Chemical Biology & Drug Design

Synthesis and Activity Study of Gefitinib Derivatives Inducing Mitochondrial Apoptosis in Hela Cells

ABSTRACT Cervical cancer is the fourth most common cancer among women globally. Its development is closely linked to accelerated cell cycle progression and the inhibition of apoptosis in cervical cancer tissues. Gefitinib has demonstrated efficacy in inhibiting cervical cancer cells, and the 1,2,3‐triazole structure is widely recognized for its role in inducing mitochondrial apoptosis in tumor cells. In this study, we employed click chemistry to modify the structure of gefitinib, leading to the synthesis of 16 derivatives containing the 1,2,3‐triazole moiety. These compounds were evaluated for their in vitro activity against Hela cells. Among them, compound 3p exhibited the most promising anticancer activity, with an IC 50 value of 4.09 ± 0.54 μM. Compound 3p significantly inhibited Hela cell colony formation in a dose‐dependent manner, accompanied by noticeable morphological changes. Further investigations revealed that 3p induced apoptosis and caused G2/M phase cell cycle arrest in Hela cells. Western blot analysis showed that 3p increased the Bax/Bcl‐2 ratio and elevated the levels of cleaved caspase‐3 and PARP1, indicating that apoptosis was mediated through the mitochondrial pathway. Additionally, 3p inhibited indoleamine 2,3‐dioxygenase 1 (IDO1) enzymatic activity, and molecular docking studies revealed a strong interaction between 3p and the IDO1 active site, suggesting that IDO1 may be a potential target. In conclusion, compound 3p shows promise as a potential therapeutic agent for cervical cancer.

Molecular targets of metformin against ovarian cancer based on network pharmacology

AbstractThe objective of this study was to analyze potential targets of metformin against ovarian cancer (OC) through network pharmacology. Pharmacodynamic targets of metformin were predicted using the Bioinformatics Analysis Tool for the molecular mechanism of traditional Chinese medicine (BATMAN), Drugbank, PharmMapper, SwissTargetPrediction, and TargetNet databases. R was utilized to analyze the gene expression of OC tissues, normal/adjacent noncancerous tissues, and screen differentially expressed genes (DEGs) in the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) + Genotype‐Tissue Expression (GTEx) datasets. STRING 11.0 was utilized to explore the protein–protein interaction (PPI) of metformin target genes differentially expressed in OC. Cytoscape 3.8.0 was used to construct the network and screen the core targets. Additionally, gene ontology (GO) annotation and enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the common targets of metformin and OC through the DAVID 6.8 database. A total of 95 potential common targets of metformin and OC were identified from the intersection of 255 potential pharmacodynamic targets of metformin and 10,463 genes associated with OC. Furthermore, 10 core targets were screened from the PPI network [e.g., interleukin (IL) 1B, KCNC1, ESR1, HTR2C, MAOB, GRIN2A, F2, GRIA2, APOE, PTPRC]. In addition, it was shown in GO enrichment analysis that the common targets were mainly associated with biological processes (i.e., response to stimuli or chemical, cellular processes, and transmembrane transport), cellular components (i.e., plasma membrane, cell junction, and cell projection), and molecular functions (i.e., binding, channel activities, transmembrane transporter activity, and signaling receptor activities). Furthermore, it was indicated by KEGG pathway analysis that the common targets were enriched in metabolic pathways. The critical molecular targets and molecular pathways of metformin against OC were preliminarily determined by bioinformatics‐based network pharmacology analysis, providing a basis, and reference for further experimental studies.

Evodiamine inhibits malignant progression of ovarian cancer cells by regulating lncRNA‐NEAT1/miR‐152‐3p/CDK19 axis

