Phytotherapy Research

Curcumin suppressed the proliferation and apoptosis of HPV‐positive cervical cancer cells by directly targeting the E6 protein

AbstractMost human papillomavirus (HPV) types, including HPV16 and HPV18, are closely related to the occurrence of cervical cancer, predominantly through the action of viral oncoproteins E6 and E7. Curcumin, the active ingredient of the turmeric plant, has been gaining attention over the past two decades as an antioxidant, anti‐inflammatory, and anticancer agent. In the present study, the HPV‐positive cervical cancer cells HeLa and CaSki were treated with curcumin, and the results showed that curcumin has a dose‐dependent and time‐dependent inhibitory effect on cell viability. In addition, apoptosis induction was further quantitatively confirmed through flow cytometric analysis. Furthermore, the influence of different concentrations of curcumin on the mitochondrial membrane potential was evaluated through JC‐1 staining and found to dramatically decrease the membrane potential in treated HeLa and CaSki cells, suggesting the critical role of the mitochondrial pathway in their apoptosis‐inducing effect. This study also demonstrated the wound‐healing potential of curcumin, and the results of transwell assays showed that curcumin treatment inhibited HeLa and CaSki cell invasion and migration in a dose‐dependent manner compared with the control treatment. Curcumin also downregulated the expression of Bcl‐2, N‐cadherin, and Vimentin and upregulated the expression of Bax, C‐caspase‐3, and E‐cadherin in both cell lines. Further research showed that curcumin also selectively inhibited the expression of the viral oncoproteins E6 and E7, as demonstrated by western blot analysis; moreover, the downregulation of E6 was more significant than that of E7. Our research also showed that coculture with cells infected with siE6 lentivirus (siE6 cells) can inhibit the proliferation, invasion, and metastasis of HPV‐positive cells. While the siE6 cells were also treated with curcumin, the effect of curcumin monotherapy was offset. In summary, our research shows that curcumin regulates the apoptosis, migration, and invasion of cervical cancer cells, and the mechanism may be related to its ability to downregulate E6. This study provides a foundation for future research on the prevention and treatment of cervical cancer.

Molecular mechanisms of action and chemosensitization of tumor cells in ovarian cancer by phytochemicals: A narrative review on pre‐clinical and clinical studies

AbstractOvarian cancer is the second‐leading cause of death among women with cancer of the genital tract. Currently, drugs derived from platinum and taxanes constitute the majority of ovarian cancer treatments. Patients undergoing this chemotherapy are susceptible to cumulative toxic effects and resistance to chemotherapy. Therefore, it is crucial to identify treatment options that are both more effective and better tolerated by patients. Phytochemicals in this context are plant‐derived chemicals with antitumor activity that can be used as therapeutic or adjuvant agents in the treatment of ovarian cancer. Consequently, the purpose of this literature review is to demonstrate through existing pre‐clinical and clinical trials the potential of phytochemicals in the treatment of ovarian cancer, the mechanisms of action involved, and to contribute to the development of new therapeutic options for ovarian cancer. For this review, the databases PubMed, Scopus, Science Direct, and ClinicalTrials.gov were queried between 2010 and 2022 using terms such as “ovarian cancer,” “phytochemicals,” “phenolic compounds,” “terpenes,” and “alkaloids.” The present review summarized the possible molecular mechanisms of action by which phytochemicals, such as phenolic acids, flavonoids, diterpenes, triterpenes, saponins, and alkaloids, inhibit this type of cancer, specifically the ability of phytochemicals to induce cell growth regulation, apoptosis, oxidative stress reduction, anti‐angiogenesis, and chemosensitization of tumors in ovarian cancer. As their action and cellular mechanism have already been demonstrated in several pre‐clinical trials, the phytochemicals identified in our study have the potential to be investigated for the treatment of ovarian cancer. Through pre‐clinical and clinical trials, our study demonstrates the potential of phytochemicals in the treatment of ovarian cancer, contributing to the development of novel therapeutic options for ovarian cancer.

