Anti-cancer agents in medicinal chemistry最新文献

{"title":"Novel Heterocyclic Compounds Exhibit Potent Antileukemic Activity through Selective Induction of Apoptosis and HDAC8 Interaction in AML Cells.","authors":"Tulio R Freitas, Fernanda de F S de Oliveira, Caique Lopes Duarte, Larissa R S P Baliza, Edward K S Goncalves, Silmara N de Andrade, Diego P Sangi, Fernando de P Varotti, Adriano de P Sabino","doi":"10.2174/0118715206370289250313062830","DOIUrl":"10.2174/0118715206370289250313062830","url":null,"abstract":"<p><strong>Introduction: </strong>Heterocyclic compounds serve as the structural framework for many commercially available drugs and are well known for their antitumor properties.</p><p><strong>Aim: </strong>This study aimed to evaluate the cytotoxic effects, apoptosis induction, changes in cell cycle progression, and gene expression alterations of new heterocyclic compounds and their precursors against the acute monocytic leukemia cell line THP-1 through in vitro experimentation and computational approaches.</p><p><strong>Methods: </strong>The study employed cytotoxicity assays, flow cytometry analyses, gene expression evaluations, oral bioavailability studies, and molecular modeling. Among the compounds tested, 6, 25, and 26 demonstrated the greatest potency and selectivity, exhibiting substantially increased cytotoxicity (1.18 μM < IC₅₀ < 7.66 μM) against the THP-1 cell line. Investigations into apoptosis induction and cell cycle changes revealed that these compounds primarily caused an increase in the number of THP-1 cells undergoing apoptosis after 48 hours of treatment. Additionally, compounds 6 and 25 induced an accumulation of cells in the G0/G1 phase in the same cell line.</p><p><strong>Results: </strong>Regarding gene expression, a shift in the expression profile of genes associated with apoptotic mechanisms was observed. Furthermore, in silico analysis revealed that these three active compounds potentially interact with histone deacetylase 8 (HDAC8), a protein known to be associated with cancer.</p><p><strong>Conclusion: </strong>These findings underscore the potential of these compounds as candidates for the development of novel therapeutic approaches in oncology.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"289-301"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision-engineered Carrageenan Gels: Boosting the Efficacy, Selectivity, and Release of Celecoxib for Lung Cancer Therapy.","authors":"Akanksha Bhatt, Priyank Purohit, Magda H Abdellattif","doi":"10.2174/0118715206376021250506104129","DOIUrl":"10.2174/0118715206376021250506104129","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer is one of the most widespread malignancies among all types of cancers. There is uncertainty in its treatment because of the selectivity. The investigation is aimed to enhance therapeutic efficacy through targeted improvements in drug selectivity and reduced toxicity by analyzing well-accepted cyclooxygenase (COX)-2, which is an enzyme target and a known therapeutic target for anti-inflammatory and antitumor agents.</p><p><strong>Objective: </strong>The objective of the present research was to identify the most suitable counterpart for celecoxib, which would produce synergistic effects and improve the selectivity index, safety, and efficacy of targeting cancer cells.</p><p><strong>Methods: </strong>The HOPE-62 cancer cell line and noncancerous LLC-MK2 cell line were used to analyze the activity of the prepared formulations. The effectiveness was compared by calculating the half-maximal inhibitory concentration (IC50) values of carrageenan, celecoxib, and celecoxib embedded with carrageenan. The release pattern of celecoxib from the carrageenan matrix was also determined by using a trans-diffusion cell; moreover, the binding sites of carrageenan and celecoxib were also evaluated through <i>in silico</i> molecular docking studies.</p><p><strong>Results: </strong>Carrageenan showed promising anticancer activity, with an IC₅₀ value of 17.3±2 μM against the HOPE- 62 cell line. When blended with celecoxib (15.6±2 μM), the combination achieved enhanced efficacy and improved selectivity over celecoxib alone (IC₅₀ of 10.3±1.5 μM). In noncancerous LLC-MK2 cells, the IC₅₀ values were observed to be significantly higher: 1484 ±6 μM in the combined formulation and with IC₅₀ values of 559±3 μM and 878±4 μM, respectively, in celecoxib and carrageenan alone.