one of the endemic species in Turkey) extracts on HeLa cell lines and determine changes in cytotoxicity and viability. For this aim, kinetic parameters such as proliferation rate have been determined by MTT assay, and apoptotic index (AI) has been researched by fluorescence micros-copies using DAPI staining. Also, some apoptosis-related genes have been examined by the RT-PCR method. Five different concentrations of both extracts from the two Colchicum species have cytotoxic effects and it has been understood that HeLa cells were more sensitive to the most effective concentration of the C. baytopiorum extract, which is 0.1 mg/ml, and it showed antitumor effects by causing apoptosis for 48 h. The cytotoxic activity and apoptotic effects of Colchicum umbrosum Steven and Colchicum baytopiorum (Colchicaceae/Liliaceae) have been studied for the first time on HeLa cell lines. We suggested that the medicines derived from natural products seem to be a new promising treatment for cancer.
... Excess free radicals were removed in certain doses. Puerarin as reported improved the tissue damage induced via ROS, then increased the ability to fight tumors (He et al., 2021). ...
Inflammation is a protective response of the body to an irritant. When an inflammatory response occurs, immune cells are recruited to the injury, eliminating the irritation. The excessive inflammatory response can cause harm to the organism. Inflammation has been found to contribute to cervical cancer if there is a problem with the regulation of inflammatory response. Cervical cancer is one of the most common malignant tumors globally, and the incidence tends to be younger. The harm of cervical cancer cannot be ignored. The standard treatments for cervical cancer include surgery, radiotherapy and chemotherapy. However, the prognosis for this treatment is poor, so it is urgent to find a safer and more effective treatment. Natural products are considered excellent candidates for the treatment of cervical cancer. In this review, we first describe the mechanisms by which inflammation induces cervical cancer. Subsequently, we highlight natural products that can treat cervical cancer through inflammatory pathways. We also introduce natural products for the treatment of cervical cancer in clinical trials. Finally, methods to improve the anticancer properties of natural products were added, and the development status of natural products was discussed.
... Both the treated and untreated cells supernatant was prepared in compliance with the protocol and was added to each well with reaction mix and substrate and kept at room temperature. Then O.D. value was measured at 405 nm and was followed by calculation of the GSH activity in fold change [19,[27][28][29]. ...
... ab134003). The experiment was done as per the protocol of the kit, which is similar to the protocol mentioned earlier under apoptosis proteome profiler [18,19,[29][30][31][32][33][34]. ...
Kaempferol, a flavonoid, contains a plethora of therapeutic properties and has demonstrated its efficacy against cancer. This study aims to unravel the molecular targets that are being modulated by kaempferol on HeLa cells. Various assays were performed, namely: MTT assay, flow cytometry to analyze DNA content and quantitate apoptosis. Quantitative PCR and protein profiling were performed to evaluate the modulated manifestation of different genes involved in apoptosis, cell growth and inflammation. Kaempferol exhibited reduction in cell viability of HeLa cells (IC50 = 50 µM 48 h), whereas it did not show any significant effect on viability of the AC-16 cell line. Kaempferol-impacted apoptosis was definitive, as it induced DNA fragmentation, caused disruption of membrane potential, accumulation of cells in the G2-M phase and augmented early apoptosis. Consistently, kaempferol induced apoptosis in HeLa cells by modulating the expression of various genes at both transcript and protein levels. It upregulated the expression of pro-apoptotic genes, including APAF1, BAX, BAD, Caspases 3, and 9, etc., at the transcript level and Bad, Bax, p27, p53, p21, Caspases 3 and 8 etc. at the protein level, while it downregulated the expression of pro-survival gene BCL-2, BIRC8, MCL-1, XIAP, and NAIP at the transcript level and Bcl-2, XIAP, Livin, clap-2 at the protein level. Kaempferol attenuated oxidative stress by upregulating GSH activity and anti-inflammatory response by suppressing NF-kB pathways. Moreover, kaempferol averted rampant cell division and induced apoptosis by modulating AKT/MTOR and MAP kinase pathways. Hence, kaempferol can be considered as a natural therapeutic agent with a differential profile.