Catalpol: An Iridoid Glycoside With Potential in Combating Cancer Development and Progression—A Comprehensive Review

ABSTRACTCatalpol, a natural iridoid glycoside known for its anti‐proliferative effects, has been proposed as an anticancer compound. Catalpol targets critical processes involved in cancer cell progression, like malignant proliferation, apoptosis, and metastasis. Additionally, catalpol presents potent anti‐inflammatory and antioxidant properties crucial for cancer prevention and intervention. Due to the absence of clinical trials, this review investigates twelve studies, encompassing in vitro and animal trials from reputable databases, such as PubMed, with no time restrictions. Therefore, we covered evidence from catalpol's effects against several types of cancer, including breast, liver, colorectal, lung, gastric, bladder, and ovarian cancer, as well as osteosarcoma, and assessed various outcomes related to cell viability, apoptosis, migration, and modulation of molecular mechanisms by catalpol. Notably, catalpol induced cancer cell death via induction of mitochondrial apoptosis pathways, regulation of the expression of specific microRNAs, modulation of Sirt1, Kras, RACK1, PARP, PI3K/Akt, Bcl‐2, and STAT3/JAK2/Src signaling pathways, and inactivation of NF‐kB and Smad 2/3 signaling pathways. Furthermore, catalpol limits cancer metastasis due to modulation of critical metalloproteinases associated with cancer migration. Catalpol also synergizes with chemotherapeutic and adjuvant agents to induce cancer control, including regorafenib in liver cancer and chloroquine in gastric cancer, promoting increased anticancer action via upregulated cancer cell apoptosis, decreased proliferation, and inhibited angiogenesis via PI3K/p‐Akt/mTOR/NF‐κB, VEGF/VEGFR2, and Bax signaling pathways modulation. Catalpol derivatives also gained attention. Pyrazole‐, imidazole‐, and hydrolyzed‐based catalpol derivatives increase cancer cell apoptosis and death and decrease tumor angiogenesis through similar pathways. This review seeks to provide understanding of catalpol's anticancer effects, its mechanisms of action, and its potential as a therapeutic anticancer agent while advocating for future research conductance.

Triptolide Promotes Ferroptosis in Cervical Cancer Cell via NRF2 / xCT / GPX4

ABSTRACT Cervical cancer (CC) is a serious risk to women's health; it is necessary to explore less toxic and more effective therapies to cure CC. Triptolide (Tri) is the principal active constituent found in “Tripterygium Wilford,” has been shown to have antitumor effects. This study set up to demonstrate whether Tri is capable of inducing ferroptosis in CC cells and its potential mechanism. In vitro, Tri was used to treat CC cells, and lipid peroxidation levels in CC cells were detected by flow cytometry, immunofluorescence, and other experiments; the molecular mechanism of Tri treatment of CC was explored by western blot; moreover, the regulatory effects of Tri on the NRF2/GPX4/xCT axis were verified by overexpressing NRF2 in reverse. In vivo, CC cells tumor‐bearing mice were constructed to observe the effect of Tri treatment on tumor growth. In vitro, we have demonstrated that Tri prevents the growth and migration of CC cells. Further investigation revealed that Tri substantially enhances ferroptosis in CC cells by increasing lipid peroxidation accumulation. Mechanically, Tri significantly reduced the expression of NRF2, leading to a corresponding repression of the NRF2 downstream targets GPX4 and xCT. Moreover, overexpressing of NRF2 effectively reversed the impact of Tri on ferroptosis in CC cells. Additionally, animal experiments indicted that Tri markedly inhibited tumor size in nude mice by inhibiting the NRF2/GPX4/xCT axis. Tri exerts antitumor effects by triggering ferroptosis in CC cells through the NRF2/GPX4/xCT axis.