</p><p><strong>Conclusion: </strong>The carrageenan-embedded celecoxib exhibited a significant increase in the selectivity index from 32 to 144, which suggests enhanced anticancer activity with a favorable safety profile. Initially, sustained release of celecoxib from the blend was at a higher rate, but steadily maintained rates were. The <i>In-silico</i> docking studies also supported the synergistic activity of the combined form through separate interaction patterns without interfering with others. These findings underscore the therapeutic potential of excipient-drug blending strategies to achieve synergistic effects, excellent selectivity, and reduced toxicity in cancer treatments.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"302-312"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the Vital Role of ACTA2-AS1 in Human Cancers: Molecular Mechanisms and Clinical Applications.","authors":"Haodong He, Lumei Xiang, Baoqin Pi, Jingjie Yang, Wenjin Peng, Moyu Li, Haoran Liu, Xinyan Zheng, Haoyi Liu, Yuxiang Peng, Pengbo Zhang, Jiahe Zhang, Xin Chen, Yanlin Zhang, Meiyan Shuai, Feng Xu, Yan Cai, Chengfu Yuan","doi":"10.2174/0118715206381499250607114710","DOIUrl":"10.2174/0118715206381499250607114710","url":null,"abstract":"<p><strong>Background: </strong>The smooth muscle α‑actin 2‑antisense 1 (ACTA2-AS1), also known as ZXF1, is an emerging cancer-associated long non-coding RNA (lncRNA) that has garnered significant attention in recent years. ACTA2-AS1 is situated on human chromosome 10 at location 10q23.31, comprising five exons and a single transcript. The aberrant expression of ACTA2-AS1 has been noted in 10 malignant tumors, correlating significantly with unfavorable clinicopathological characteristics and poor patient prognosis.</p><p><strong>Objective: </strong>This review encapsulates recent progress in ACTA2-AS1 research, examining its expression profile, biological functions, molecular mechanisms, and anticipated influence on cancer diagnosis, treatment, and prognosis, emphasizing its potential as a novel therapeutic target based on lncRNA and its prognostic utility as a biomarker.</p><p><strong>Methods: </strong>Based on a comprehensive search of the PubMed database for the biological function of lncRNA ACTA2-AS1 in malignant tumors, the current research is systematically summarized and critically analyzed.</p><p><strong>Results: </strong>ACTA2-AS1 plays a complex role in various biological processes in tumor cells, encompassing proliferation, apoptosis, and cell cycle arrest. It also contributes to migration, invasion, epithelial-mesenchymal transition (EMT), and drug resistance. Mechanistically, ACTA2-AS1 influences oncogenic or tumor-suppressive effects via a complex regulatory network. It can adsorb specific 5 miRNAs as competitive endogenous RNAs (ceRNAs), thereby mitigating the suppression of downstream mRNA targets implicated in tumorigenesis (e.g., SOX7, KLF9, CXCL2, BCL2L11, etc.) and modulating their downstream signaling pathways (e.g., Wnt5a/PKC, SMAD3, mTOR, etc.), demonstrating a broad spectrum of dual roles in carcinogenesis and tumor suppression.</p><p><strong>Conclusion: </strong>ACTA2-AS1 is a promising biomarker and molecular target for the treatment of cancer.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"254-267"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial-Derived Anti-Cancer Compounds: Advances in Drug Discovery, Bioengineering, and Therapeutic Applications.","authors":"Ekta Tyagi, Divya Jain, Rajabrata Bhuyan, Anand Prakash","doi":"10.2174/0118715206399680250814104403","DOIUrl":"10.2174/0118715206399680250814104403","url":null,"abstract":"<p><strong>Introduction: </strong>Microbial metabolites represent a valuable source of bioactive compounds with promising anticancer properties. However, conventional drug discovery approaches are time-intensive and resource-demanding.