AbstractEvodiamine (EVO) has been demonstrated to promote apoptosis of ovarian cancer cells, and upregulate miR‐152‐3p level in colorectal cancer. Here, we explore part of the network mechanism of EVO and miR‐152‐3p in ovarian cancer. The bioinformatics website, dual luciferase reporter assay, and quantitative real‐time polymerase chain reaction were applied to analyze the network among EVO, lncRNA, miR‐152‐3p, and mRNA. The effect and mechanism of EVO on ovarian cancer cells were determined using cell counting kit‐8, flow cytometry, TUNEL, Western blot, and rescue experiments. As a result, EVO dose‐dependently attenuated cell viability, induced G2/M phase arrest and apoptosis, promoted miR‐152‐3p level (4.5‐ or 2‐fold changes), and inhibited expressions of NEAT1 (0.225‐ or 0.367‐fold changes), CDK8 (0.625‐ or 0.571‐fold changes), and CDK19 (0.25‐ or 0.147‐fold changes) in OVCAR‐3 and SKOV‐3 cells. In addition, EVO decreased Bcl‐2 expression, but increased the expressions of Bax and c‐caspase‐3. NEAT1 targeted miR‐152‐3p which bound to CDK19. The impacts of EVO on cell viability, cycle, apoptosis, and apoptosis‐related proteins were partially reversed by miR‐152‐3p inhibitor, NEAT1 overexpression, or CDK19 overexpression. Furthermore, miR‐152‐3p mimic offset the effects of NEAT1 or CDK19 overexpression. The role of NEAT1 overexpression in the biological phenotype of ovarian cancer cells was counteracted by shCDK19. In conclusion, EVO attenuates ovarian cancer cell progression via the NEAT1‐miR‐152‐3p‐CDK19 axis.

MicroRNA‐33b replacement effect on growth and migration inhibition in ovarian cancer cells

AbstractPurposeOvarian cancer is a devastating gynecological disease which is considered the major cause of cancer fatality around the world. The down‐regulation of microRNA‐33b (miR‐33b) was reported in some malignancies. Hence, we transfected the miR‐33b mimic into SKOV3 cells and evaluated the impacts of this interference on the growth and migration repression of these tumor cells as well as on targeted genes expression.MethodsIn our study, transfecting the miR‐33b mimic and inhibitor, negative control (NC), and NC inhibitor were established using Lipofectamine 2000. The cytotoxic effects of miR‐33b were evaluated by MTT. To assess the miR‐33b effects on cell migration, a scratching test was applied. The expression levels of miR‐33b, ADAMTS, C‐Myc, MMP9, K‐Ras, and CXCR4 were evaluated using qRT‐PCR.ResultsThese findings indicate that transfection of miR‐143 mimic had no marked effects on the SKOV3 cell line. As expected, miR‐33b relative expression levels were as follows: miR‐33b mimic >NC and NC inhibitor >miR‐33b inhibitor (p < 0.01). Moreover, transfected miR‐33b mimic could suppress SKOV3 cells’ proliferation, whereas transfected miR‐33b inhibitor could promote cell proliferation (p < 0.01). MiR‐33b overexpression significantly down‐regulated the MMP9, CXCR‐4, c‐Myc, ADAMTS, and K‐Ras mRNA levels (p < 0.05).ConclusionAs expected, these results confirm the tumor‐suppressive effect of miR‐33b in the SKOV3 ovarian cancer cell line by reducing cell survival, proliferation, and migration.

LINC00460 knockdown sensitizes cervical cancer to cisplatin by downregulating TGFBI

AbstractThe acquired resistance of cancer to cisplatin (DDP) limits the efficacy of chemotherapy. The prognostic value of long noncoding RNA (lncRNA) LINC00460 has been reported in cervical cancer. However, its effect on DDP sensitivity in cervical cancer remains poorly understood. In present study, LINC00460 was screened out through bioinformatics analysis. The expression levels of mRNAs and proteins were measured by reverse transcription‐quantitative PCR (RT‐qPCR) or western blot analysis. The sensitivity to DDP was investigated using an CCK8 assay. Cell apoptosis was determined by flow cytometry. The differentially expressed genes that were associated with the poor prognosis of cervical cancer were screened, and their correlations with LINC00460 expression were explored using Pearson's correlation analysis. Tumor xenograft model was used to assess the effect of LINC00460 knockdown on DDP sensitivity in vivo. The interaction between miR‐338‐3p and LINC00460 or transforming growth factor β‐induced protein (TGFBI) was confirmed by RNA immunoprecipitation (RIP) and luciferase reporter assays. LINC00460 expression was increased in cervical cancer tissues and cells. High expression of LINC00460 was associated with dismal prognosis in cervical cancer patients. Silencing of LINC00460 increased drug sensitivity and induced apoptosis in DDP‐resistant‐cervical cancer cells. LINC00460 knockdown enhanced DDP sensitivity in cervical cancer cells largely by downregulating TGFBI expression. LINC00460 knockdown enhanced the sensitivity of cervical cancer to DDP in vivo, and this effect was partly mediated by the downregulation of TGFBI. LINC00460 positively regulated TGFBI expression, possibly by acting as a sponge of miR‐338‐3p. LINC00460 knockdown contributed to DDP sensitivity of cervical cancer by downregulating TGFBI, providing a novel mechanism underlying the acquisition of DDP sensitivity.