MicroRNA216b mediated downregulation of HSP27/STAT3/AKT signaling is critically involved in lambertianic acid induced apoptosis in human cervical cancers

Since heat shock protein (HSP27) is a prognostic marker in cervical cancer, in the present study, the apoptotic mechanism of lambertianic acid (LA) was investigated in human cervical cancers in association with HSP27/STAT3/AKT signaling axis. LA exerted significant cytotoxicity, induced sub‐G1 population, and increased the cleavage of Poly (ADP‐ribose) polymerase (PARP) and cysteine aspartyl‐specific protease 3 (caspase3) in HeLa and Caski cancer cells. Consistently, LA downregulated anti‐apopotic genes such as B‐cell lymphoma 2 (Bcl‐2) and inhibitors of apoptosis proteins (c‐IAP) in HeLa and Caski cells. Furthermore, LA‐inhibited phosphorylation of HSP27, signal transducer, and activator of transcription 3 (STAT3) and Protein kinase B (AKT) through disturbing the binding of HSP27 with STAT3 or AKT in HeLa cells. Notably, LA upregulated the level of miR216b in HeLa and Caski cells. Consistently, miR216b mimic suppressed phosphorylation of HSP27 and reduced the expression of pro‐PARP, while miR216b inhibitor reversed the ability of LA to attenuate phosphorylation of AKT, HSP27, and STAT3 and to reduce the expression of pro‐PARP in HeLa cells. Overall, our findings suggest that miRNA216b mediated inhibition of HSP27/STAT3/ AKT signaling axis is critically involved in LA‐induced apoptosis in cervical cancers.

Anticancer effects of root and beet leaf extracts (Beta vulgaris L.) in cervical cancer cells (HeLa)

Cervical cancer is the fourth leading cause of cancer mortality in women worldwide. Beetroot (Beta vulgaris L.) has bioactive compounds that can inhibit the progression of different types of cancer. To analyze the antiproliferative effects of beet leaf and root extracts, we performed MTT, clonogenic survival, cell cycle analysis, Annexin/PI labeling, and western blotting. Here, we report that 10 and 100 μg/ml of root and leaf extracts decreased cell viability and potentiated rapamycin and cisplatin effects while decreased the number of large colonies, especially at 10 μg/ml (293.6 of control vs. 200.0 of leaf extract, p = .0059; 138.6 of root extract, p = .0002). After 48 hr, 100 μg/ml of both extracts led to increased sub‐G1 and G0/G1 populations. In accordance, 100 μg/ml of root extract induced early apoptosis (mean = 0.64 control vs. 1.56 root; p = .048) and decreased cell size (p < .0001). Both extracts decreased phosphorylation and expression of mechanistic Target of Rapamycin (mTOR) signaling, especially by inhibiting ribosomal protein S6 (S6) phosphorylation, increasing cleaved poly(ADP‐ribose) polysomerase 1 (PARP1) and Bcl‐2‐like protein 11 (BIM), and decreasing cyclin D1 expression, which regulates cell cycle progression. Here, we demonstrate that beetroot and leaf extracts could be an efficient strategy against cervical cancer.

Comprehensive exploration of Biochanin A as an oncotherapeutics potential in the treatment of multivarious cancers with molecular insights

AbstractCancer is considered a leading cause of mortality. This rising cancer death rate and several existing limitations like side effects, poor efficacies, and high cost of the present chemotherapeutic agents have increased the demand for more potent and alternative cancer treatments. This review elucidated a brief overview of Biochanin A (BCA) and its potentiality on various cancers with details of anticancer mechanism. According to our review, a number of studies including in silico, in vitro, pre‐clinical, and clinical trials have tested to evaluate the efficacy of BCA. This compound is effective against 15 types of cancer, including breast, cervical, colorectal, gastric, glioblastoma, liver, lung, melanoma, oral, osteosarcoma, ovarian, pancreatic, pharynx, prostate, and umbilical vein cancer. The general anticancer activities of this compound are mediated via several molecular processes, including regulation of apoptosis, cell proliferation, metastasis and angiogenesis, signaling, enzymatic pathways, and other mechanisms. Targeting both therapeutic and oncogenic proteins, as well as different pathways, makes up the molecular mechanism underlying the anticancer action. Many signaling networks and their components, such as EFGR, PI3K/Akt/mTOR, MAPK, MMP‐2, MMP‐9, PARP, Caspase‐3/8/9, Bax, Bcl2, PDL‐1, NF‐κB, TNF‐α, IL‐6, JAK, STAT3, VEGFR, VEGF, c‐MY, Cyclin B1, D1, E1 and CDKs, Snail, and E‐cadherin proteins, can be regulated in cancer cells by BCA. Such kind of anticancer properties of BCA could be a result of its correct structural chemistry. The use of BCA‐based therapies as nano‐carriers for the delivery of chemotherapeutic medicines has the potential to be very effective. This natural compound synergises with other natural compounds and standard drugs, including sorafenib, 5‐fluorouracil, temozolomide, doxorubicin, apigenin, and genistein. Moreover, proper use of this compound can reverse multidrug resistance through numerous mechanisms. BCA has better drug‐likeness and pharmacokinetic properties and is nontoxic (eye, liver, kidney, skin, cardio) in human bodies. As having a wide range of cancer‐fighting mechanisms, synergistic effects, and good pharmacokinetic properties, BCA can be used as a supplementary food until standard drugs are available at pharma markets.