</p><p><strong>Methods: </strong>Recent developments in artificial intelligence (AI), machine learning (ML), molecular docking, and quantitative structure-activity relationship (QSAR) modeling have been examined for their role in the identification and optimization of microbial metabolites.</p><p><strong>Results: </strong>AI-driven approaches have significantly enhanced compound screening and prediction of therapeutic efficacy. Nanocarrier-based drug delivery systems have improved the bioavailability, specificity, and stability of microbial metabolites while minimizing systemic toxicity. Despite these advancements, challenges remain in clinical translation due to the lack of <i>in vivo</i> validation and comprehensive pharmacokinetic data.</p><p><strong>Discussion: </strong>This review highlights the integration of advanced computational tools and nanotechnology in accelerating the discovery and delivery of microbial-derived anticancer agents.</p><p><strong>Conclusion: </strong>Future directions should focus on integrating AI with synthetic biology to engineer microbial strains capable of producing enhanced bioactive compounds. Additionally, leveraging nanotechnology could refine targeted delivery mechanisms. A deeper understanding of molecular pathways and drug resistance mechanisms is essential to support the development of combination therapies. Overall, microbialderived compounds hold substantial potential in advancing precision oncology.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"371-383"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting SHP2 Reverses BRAF Inhibitor Tolerance in Anaplastic Thyroid Carcinoma.","authors":"Tao Tang, Jie Zhou, Li-Xin Zhang, Gang Yang, Wei-Nan Li, Jian-Jiao Zhu, Yong-Fu Xiong, Jing-Dong Li","doi":"10.2174/1871520623666230214093122","DOIUrl":"10.2174/1871520623666230214093122","url":null,"abstract":"<p><strong>Background: </strong>To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatment of anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer.</p><p><strong>Methods: </strong>Firstly, a drug resistance model was established, and the expression levels of related RTK were detected by qPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferation activity. <i>In vivo</i> model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate the expression of p-ERK, p-AKT and Ki67 in mouse tumors.</p><p><strong>Results: </strong>In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drugresistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantly reduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect <i>in vivo</i>.</p><p><strong>Conclusion: </strong>The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibiting the reactivated RAS signaling pathway in anaplastic thyroid cancer.The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"70-76"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10767562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Lead Compounds Targeting Transcriptional Regulation.","authors":"Yihua Chen","doi":"10.2174/0118715206452637251023043925","DOIUrl":"10.2174/0118715206452637251023043925","url":null,"abstract":"","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"119-120"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145480645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timosaponin A-III Induces ROS-mediated Apoptosis and Triggers Protective Autophagy <i>via</i> the AMPK/mTOR Pathway in Prostate Cancer.","authors":"Jianjian Wu, Juntao Li, Qiang Guo, Chutian Xiao, Yifei Zhang, Dejuan Wang, Qiong Wu, Jianguang Qiu","doi":"10.2174/0118715206389520250805135535","DOIUrl":"10.2174/0118715206389520250805135535","url":null,"abstract":"<p><strong>Introduction: </strong>Timosaponin A-III (TAIII) is an effective anti-tumor ingredient extracted from the rhizomes of <i>Anemarrhena asphodeloides</i>. However, the effect of TAIII on prostate cancer cells (PCa) and its underlying mechanisms is rarely investigated. The current study aimed to investigate the anti-tumor effect and potential mechanisms of TAIII in PCa cells.