Platinum‐Based Chemotherapeutics in the Modern Era: From Classical DNA ‐Targeting Mechanisms to Next‐Generation Innovations in Cancer Therapy

ABSTRACT Thanks to their DNA‐crosslinking methods, platinum‐based chemotherapeutics—which were first introduced by the coincidental discovery of cisplatin in 1965—have long been a mainstay of cancer treatment, with notable effectiveness in treating colorectal, ovarian, and testicular cancers. In order to address the enduring problems of toxicity, resistance, and restricted selectivity, this study charts their development from the traditional agents cisplatin, carboplatin, and oxaliplatin to next‐generation developments. Classical mechanisms, rooted in aquation and apoptotic induction, are now complemented by emerging targets, including RNA, mitochondria, and protein–protein interactions, alongside novel cell death pathways like ferroptosis. Nonclassical complexes, such as Pt(IV) prodrugs and multinuclear agents, enhance delivery and overcome resistance, while synergistic strategies with immunotherapy (e.g., PD‐1 inhibitors), nanoparticle delivery, and radiotherapy amplify efficacy. Precision medicine advances patient stratification via genomic (e.g., TP53 and BRCA) and proteomic biomarkers, liquid biopsies for real‐time monitoring, and pharmacogenomics to adapt dosing. Sustainability initiatives, stable formulations, affordable generics, and green synthesis guarantee worldwide access, especially in low‐resource environments. Recent trials have validated the use of hypoxia‐activated prodrugs, AI‐driven predictive models, and DNA repair inhibitors (e.g., NER and PARP) in the fight against resistance. Looking forward, integration with CRISPR, 3D tumor modeling, and epigenetic targeting heralds a new frontier, supported by interdisciplinary collaboration bridging chemistry, biology, and technology. This convergence of foundational principles and cutting‐edge innovations positions platinum therapy for a transformative era, promising enhanced precision, efficacy, and equity in cancer care worldwide.

Comprehensive Analysis of NADH:Ubiquinone Oxidoreductase Subunit B3 in Gynecological Tumors and Identification of Its Natural Inhibitor Wedelolactone

ABSTRACTThe aim of this study was to explore the role of NADH:ubiquinone oxidoreductase subunit B3 (NDUFB3) in human gynecological malignancies and to screen potential natural compounds targeting it. GEPIA and HPA databases were used to study the expression characteristics of NDUFB3. GO and KEGG enrichment analyses were performed using the R software clusterProfiler package. GSEA for NDUFB3 was performed using the LinkedOmics database. Natural compounds targeting NDUFB3 were screened by virtual screening and molecular docking. After NDUFB3 was depleted or wedelolactone treatment, cell proliferation was detected by CCK‐8 assay. The production of reactive oxide species (ROS) in tumor cells was detected by dihydroethidium fluorescent probe. The cell cycle and apoptosis were evaluated by flow cytometry. It was revealed that NDUFB3 was highly expressed in ovarian cancer (OV), uterine corpus endometrial carcinoma (UCEC), and cervical squamous cell carcinoma (CESC). NDUFB3 expression was associated with multiple immunomodulators in CESC, OV, and UCEC. NDUFB3 was predicted to modulate MAPK signaling pathways in CESC, OV, and UCEC. Knocking down NDUFB3 inhibited the proliferation of CESC, OV, and UCEC cells, increased intracellular ROS production, and induced cell cycle arrest and apoptosis. Wedelolactone was a potential small molecule with a strong ability to bind with the active pocket of NDUFB3, and wedelolactone could kill CESC, OV, and UCEC cells partly via NDUFB3. In conclusion, NDUFB3 may be a potential biomarker and a new target for gynecological tumors, and wedelolactone may exert antitumor activity via targeting NDUFB3.