A Systematic Review and Meta‐Analysis of the Effects of Dietary Isoflavones on Female Hormone‐Dependent Cancers for Benefit–Risk Evaluation

ABSTRACTFemale hormone‐dependent cancers depend on estrogen for their growth. Numerous studies have explored the antitumor effect of dietary isoflavones on female hormone‐dependent cancers. Still, few clinical evidence supports the use of isoflavones in female hormone‐dependent cancer patients. This study was performed to examine the impact of dietary isoflavones on tumor growth of female hormone‐dependent cancers and accelerate the transformation of research from bench to bedside. We searched PubMed Medline, Web of Science, and Google Scholar for relevant articles related to the effect of dietary isoflavone on tumor growth of experimental animal models of female hormone‐dependent cancers from 1998 to 2024. The effects of dietary isoflavones on tumor growth were analyzed between the control and treatment groups using comprehensive meta‐analysis software (CMA). We included 30 studies describing tumor growth focused on female hormone‐dependent cancer types, including breast, ovarian, and uterine cancers. Overall, a pooled analysis revealed that dietary isoflavones reduced tumor volume (Hedge's g = −1.151, 95% CI = −1.717 to −0.585, p = 0.000) and tumor weight (Hedge's g = −2.584, 95% CI = −3.618 to −1.549, p = 0.000). On the other hand, dietary isoflavones increased tumor area (Hedge's g = 1.136, 95% CI = 0.752 to 1.520, p = 0.000). Dietary isoflavones have potential benefits and risks in female hormone‐dependent cancers. Therefore, caution should be exercised when considering the intake of dietary isoflavones in female hormone‐dependent cancer patients, particularly in the form of supplements.

Anticancer activity and other biomedical properties of β‐sitosterol: Bridging phytochemistry and current pharmacological evidence for future translational approaches

AbstractSterols, including β‐sitosterol, are essential components of cellular membranes in both plant and animal cells. Despite being a major phytosterol in various plant materials, comprehensive scientific knowledge regarding the properties of β‐sitosterol and its potential applications is essential for scholarly pursuits and utilization purposes. β‐sitosterol shares similar chemical characteristics with cholesterol and exhibits several pharmacological activities without major toxicity. This study aims to bridge the gap between phytochemistry and current pharmacological evidence of β‐sitosterol, focusing on its anticancer activity and other biomedical properties. The goal is to provide a comprehensive understanding of β‐sitosterol's potential for future translational approaches. A thorough examination of the literature was conducted to gather relevant information on the biological properties of β‐sitosterol, particularly its anticancer therapeutic potential. Various databases were searched, including PubMed/MedLine, Scopus, Google Scholar, and Web of Science using appropriate keywords. Studies investigating the effects of β‐sitosterol on different types of cancer were analyzed, focusing on mechanisms of action, pharmacological screening, and chemosensitizing properties. Modern pharmacological screening studies have revealed the potential anticancer therapeutic properties of β‐sitosterol against various types of cancer, including leukemia, lung, stomach, breast, colon, ovarian, and prostate cancer. β‐sitosterol has demonstrated chemosensitizing effects on cancer cells, interfering with multiple cell signaling pathways involved in proliferation, cell cycle arrest, apoptosis, survival, metastasis invasion, angiogenesis, and inflammation. Structural derivatives of β‐sitosterol have also shown anti‐cancer effects. However, research in the field of drug delivery and the detailed mode of action of β‐sitosterol‐mediated anticancer activities remains limited. β‐sitosterol, as a non‐toxic compound with significant pharmacological potential, exhibits promising anticancer effects against various cancer types. Despite being relatively less potent than conventional cancer chemotherapeutics, β‐sitosterol holds potential as a safe and effective nutraceutical against cancer. Further comprehensive studies are recommended to explore the biological properties of β‐sitosterol, including its mode of action, and develop novel formulations for its potential use in cancer treatment. This review provides a foundation for future investigations and highlights the need for further research on β‐sitosterol as a potent superfood in combating cancer.

