Anti-cancer agents in medicinal chemistry最新文献

{"title":"HSP Inhibitor Sensitize Resistant MCF-7 Cells to Doxorubicin through Suppressing HSP90AB4P Pseudogene and HSPB1 Expression.","authors":"Kubra Acikalin Coskun, Lütfi Tutar, Elif Cansu Abay, Levent Gülüm, Ayşe Büşranur Çelik, Mehmet Gumus, İrfan Koca, Yusuf Tutar","doi":"10.2174/0118715206374072250530103333","DOIUrl":"https://doi.org/10.2174/0118715206374072250530103333","url":null,"abstract":"<p><strong>Introduction: </strong>Doxorubicin, a first-line chemotherapeutic agent, often faces resistance in breast cancer subtypes, leading to treatment failure. HSPs (Heat shock proteins), especially HSP90, and their pseudogenes like HSP90AB4P have been implicated in fostering resistance mechanisms by regulating apoptotic and survival pathways in cancer cells. The aim of this study is to investigate how inhibiting HSPs using a novel pyro-salicylic acid derivative (7A) can sensitize doxorubicin-resistant breast cancer cells (MCF-7/ADR) to chemotherapy.</p><p><strong>Methods: </strong>The potential role of HSP inhibitor with doxorubicin at different concentrations was tested to reveal synergetic and additive effects by combination index (CI) analysis. Cell cycle analysis, apoptosis assays, and gene expression profiling via PCR arrays supported the impact of 7A over MCF-7/ADR cells' molecular pathways.</p><p><strong>Results: </strong>HSP inhibitor efficiently suppressed doxorubicin resistance over invasive breast ductal carcinoma and has a synergetic effect. The inhibitor decreases HSP90AB4P and small HSPB1 expression efficiently.</p><p><strong>Conclusion: </strong>Our findings demonstrate that 7A suppresses doxorubicin resistance in MCF-7/ADR cells by reducing the expression of HSP90AB4P and small HSPB1, leading to an increase in apoptosis and cell cycle arrest. The combination of 7A and doxorubicin exhibits a synergistic effect (CI < 1), enhancing cytotoxicity and overcoming resistance mechanisms. The cells are driven to apoptosis and the inhibitor significantly decreases doxorubicin resistance. Targeting HSPB1 and its pseudogene HSP90AB4P with 7A offers a promising therapeutic strategy to overcome doxorubicin resistance in breast cancer.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282035","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":"Exploring the Therapeutic Potential of Ocimum sanctum and Phanera variegata in Breast Cancer Treatment: A Promising Natural Approach.","authors":"Tohfa Siddiqui, Md Nasar Mallick, Vikram Sharma","doi":"10.2174/0118715206375507250603074251","DOIUrl":"https://doi.org/10.2174/0118715206375507250603074251","url":null,"abstract":"<p><p>Breast cancer is one of the most common malignancies affecting women worldwide. It is a complex, heterogeneous disease, classified into several subtypes, including hormone receptor-positive and triple-negative breast cancer (TNBC), each with distinct therapeutic challenges. TNBC, in particular, is characterized by its aggressive nature and lack of targeted therapies due to the absence of estrogen, progesterone, and HER2 receptors. This review explores the potential of natural plant-based compounds, especially focusing on Clove Basil (Ocimum sanctum) and Phanera variegata, in combating breast cancer. These plants have been traditionally used for their medicinal properties and are now being studied for their anticancer effects. Ocimum sanctum has demonstrated significant antiproliferative and pro-apoptotic effects against breast cancer cells, particularly the MCF-7 line, through mitochondrial pathway activation and gene regulation. Similarly, Phanera variegata exhibits potential through its rich content of flavonoids and other bioactive compounds, which have been shown to induce apoptosis, reduce tumor growth, and offer antioxidant benefits. The review highlights how these plant extracts, with their multiple mechanisms, including immune modulation and direct cytotoxic effects, hold promise as adjunctive or alternative therapies in breast cancer treatment, particularly for hard-to-treat subtypes like TNBC. Continued research into their molecular pathways and therapeutic efficacy could lead to new, less toxic treatment options.