Pachymic Acid Suppresses Endometrial Cancer Cell Migration by Inhibiting the NR3C1 / TGF ‐β/Smad Signaling Pathway

ABSTRACT Pachymic acid exerts antitumor effects against renal cell carcinoma and breast, lung, and pancreatic cancers; however, its specific inhibitory effect on endometrial cancer progression remains unclear. Therefore, in this study, we investigated the antitumor effects of pachymic acid against endometrial cancer using cell counting kit 8, flow cytometry, wound healing, transwell, cycloheximide chase, and western blot assays. Notably, pachymic acid significantly suppressed the viability, proliferation, and migration of endometrial cancer cells. Nuclear receptor subfamily 3 group C member 1 (NR3C1) was identified as its potential target against endometrial cancer. Pachymic acid promoted NR3C1 degradation. However, NR3C1 overexpression reversed the inhibitory effects of pachymic acid on the proliferation and migration of endometrial cancer cells. Furthermore, an association was observed between NR3C1 expression and the transforming growth factor beta (TGF‐β) pathway. NR3C1 knockdown and pachymic acid treatment reduced protein levels of TGF‐β1 and p‐Smad2/3. TGF‐β pathway inhibitor galunisertib reversed the NR3C1 overexpression‐induced increase in endometrial cancer cell migration. Collectively, our findings suggest that pachymic acid suppresses endometrial cancer cell migration by inhibiting the NR3C1/TGF‐β/Smad signaling pathway, highlighting its potential as a therapeutic agent for endometrial cancer.

Cytotoxic activity and cell specificity of a novel LHRH peptide drug conjugate, D‐Cys6‐LHRH vedotin, against ovarian cancer cell lines

AbstractOvarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor‐positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker‐toxin with vedotin (MC‐VC‐PABC‐MMAE), yielding the novel peptide drug conjugate D‐Cys6‐LHRH vedotin. A GI50 and cell specificity comparison against cancerous and non‐cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI50 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D‐Cys6‐LHRH vedotin can potentially be used as a treatment for ovarian cancer.

Discovery of Novel Oxadiazole‐Triazole Hybrids as Lung and Cervical Cancer Agents: Synthesis, Docking, Biological Evaluation, and SAR Studies

ABSTRACT The number of new cancer cases and cancer‐related fatalities continues to rise nowadays as a result of better lives and higher survival rates. Recent research has primarily focused on developing multi‐target drug designs. A new series of fluorinated 1,3,4‐oxadiazole‐1,2,3‐triazole hybrids was designed and synthesized with high yield utilizing the substructure approach. The newly synthesized compounds were characterized using spectral analyses, including NMR ( 1 H, 13 C, and 19 F), mass spectrometry (MS), and high‐performance liquid chromatography (HPLC). Additionally, their in vitro anti‐cancer activity was evaluated against lung cancer A549 and cervical cancer HeLa cell lines. The results indicated that a number of the synthesized hybrids showed encouraging cytotoxic effects, significantly reducing cell proliferation in comparison to the control groups. Compounds ( 7c ), ( 9a ), and ( 9b ) exhibited high cytotoxicity against lung cancer cell lines, with IC 50 values of 19.47 to 21.65 μg/mL. Compound ( 7c ) exhibited significant activity against lung cancer, with an IC 50 value of 19.47 μg/mL. Compounds ( 7c ), ( 9a ), and ( 9b ) exhibited broad cytotoxic effects against the HeLa cell line, with IC 50 values of 17.07 μg/mL for ( 7c ), 19.21 μg/mL for ( 9a ), and 20.85 μg/mL for ( 9b ). Compound ( 7b ) outperformed the other compounds in anticancer activity against the cervical carcinoma HeLa cell line. In silico drug‐like properties indicated that they could be promising molecular frameworks for further studies. The binding modes of compounds ( 9a ) and ( 9b ) were analyzed, revealing the most favorable poses of these compounds within the active site of the tested EGFR (PDB ID: 8SC7) through a molecular docking study. Molecular dynamics simulations of compounds ( 9a ) and ( 9b ) highlighted the key amino acids in the enzyme's active region and provided insight into the mechanism of enzyme interactions.