Dioscin Suppresses Ovarian and Gastric Tumor Progression by Inhibiting ALDH1A3 ‐Mediated Retinoic Acid Metabolism and Cancer Stemness

ABSTRACT Background ALDH1A3 is a key factor associated with tumor stemness and chemotherapy resistance, making it a promising therapeutic target. Screening various compounds with potential inhibition of cancer stem cells led to the discovery of a naturally occurring Dioscin as a novel ALDH1A3 inhibitor. However, the precise mechanism underlying its action remains unexplored. Experimental Procedure Immunohistochemical analysis of 90 ovarian serous tumor samples revealed the clinical significance of ALDH1A3 in tumor progression. TCGA data was used to identify genes highly correlated with ALDH1A3 in ovarian cancer. Using CRISPR/Cas9‐generated ALDH1A3 knockout (KO) cell lines, we investigated its oncogenic influence in ovarian and gastric cancers. The anti‐tumor effects of Dioscin were assessed through MTT, scratch, and 3D spheroid formation assays. In vivo efficacy of Dioscin was assessed using a xenograft mouse model. Mechanistic investigations of Dioscin with ALDH1A3 were predicted by molecular docking and assessed through ALDH1A3 enzymatic activity and retinoic acid (RA) metabolism analyses. Results ALDH1A3 expression correlates with early‐stage ovarian cancer progression. Genetic ablation of ALDH1A3 significantly suppressed cell proliferation, migration, and stemness properties. ALDH1A3 is significantly associated with ECM‐related genes in ovarian cancer. Dioscin exhibited an ALDH1A3‐dependent anti‐tumor effect by inhibiting ALDH1A3 enzymatic activity, disrupting RA metabolism, and downregulating the expression of stemness‐ and migration‐associated proteins (CD44 and MMP2). Furthermore, Dioscin effectively delays tumor growth without obvious signs of toxicity. Conclusion Our study provides the first evidence that Dioscin inhibits ALDH1A3‐mediated RA metabolism and cancer stemness. Our data will further support its potential as a therapeutic agent for cancer treatment.

Targeting CDK 9 With Harmine Induces Homologous Recombination Deficiency and Synergizes With PARP Inhibitors in Ovarian Cancer