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282034","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":"Novel Heterocyclic Compounds Exhibit Potent Antileukemic Activity through Selective Induction of Apoptosis and HDAC8 Interaction in AML Cells.","authors":"Túlio R Freitas, Fernanda de F S de Oliveira, Caique Lopes Duarte, Larissa R S P Baliza, Edward K S Gonçalves, Silmara N de Andrade, Diego P Sangi, Fernando de P Varotti, Adriano de P Sabino","doi":"10.2174/0118715206370289250313062830","DOIUrl":"https://doi.org/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":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-05","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":"Innovative Therapies for Oncogenic KRAS Mutations: Precision Strategies with PROTACs in Cancer Treatment.","authors":"Praveen Halagali, Himanshu Sharma, Mahalaxmi Rathnanand, Vamshi Krishna Tippavajhala","doi":"10.2174/0118715206377691250523095407","DOIUrl":"https://doi.org/10.2174/0118715206377691250523095407","url":null,"abstract":"<p><p>The KRAS (Kirsten rat sarcoma viral oncogene homolog) gene mutation is commonly found in colorectal, lung, and pancreatic carcinomas. Unfortunately, blocking KRAS straight away has proven to be challenging. PROTACs (Proteolysis Targeting Chimeras), a class of bifunctional molecules, are designed to break down proteins, offering a unique strategy to target KRAS and overcome the limitations of traditional inhibition. This review discusses PROTACs targeting KRAS mutations in cancer, highlighting major findings, current limitations, and future perspectives. To achieve this, we thoroughly analyzed literature sourced from reputable databases, including PubMed, Google Scholar, and ScienceDirect. Various relevant articles were obtained from the reference section of the selected papers. PROTACs successfully induce the degradation of mutant KRAS in cell lines, leading to a decrease in cell viability compared to control groups. PROTAC treatment results in the suppression of downstream signalling pathways associated with KRAS, such as the MAPK and PI3K/AKT pathways. Animal studies demonstrate the ability of the PROTAC to effectively target KRAS-mutant tumors, inhibiting tumour growth without significant toxicities. New advances in this field can lead to cancer treatments that specifically target KRAS-mutant tumors.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224074","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":"Phytochemical Profiling and Anticancer Potential of Fagonia cretica L. Extract on Liver Cancer (Hepg2) Cells using In vitro and In silico Approaches.","authors":"Fatima Arshad, Awais Altaf, Ali Raza Arshad, Asia Kiran, Muhammad Sarwar, Sumaira Sharif, Tahir Maqbool, Turki S Abujamel, Absarul Haque, Muhammad Imran Naseer","doi":"10.2174/0118715206377419250527105350","DOIUrl":"https://doi.org/10.2174/0118715206377419250527105350","url":null,"abstract":"<p><strong>Background: </strong>Cancer is a complex multifactorialdisease charcterized by the progression of genetic and epigenetic changes in human cells . Plant-based derivatives with antioxidant and anticancer properties have been of great interest in treating several human ailments.</p><p><strong>Objective: </strong>This study investigates the in-vitro antioxidative, cytotoxic, and apoptotic activities of different Fagonia cretica L. (F. cretica) leaf extracts.</p><p><strong>Methods: </strong>In-vitro DPPH, nitric oxide, superoxide anion, and hydrogen peroxide assays were used to evaluate the antioxidative potential of ethanolic extract of F. cretica (EFC) and hexane extract of F. cretica (HFC). The antiproliferative potential was determined using MTT, crystal violet, and annexin V/PI staining protocols on liver cancer (HepG2) and noncancerous (HEK-293) cell lines. Through In silico analysis, bioactive drug-like phytocompounds identified by GC-MS were evaluated.</p><p><strong>Results: </strong>Higher concentrations of total flavonoid contents (TFCs), total phenolic contents (TPCs), and tannins with strong antioxidant potential were observed in EFC extract as compared to HFC extract. Furthermore, the EFC extract proved to be more cytotoxic with a selective index (SI) of 12.92 than HFC (SI; 5.46) towards experimental cell lines. Moreover, EFC extract showed 82.31% apoptotic induction on HepG2 cells compared to hexane extract and cisplatin (standard drug). From the GC-MS analysis of F. cretica, 32 bioactive compounds were identified from the EFC extract and 21 from the HFC extract. In silico study revealed that 5-(4,5-Dihydro-3Hpyrrol- 2-ylmethylene)-4,4-dimethylpyrrolidine-2-thione showed the highest docking score of -8.9 kcal/mol and - 8.6 kcal/mol against TNF-α and TGF-β, respectively.</p><p><strong>Conclusion: </strong>In conclusion, EFC extract and its bioactive compounds have a scientifically proven role in liver cancer management, but further research is required to validate their therapeutics through clinical trials.