</p><p><strong>Methods: </strong>The effect of TAIII on the cell proliferation of PCa was evaluated by CCK-8 assay, colony formation assay, and EDU assay. Cell apoptosis and reactive oxygen species (ROS) production were evaluated by flow cytometry. The puncta of LC3 were detected by immunofluorescence analysis. The protein levels of apoptosis, autophagy, and AMPK/mTOR pathway were assessed by western blot. Finally, a PC3 xenograft nude mouse model was constructed to determine the effect of TAIII combined with chloroquine (CQ) in vivo.</p><p><strong>Results: </strong>Our data showed that TAIII inhibited the proliferation of PCa cells and induced ROS-dependent apoptosis. TAIII treatment dramatically promoted the formation of LC3-positive puncta, and increased the expression of LC3B-II and P62 protein. Moreover, the combination of TAIII with CQ significantly enhanced the pro-apoptosis effect of TAIII in PCa cells and the PC3 xenograft model. In addition, the activation of the AMPK/mTOR pathway and the induction of autophagy induced by TAIII were reversed by Compound C. Suppressing AMPK with Compound C enhanced the apoptosis induced by TAIII in PCa cells.</p><p><strong>Discussion: </strong>This study establishes TAIII as a potent anti-prostate-cancer agent that kills tumor cells via ROSdriven apoptosis while simultaneously triggering cytoprotective autophagy through the AMPK-mTOR axis. However, TAIII's clinical potential awaits pharmacokinetic, bioavailability, and toxicity evaluation.</p><p><strong>Conclusion: </strong>TAIII induced ROS-mediated cell apoptosis and promoted cytoprotective autophagy via the AMPK/mTOR pathway in PCa. These findings may provide a new strategy for combining TAIII with CQ together for PCa treatment.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"413-424"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Evaluation of Optical Properties, SHP2 Inhibitory Activity, and Cellular Imaging for Novel 2-Quinolone Derivatives.","authors":"Chun Zhang, Yuting Yang, Li-Xin Gao, Suya Gan, Jia Li, Xin Wang, Yu-Bo Zhou, Wen-Long Wang","doi":"10.2174/0118715206337347250219112715","DOIUrl":"10.2174/0118715206337347250219112715","url":null,"abstract":"<p><strong>Introduction: </strong>Although the development of SHP2 inhibitors has made striking progress, there is no inhibitor in clinical evaluation because of the potential side effects induced by poor drug distribution. Fluorescence imaging technology is widely used in the process of diagnosis and treatment of diseases because of the advantages of rapid imaging and non-destructive detection and might provide a new way to explore the mechanism of drug-target interactions in intact tissue.</p><p><strong>Methods: </strong>A series of 2-quinolone derivatives as fluorescent inhibitors against SHP2 were designed and synthesized, and their spectral properties and biological activities were evaluated in this report. The representative compound 8A had excellent fluorescence properties (λ^emi_max : 562 nm, Stokes shift: 170 nm, fluorescence quantum yield: 0.072) and optical stability.</p><p><strong>Results: </strong>Moreover, compound 8A emitted a blue signal in SHP2WT U2OS cells and inhibited the SHP2 enzyme abilities (IC₅₀: 20.16 ± 0.95 μM) without the extra combination of suitable fluorophores, linker, or selectiveactivated molecules.</p><p><strong>Conclusion: </strong>Therefore, we hope that compound 8A could act as a lead to develop novel, convenient, and bifunctional chemical tools to explore the mechanism of drug-target interactions in intact tissue and promote the integrated research progress of diagnosis and treatment of SHP2 related diseases.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"165-174"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Talimogene Laherparepvec (T-VEC): Expanding Horizons in Oncolytic Viral Therapy Across Multiple Cancer Types.","authors":"Run-Bin Tan, Yeannie Hui-Yeng Yap","doi":"10.2174/0118715206379105250429115604","DOIUrl":"10.2174/0118715206379105250429115604","url":null,"abstract":"<p><p>Talimogene laherparepvec (T-VEC), the first FDA-approved oncolytic viral therapy, has transformed cancer immunotherapy since its 2015 approval for unresectable melanoma. Engineered from Herpes Simplex Virus type 1 (HSV-1) with deletions in ICP34.5 and ICP47 genes and GM-CSF insertion, T-VEC selectively replicates within the tumor cells, inducing lysis and releasing tumor-derived antigens while stimulating systemic antitumor immunity