ABSTRACT Ovarian cancer patients with homologous recombination (HR) proficiency are more likely to develop resistance to poly (ADP‐ribose) polymerase (PARP) inhibitors, resulting in poor prognosis. Harmine, a natural compound with verified clinical safety, is a potential inhibitor of HR activity. However, its effect on HR has not been tested in ovarian cancer. More importantly, its specific target involving the HR pathway is still unknown. A fluorescent reporter cell system was employed to assess the HR efficiency of cells treated by harmine. The target of harmine in the HR pathway was identified via a molecular docking screening in silico and confirmed using a cellular thermal shift assay. Evaluation of harmine treatment combined with the PARP inhibitor olaparib in BRCA1/2 wild‐type ovarian cancer was performed. Treatment with harmine inhibited HR activity in a dose‐dependent manner in ovarian cancer cells and selectively suppressed HR‐proficient cells with high replication stress, marked with CCNE1 amplification. HR‐related protein cyclin‐dependent kinase 9 (CDK9) was identified as the target of harmine. Specifically, harmine diminished the interaction of CDK9 with cyclin T, resulting in impaired formation of the p‐TEFb complex and subsequent transcription elongation. Hence, harmine downregulated the transcription of key HR‐related genes. Moreover, harmine synergized with PARP inhibitor olaparib in BRCA1/2 wild‐type ovarian cancer. Harmine inhibits HR repair by interfering with CDK9‐mediated transcription elongation for HR‐related genes, thus enhancing the potency of olaparib, providing a promising therapeutic strategy to improve the prognosis of HR‐proficient ovarian cancer patients.

A Comprehensive Review of Biologically Active Natural Products on Human Papillomavirus (HPV) at a Glance

ABSTRACTHuman papillomavirus (HPV) is widespread known as the sexually transmitted infection, which is responsible, for genital warts and certain types of cancer. Low‐risks HPV types are responsible for genital warts. Genital warts can be treated through various medical and surgical methods. High‐risks HPV types may cause dangerous cancers such as cervical cancer. The clinical approach in treatment of HPV‐related cancers were different depending on the diseases stage ranging from surveillance and minor procedures for dysplasia to chemotherapy for more advanced cases. It is crucial to vaccinate adolescents against HPV to prevent infections from high risk strains. Researchers have explored natural products as potential solutions against viral infections with eight biologically active compounds. Including EGCG, curcumin, podophyllotoxin, resveratrol, pterostilbene, tanshinone IIA, indole‐3‐carbinol, and carrageenan. They are showing promising therapeutic effects in treating different stages of HPV‐related diseases. Clinical trials have demonstrated the effectiveness of EGCG and podophyllotoxin in treating warts while other compounds, like curcumin, resveratrol, pterostilbene, indole‐3‐carbinol, and tanshinone IIA offer benefits in combating cervical cancer. In addition, carrageenan shows promising effects in HPV transmission prevention. It appears that compounds from nature may have an impact, on different phases of the HPV infection like genital warts treatment, disease transmission prevention, and healing‐related cancers. These findings highlight the potential of natural products as valuable sources to combat HPV infection and related cancers. Further more extensive studies are necessary to discover the effective mechanism of these natural compounds as anti‐HPV agents.

Enterolactone and trabectedin suppress epithelial ovarian cancer synergistically via upregulating THBS1

AbstractEpithelial ovarian cancer (EOC) is the most common and fatal subtype of ovarian malignancies, with no effective therapeutics available. Our previous studies have demonstrated extraordinary suppressive efficacy of enterolactone (ENL) on EOC. A chemotherapeutic agent, trabectedin (Trabe), is shown to be effective on ovarian cancer, especially when combined with other therapeutics, such as pegylated liposomal doxorubicin or oxaliplatin. Thrombospondin 1 (THBS1), a kind of matrix glycoprotein, plays important roles against cancer development through inhibiting angiogenesis but whether it is involved in the suppression of EOC by ENL or Trabe remains unknown. To test combined suppressive effects of ENL and Trabe on EOC and possible involvement of THBS1 in the anticancer activities of ENL and Trabe. The EOC cell line ES‐2 was transfected with overexpressed THBS1 by lentivirus vector. We employed tube formation assay to evaluate the anti‐angiogenesis activity of ENL and of its combined use with Trabe after THBS1 overexpression and established drug intervention and xenograft nude mouse cancer models to assess the in vivo effects of the hypothesized synergistic suppression between the agents and the involvement of THBS1. Mouse fecal samples were collected for 16S rDNA sequencing and microbiota analysis. We detected strong inhibitory activities of ENL and Trabe against the proliferation and migration of cancer cells and observed synergistic effects between ENL and Trabe in suppressing EOC. ENL and Trabe, given either separately or in combination, could suppress the tube formation capability of human microvascular endothelial cells, and this inhibitory effect became even stronger with THBS1 overexpression. In the ENL plus Trabe combination group, the expression of tissue inhibitor of metalloproteinases 3 and cluster of differentiation 36 was both upregulated, whereas matrix metalloproteinase 9, vascular endothelial growth factor, and cluster of differentiation 47 were all decreased. With the overexpression of THBS1, the results became even more pronounced. In animal experiments, combined use of ENL and Trabe showed superior inhibitory effects to either single agent and significantly suppressed tumor growth, and the overexpression of THBS1 further enhanced the anti‐cancer activities of the drug combination group. ENL and Trabe synergistically suppress EOC and THBS1 could remarkably facilitate the synergistic anticancer effects of ENL and Trabe.