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214658","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":"Analytical Techniques as Indicators of Biomarkers in Proteomics Cancer Diagnosis.","authors":"Pawan Kumar Goswami, Ranjeet Kumar, Dharmendra Kumar, Shubham Dhiman","doi":"10.2174/0118715206377391250526054417","DOIUrl":"https://doi.org/10.2174/0118715206377391250526054417","url":null,"abstract":"<p><strong>Background: </strong>Cancer is a complex disease marked by changes in the levels and functions of key cellular proteins, including oncogenes and tumor suppressors. Proteomics technology enables the identification of crucial protein targets and signaling pathways involved in cancer cell proliferation and metastasis. Various proteomics techniques have been employed to investigate the molecular mechanisms of cancer, aiding in the confirmation and characterization of heritable disorders.</p><p><strong>Method: </strong>A comprehensive literature search was conducted using PubMed, ScienceDirect, and Google Scholar with search terms like \"Cancer and proteomics\" and \"Mass spectrometry in oncology,\" utilizing Boolean operators for refinement. Selection criteria included peer-reviewed articles in English on MS-based biomarker detection, tumor-specific proteins, and drug resistance markers, excluding non-peer-reviewed works and pre-2000 publications unless foundational. Extracted data focused on MS methodologies, biomarker sensitivity, and clinical applications, particularly advances in detecting low-abundance biomarkers and monitoring treatment response. Methodological quality was assessed using PRISMA, evaluating study design, sample size, reproducibility, and statistical analysis. Ethical approval was not required, but adherence to systematic review guidelines and proper citation were ensured.</p><p><strong>Result: </strong>In this review, we highlighted the advanced analytical technique for cancer diagnosis and management of cancer, and described the objective of novel cancer biomarkers. Mass spectrometry (MS) is transforming cancer diagnostics and personalized medicine by enabling precise biomarker detection and monitoring. Unlike traditional antibody-based methods, MS provides high-throughput, quantitative analysis of tumor-specific proteins in clinical samples like blood and tissue. Advanced MS techniques improve sensitivity, allowing for the identification of low-abundance biomarkers and tumor-associated proteoforms, including post-translational modifications and drug resistance markers. In research, MS-based proteomics supports multi-center biomarker validation studies with standardized protocols, enhancing reproducibility. The integration of proteomic data with genomic and transcriptomic datasets through proteogenomics is refining precision oncology strategies. These advancements are bridging the gap between research and clinical application, making MS a critical tool for early cancer detection, prognosis, and therapy selection.</p><p><strong>Conclusion: </strong>Advancements in technology and analytical techniques have helped to produce more accurate and sensitive cancer-specific biomarkers. These methods are advancing rapidly, and developing high-throughput platforms has yielded great results. However, The substantial variation in protein concentrations makes cancer protein profiling extremely complicated. This shows that more technic","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198134","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":"The Role of Cisplatin Prodrugs Bonded to Polymer Carriers for Nanodrug-targeted Treatment of In situ Hepatocellular Carcinoma.","authors":"Zhijian Li, Lan Luo, Zhan Wang, Jie Hou","doi":"10.2174/0118715206347681250312142125","DOIUrl":"https://doi.org/10.2174/0118715206347681250312142125","url":null,"abstract":"<p><strong>Background: </strong>The toxic effects of cisplatin limit its therapeutic efficacy on hepatocellular carcinoma (HCC). Cisplatin(IV) (Pt(IV)) with better stability needs an effective drug delivery strategy. Here, we explored the toxic and inhibitory effects and cell Pt contents of monomethoxyl poly(ethylene glycol)-block-poly(ecaprolactone)- block-poly(L-lysine) (MPEG-b-PCL-b-PLL)/Pt(IV) micelles (M(P3)) on HCC, and evaluated the therapeutic effect of (M (Pt (IV)) on HCC in vitro and in vivo.</p><p><strong>Methods: </strong>We successfully constructed HCC model in BALB/c mice and prepared M(P3). The H22 and HepG2 cells were incubated with cisplatin, M(P3), and cisPt(IV)-(COOH)2 at 2, 10, 20, 50, 100 and 250 μM equivalent platinum (Pt) concentrations for 48 h and at 5 μM for 2/6 h. The HCC mice received cisplatin, M(P3), and cisPt(IV)-(COOH)2 (5 mg equivalent Pt/kg, once a week) for five weeks. The cell activity was assessed by MTT assay. The Pt contents were assayed by an inductively coupled plasma mass spectrometer (ICP-MS). The liver tumor weight was measured. The levels of liver tumor hepatorenal function indicators and malignant indicators were estimated by biochemical analysis and Western blot.