Combination of Metabolomics and Bioinformatics to Reveal the Mechanism of Luteolin in the Treatment of Cervical Cancer

ABSTRACTThe incidence of cervical cancer is high among women globally. The potential therapeutic efficacy of luteolin in the treatment of cervical cancer has been identified. Therefore, we aim to elucidate the mechanism of action of luteolin in the treatment of cervical cancer through a comprehensive approach that integrates metabolomics with bioinformatics. The first step involved the identification of differential metabolites through UHPLC‐Q‐Orbitrap‐MS, which were then utilized for enrichment analysis of metabolic pathways and to determine the targets associated with these differential metabolites. Subsequently, the differential analysis and WGCNA were employed to identify DEGs and functional module genes respectively. The common targets were obtained by intersecting the results from the aforementioned three analyses, followed by conducting GO and KEGG pathway enrichment analysis on these targets. Subsequently, PPI networks were constructed using these common targets, and key targets were identified utilizing the MCC, EPC, Degree, Closeness Centrality, Betweenness Centrality, and Bottleneck algorithms in the CytoHubba plug‐in. The subsequent steps involved the analysis of key genes for constructing a nomogram, conducting a ROC curve, examining content expression and survival analysis, and ultimately employing molecular docking to investigate the interaction between luteolin and crucial targets. The metabolomics analysis revealed the identification of a total of 45 distinct metabolites in this study, primarily associated with amino acid and nucleotide metabolism. The intersection of 773 differential metabolite targets, 3493 cervical cancer differential genes, and 3245 WGCNA‐associated module genes yielded a set of 32 target genes associated with luteolin therapy for cervical cancer. The GO and KEGG pathway enrichment analysis also revealed that these targets were primarily associated with amino acid metabolism and nucleotide metabolism. The CytoHubba plug‐in was utilized to identify three key genes (DMNT1, EZH2, and GMPS) through the application of multiple algorithms. Additionally, the datasets GSE63514, GSE67522, and GEPIA2 revealed a significant upregulation of all three genes in tumor tissue. ROC analysis demonstrated the good predictive ability of these three hub genes. Finally, the molecular docking results demonstrated the high binding affinity of luteolin towards DMNT1, EZH2, and GMPS. In conclusion, this study has unveiled the potential of luteolin in modulating amino acid and nucleotide metabolism for the treatment of cervical cancer, thereby providing a theoretical foundation for further investigation into the intricate association between luteolin and cervical cancer.

BSV163/DOPE‐mediated TRAIL gene transfection acts synergistically with chemotherapy against cisplatin‐resistant ovarian cancer

AbstractOvarian cancer is the seventh most frequently diagnosed cancer among women worldwide. Most patients experience recurrence and succumb eventually to resistant disease, underscoring the need for an alternative treatment option. In the presented manuscript, we investigated the effect of the TRAIL‐gene, transfected by an innovative bioinspired lipid vector BSV163/DOPE in the presence or absence of cisplatin, to fight against sensitive and resistant ovarian cancer. We showed that BSV163/DOPE can transfect ovarian cancer cell lines (Caov3, OVCAR3, and our new cisplatin‐resistant, CR‐Caov3) safely and efficiently. In addition, TRAIL‐gene transfection in association with cisplatin inhibited cellular growth more efficiently (nearly 50% in Caov3 cells after the combined treatment, and 15% or 25% by each treatment alone, respectively) owing to an increase in apoptosis rate, caspases activity and TRAIL's death receptors expression. Most importantly, such synergistic effect was also observed in CR‐Caov3 cells demonstrated by an apoptosis rate of 35% following the combined treatment in comparison with 17% after TRAIL‐gene transfection or 6% after cisplatin exposition. These results suggest this combination may have potential application for sensitive as well as refractory ovarian cancer patients.

Common cancer biomarkers of breast and ovarian types identified through artificial intelligence

AbstractBiomarkers can offer great promise for improving prevention and treatment of complex diseases such as cancer, cardiovascular diseases, and diabetes. These can be used as either diagnostic or predictive or as prognostic biomarkers. The revolution brought about in biological big data analytics by artificial intelligence (AI) has the potential to identify a broader range of genetic differences and support the generation of more robust biomarkers in medicine. AI is invigorating biomarker research on various fronts, right from the cataloguing of key mutations driving the complex diseases like cancer to the elucidation of molecular networks underlying diseases. In this study, we have explored the potential of AI through machine learning approaches to propose that these methods can act as recommendation systems to sort and prioritize important genes and finally predict the presence of specific biomarkers. Essentially, we have utilized microarray datasets from open‐source databases, like GEO, for breast, lung, colon, and ovarian cancer. In this context, different clustering analyses like hierarchical and k‐means along with random forest algorithm have been utilized to classify important genes from a pool of several thousand genes. To this end, network centrality and pathway analysis have been implemented to identify the most potential target as CREB1.

Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK

AbstractThe release of an active drug from the prodrug generates a pro‐fragment that typically has no biological activity and could result in adverse effects. By combining two drugs, wherein each drug acts as a pro‐fragment of the other drug will eliminate the pro‐fragment in the prodrug. As they are prodrugs of each other and are symbiotic, we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NFκB inhibitors that contain the reactive α‐methylene‐γ‐butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of α‐methylene‐γ‐butyrolactone containing NFκB inhibitors undergo slow release over a 72 hr period. Using an alkyne‐tagged secondary amine prodrug of α‐methylene‐γ‐butyrolactone containing NFκB inhibitor, we demonstrate target engagement. The NFκB‐CDK SymProDs were ~20‐ to 200‐fold less active against the corresponding CDK inhibitors in in vitro CDK kinase assays. Growth inhibition studies in a panel of ovarian cancer cell lines revealed potency trends of the SymProDs mirrored those of the single treatments suggesting their dissociation in cells. In conclusion, our results suggest that SymProDs offer a productive path forward for advancing compounds with reactive functionality and can be used as dual targeting agents.

Sanguinarine enhances cisplatin sensitivity via glutathione depletion in cisplatin‐resistant ovarian cancer (A2780) cells

AbstractOvarian cancer is considered as one of the most lethal gynecological cancers, and cisplatin‐based therapy has an important role as the first‐line option for chemotherapy. Resistance to chemotherapy is the main obstacle against successful cancer chemotherapy with cisplatin. Therefore, identifying potent compositions and molecules with fewer side‐effects is a big challenge to overcome cisplatin resistance. In this study, we investigated the possible mechanism and potency of sanguinarine, a plant‐derived alkaloid, in human cisplatin‐resistant ovarian cancer (A2780/R) cells. The effect of sanguinarine on cytotoxicity of cisplatin was determined by MTT assay. Apoptosis‐inducing effect of sanguinarine alone and in combination with cisplatin was evaluated by annexin V/PI assay and DAPI staining. Intracellular glutathione (GSH) content was quantitated using GSH assay kit after treatment with sanguinarine. Results indicated that sanguinarine enhances the sensitivity of A2780/R cells to cisplatin. Apoptosis‐inducing effect of cisplatin was also enhanced when combined with sanguinarine. Furthermore, sanguinarine reduced intracellular GSH content in a dose‐dependent but not time‐dependent manner. These findings suggest that sanguinarine could reverse cisplatin resistance in A2780/R cells through GSH reduction. Therefore, sanguinarine can be used as one of the potent adjuvants for ovarian cancer chemotherapy.

Diosgenin inhibits proliferation and migration of ovarian cancer cells and induce apoptosis via upregulation of PTEN

AbstractDiosgenin, a natural steroidal sapogenin, has recently attracted a high amount of attention, as an effective anticancer agent in ovarian cancer. However, diosgenin mediated anticancer impacts are still not completely understood. Thus, the present study evaluated the effect of diosgenin on the proliferation, apoptosis, and metastasis of ovarian cancer cells. OVCAR‐3 and SKOV‐3 cells were treated with diosgenin, cellular viability was assessed by MTT assay and apoptosis was measured by ELISA and evaluated the protein expression levels of apoptotic markers through western blotting. Cell migration was examined by measuring the mRNA levels of genes involved in the cell invasion. The protein expression levels of main components of PI3K signaling were evaluated via western blotting. Diosgenin led to significant inhibition of cellular proliferation in a dose‐dependent manner. It also induced apoptosis through upregulating pro‐apoptotic markers and downregulating antiapoptotic mediators. In addition, OVCAR‐3 cells exposure to diosgenin decreased cell migration and invasion. More importantly, diosgenin downregulated the expression levels of main proteins in PI3K signaling including PI3K, Akt, mTOR, and GSK3. Diosgenin inhibited the proliferation and migration of OVCAR‐3 ovarian cancer cells and induced apoptosis, which may be mediated by targeting PI3K signaling.