Phytoestrogen Signal Pathways and Estrogen Signaling in Ovarian Cancer: A Narrative Review

ABSTRACT Ovarian cancer (OC) is the second most common gynecological cancer and the leading cause of death from gynecological malignancies. Ovarian cancer mortality rate ranks fifth among cancer‐related deaths in Western societies. Hence, novel preventive and therapeutic ways are still in great demand to reduce the incidence and mortality rate of ovarian cancer. Phytoestrogens, referred to as dietary estrogens, provide benefits to all mammals, including humans. Research indicates that phytoestrogens may be possible hormonal treatment options for ovarian cancer patients. They are non‐steroidal plant compounds that undergo metabolism to produce compounds structurally and functionally related to ovarian and placental estrogens. Some studies suggest that estrogen receptors (ER‐α and ER‐β) and G protein‐coupled estrogen receptor (GPER) are potential targets for ovarian cancer prevention and treatment. Current studies indicate multiple signal pathways of phytoestrogens in the management of ovarian cancer. Even so, literature suggests that the signaling mechanisms in ovarian cancer and the signaling mechanisms of phytoestrogens are still not exactly understood. With this, phytoestrogens may act on multiple signaling pathways such as ER (endoplasmic reticulum)‐dependent signaling, GnRH receptor, FSH or LH receptors and hormones, and GFR, which help to regulate the expression of AKT, RAS, RAF, Caspase‐3, NF‐kB, and Bcl‐2. In summary, this narrative review discusses the possible targets of phytoestrogens in ovarian cancer and sheds a light on improving novel phytoestrogens‐based dietary supplements against ovarian cancers.

Neferine, an alkaloid from lotus seed embryo targets HeLa and SiHa cervical cancer cells via pro‐oxidant anticancer mechanism

Apoptosis and autophagy are important processes that control cellular homeostasis and have been highlighted as promising targets for novel anticancer drugs. This study aims to investigate the inhibitory effects and mechanisms of Neferine (Nef), an alkaloid from the lotus seed embryos of Nelumbo nucifera (N. nucifera), as a dual inducer of apoptosis and autophagy through the reactive oxygen species (ROS) activation in cervical cancer cells. Nef and N. nucifera extract suppressed the cell viability of HeLa and SiHa cells in a dose‐dependent manner. Importantly, Nef showed minimal toxicity to normal cells. Furthermore, Nef inhibited anchorage‐independent growth, colony formation and migration ability of cervical cancer cells. Nef induces mitochondrial apoptosis by increasing pro‐apoptotic protein bax, cytochrome‐c, cleaved caspase‐3 and caspase‐9, poly‐ADP ribose polymerase (PARP) cleavage, DNA damage (pH2AX) while downregulating Bcl‐2, procaspase‐3 and procaspase‐9, and TCTP. Of note, apoptotic effect by Nef was significantly attenuated in the presence of N‐acetylcysteine (NAC), suggesting pro‐oxidant activity of this compound. Nef also promoted autophagy induction through increasing beclin‐1, atg‐4, atg‐5 and atg‐12, LC‐3 activation, and P62/SQSTM1 as determined by western blot analysis. Collectively, these results demonstrate that Nef is a potent anticancer compound against cervical cancer cells through inducing apoptosis and autophagic pathway involving ROS.