</p><p><strong>Results: </strong>The activity of H22 and HepG2 cells: cisPt(IV)-(COOH)2-treated > M(P3)-treated > cisplatin-treated. The Pt contents of H22 and HepG2 cells: M(P3)-treated > cisplatin-treated > cisPt(IV)-(COOH)2-treated cells. The hepatorenal function of HCC mice: M(P3)-treated > cisPt(IV)-(COOH)2-treated > cisplatin-treated. According to the weight and levels of malignant indicators of liver tumor, the therapeutic effect on HCC mice: cisplatintreated > M(P3)-treated > cisPt(IV)-(COOH)2-treated.</p><p><strong>Conclusions: </strong>Although the inhibitory effect of M(P3) on HCC is not as good as cisplatin, M(P3) has significantly lower hepatorenal toxicity and remarkably higher cell Pt contents.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179576","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":"Maternal Embryonic Leucine Zipper Kinase (MELK) as a Promising Therapeutic Target in Triple Negative Breast Cancer.","authors":"Amiya Das, Ajmer Singh Grewal, Pallavi Agarwal, Deepti Pandita, Viney Lather","doi":"10.2174/0118715206389899250522091159","DOIUrl":"https://doi.org/10.2174/0118715206389899250522091159","url":null,"abstract":"<p><strong>Introduction: </strong>Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine protein kinase involved in regulating key cellular processes, including cell cycle progression, apoptosis, embryonic development, spliceosome assembly, and gene expression. Notably, MELK is overexpressed in Triple-Negative Breast Cancer (TNBC), an aggressive malignancy associated with poor prognosis, high drug resistance, and limited treatment options. Given its critical role in TNBC pathogenesis, MELK has emerged as a potential biomarker and therapeutic target. This review explores the molecular functions of MELK, its involvement in oncogenic signaling pathways, and the development of MELK-targeting small-molecule inhibitors.</p><p><strong>Methods: </strong>A comprehensive literature review was conducted to evaluate current knowledge on MELK, including its molecular functions, interactions within signaling pathways, role in TNBC progression, and potential as a therapeutic target. Relevant databases, including PubMed, Web of Science, Embase, and Scopus, were searched for studies related to MELK expression, signaling mechanisms, and experimental therapeutic approaches.</p><p><strong>Results: </strong>MELK plays a central role in oncogenic signaling pathways that drive TNBC proliferation and survival. Preclinical studies have demonstrated that MELK inhibition can suppress TNBC cell growth and enhance chemotherapy efficacy. Several small-molecule inhibitors targeting MELK have shown promising anti-tumor activity in preclinical models. However, challenges remain in translating these findings into clinical applications due to drug specificity limitations and resistance mechanisms.</p><p><strong>Conclusion: </strong>MELK is a promising biomarker and therapeutic target in TNBC. However, further research is required to refine MELK inhibitors, enhance clinical efficacy, and overcome drug resistance mechanisms. Targeting MELK could offer a novel therapeutic strategy to improve TNBC treatment outcomes.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141169","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":"Combined Effects of Curcumin and Carboplatin on Mitochondrial Depolarization and Caspase Activation in Human Lung Adenocarcinoma Cells.","authors":"Yüksel Öğünç Keçeci, Mine Ezer Oktay, Zerrin Incesu, Filiz Özdemir","doi":"10.2174/0118715206360549241209111501","DOIUrl":"https://doi.org/10.2174/0118715206360549241209111501","url":null,"abstract":"<p><strong>Background: </strong>In various kinds of cancer, including Non-Small Cell Lung Cancer (NSCLC), treatment resistance diminishes the effectiveness of current therapeutic approaches and underscores the need for new treatment strategies.</p><p><strong>Aim: </strong>This study aimed to investigate the combined and individual effects of the anticancer drug carboplatin and the natural antioxidant curcumin, as well as the apoptotic effects of these drugs on the A549 cancer cells.</p><p><strong>Objectives: </strong>The synergistic effect of the combined treatment with curcumin and carboplatin on lung cancer cells was evaluated, focusing on early apoptosis, caspase-3/9 activity, and mitochondrial membrane potential.</p><p><strong>Methods: </strong>The cytotoxic effects were determined using the MTT method. Apoptotic changes were examined using the Annexin V-FITC labeling method. Activation of caspases-9 and -3 and mitochondrial membrane potential were measured using flow cytometry.