through dendritic cell activation. Although extensively studied for melanoma, its potential extends beyond this malignancy, with emerging applications in breast cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), and other solid tumors. This review synthesizes T-VEC's mechanism of action, leveraging dysregulated Ras signalling, impaired interferon pathways in cancer cells, its clinical outcomes, and safety profile across these indications. While prior literature emphasizes melanoma monotherapy and combinations with immune checkpoint inhibitors, less attention has been given to its efficacy in non-melanoma cancers and synergistic potential with chemotherapy or radiation therapy. By exploring recent trials, such as T-VEC with neoadjuvant chemotherapy in triple-negative breast cancer and pembrolizumab in HNSCC, highlighting its versatility. Comparative analysis with other oncolytic viruses like HF-10, oncorine (H101), and measles virus variants positions T-VEC within the virotherapy landscape. Key challenges-systemic delivery, immune clearance, and biomarker development for patient selection-are addressed alongside strategies to enhance immune modulation through novel combinations. This review underscores T-VEC's expanding role in cancer treatment, offering clinicians' and researchers' insights to optimize its therapeutic horizons across diverse malignancies.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"175-185"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luteolin Enhances Anticancer Effects of PX-478 during Hypoxic Response in Metastatic Breast Cancer Cells.","authors":"Muzaffer Dukel, Fatema Zarzour","doi":"10.2174/0118715206384227250901064037","DOIUrl":"10.2174/0118715206384227250901064037","url":null,"abstract":"<p><strong>Introduction: </strong>The presence of severe hypoxic stress can drive tumor growth, angiogenesis, and metastatic characteristics via up-regulated hypoxia-inducible factor 1-alpha (HIF-1α). Hence, targeting HIF-1α is considered a promising strategy, as increased HIF-1α activity is a key factor in the aggressive phenotype of malignancies. In this study, we aimed to investigate the anti-cancer effects of several flavonoids, both single and in combination with PX-478, in breast cancer cell lines.</p><p><strong>Methods: </strong>We tested the effects of luteolin and PX-478, both alone and in combination, on HIF-1α level in breast cancer cells under hypoxia using the cell viability assay. To determine the rationale for the cell growth inhibition induced by the luteolin+PX-478 combination, we conducted experiments to assess cell survival, apoptosis, cell cycle, invasion, and migration under both normoxic and hypoxic conditions. Furthermore, we evaluated the effect of this combination on DNA damage response under hypoxic stress via Comet assay and immunofluorescence staining.</p><p><strong>Results: </strong>Our findings revealed that the luteolin+PX-478 combination significantly suppressed the growth of MDA-MB-231 cells. In addition, we assessed time-dependent expression of HIF1α in MDA-MB-231 cells and observed that the combination of luteolin and PX-478 down-regulated the HIF-1α level. Finally, we found that the luteolin+PX-478 combination induced apoptosis and G2 cell cycle arrest and enhanced DNA damage response. This combination also sensitized breast cancer cells to ionizing radiation in hypoxic stress.</p><p><strong>Discussion: </strong>The findings suggested that targeting HIF-1α with a combination of luteolin and PX-478 may provide a synergistic approach to suppressing tumor growth and enhancing therapeutic response under hypoxic conditions. The observed effects on apoptosis, cell cycle arrest, and DNA damage response indicated that this combination could be a promising strategy for overcoming hypoxia-induced resistance in breast cancer therapy.</p><p><strong>Conclusion: </strong>Collectively, our results suggested the combination of luteolin and PX-478 to enhance the anticancer effects of PX-478 in breast carcinoma cells by impeding the cell growth and inducing DNA damage response under hypoxia.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"105-117"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}