</p><p><strong>Results: </strong>The IC50 values of curcumin and carboplatin against A549 cells were determined to be 60±8 μM and 100±9 μM, respectively. The combination of curcumin and carboplatin showed a synergistic effect. After treating A549 cells with carboplatin, curcumin, or the combined use of curcumin+carboplatin for 12 hours, the rates of early apoptotic cells were determined to be 9.5±1.3%, 8.1±0.3%, and 22.2±2.9%, respectively. The rate of early apoptosis in combined use was significantly higher compared to individual use. Similarly, when the combined treatment of curcumin and carboplatin was compared to the administration of carboplatin alone, a higher level of mitochondrial membrane depolarization was observed. There was a slight increase in caspase 9 activity in the combined treatment group compared to the individual treatments. Furthermore, after treating A549 cells with the specified doses, the caspase 3 activity was determined for carboplatin (0.5±0.1%), curcumin (1.9±0.0%), and the combination of both (7.3±0.8%).</p><p><strong>Conclusion: </strong>These results indicated that the combined use of curcumin and carboplatin enhanced apoptosis and mitochondrial depolarization, demonstrating that the combined treatment of drugs reduced the toxic dose of carboplatin. However, further research is needed to comprehensively understand the potential of this effect in in vivo studies.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075410","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":"Computational Optimization and In Silico Analysis for the Discovery of New HER2 and CDK4/6 Drug Candidates for Breast Cancer.","authors":"Salma Elmallah","doi":"10.2174/0118715206382065250507114908","DOIUrl":"https://doi.org/10.2174/0118715206382065250507114908","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is an abnormal cell growth that develops in the breast and spreads throughout the body. Despite cancer being the second leading cause of death, survival rates are increasing as a result of progress in cancer screening and therapy. Breast cancer is the most frequently diagnosed cancer type among women, but in most cases, there are no obvious symptoms. Screening mammograms can be used for early detection of cancer. The size of the tumor and the extent of cancer spread determine the type of needed treatment. There are different forms of treatment, where targeted therapy is generally the least harmful. It targets specific characteristics of cancer cells, such as human epidermal growth factor receptor 2 (HER2). Tyrosine kinase inhibitors are effective targeted treatment of HER2 positive breast cancer. A newer class has emerged, cyclin dependent kinase (CDK4/6), which is used to treat metastatic breast cancer.</p><p><strong>Objectives: </strong>Although CDK4/6 inhibitors class of therapy has revolutionized the treatment of metastatic breast cancer, some patients showed resistance and decreased efficacy. This study is the first to propose innovative computational strategies to improve the effectiveness and pharmacokinetic properties of existing HER2/CDK4/6 inhibitors anti-cancer agents. Through computer-aided drug design, the activity of existing breast cancer drug candidates has been tested. Structural modifications have been applied for in-silico optimization of their biological activity.</p><p><strong>Methods: </strong>In this research, twenty-two analogues of the tested compounds have been proposed. Their biological activity and pharmacokinetic properties (ADMET) have been tested using BIOVIA Discovery Studio software.</p><p><strong>Results: </strong>Out of the designed analogous compounds, seven proposed structures demonstrated superior efficacy compared to the original drugs. The research study docking studies revealed that modifications to lapatinib and tucatinib improved binding affinity to HER2 by 15-25%, with docking scores of -18.34 kcal/mol and -1.04 kcal/mol, respectively. Similarly, CDK4/6 inhibitors exhibited enhanced selectivity, with abemaciclib showing the highest binding energy of -13.2 kcal/mol. ADMET predictions suggested improved solubility and reduced toxicity risks compared to the original drugs.</p><p><strong>Conclusion: </strong>The research study results demonstrate that the synthesis of more lipophilic analogues of lapatinib or tucatinib and, likewise designing of fluorinated derivatives of CDK4/6 inhibitors play a crucial role in improving the efficacy of these anti-cancer agents. These findings highlight the potential of the proposed modifications as promising candidates for further pharmacological and in vitro and in vivo clinical validation.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075413","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}