Drug Development Research最新文献_第8页

Santamarine Synergizes With Cisplatin via ROS/JNK Axis to Selectively Induce Apoptosis and DNA Damage in Oral Cancer Cells In Vitro. 通过ROS/JNK轴与顺铂协同作用选择性诱导口腔癌细胞凋亡和DNA损伤

IF 4.2 4区医学

Drug Development Research Pub Date : 2026-06-01 DOI: 10.1002/ddr.70327

Hsin-I Lu, Kuan-Liang Chen, Chung-Yi Chen, Ching-Yu Yen, Ammad Ahmad Farooqi, Tsu-Ming Chien, Jiiang-Huei Jeng, Bing-Hung Chen, Hsueh-Wei Chang

{"title":"Santamarine Synergizes With Cisplatin via ROS/JNK Axis to Selectively Induce Apoptosis and DNA Damage in Oral Cancer Cells In Vitro.","authors":"Hsin-I Lu, Kuan-Liang Chen, Chung-Yi Chen, Ching-Yu Yen, Ammad Ahmad Farooqi, Tsu-Ming Chien, Jiiang-Huei Jeng, Bing-Hung Chen, Hsueh-Wei Chang","doi":"10.1002/ddr.70327","DOIUrl":"10.1002/ddr.70327","url":null,"abstract":"Santamarine (SAMA), a Michelia compressa-derived sesquiterpene lactone, exhibits ROS‑mediated anticancer activity; however, its potential mechanisms and synergy with cisplatin in oral cancer have not been explored. This study investigated SAMA and cisplatin's combined effects and underlying ROS/MAPK mechanisms of action on oral cancer cells. The combination significantly reduced viability (ATP assay) in oral cancer Ca9‑22 and CAL 27 cells compared with either agent alone, with synergistic indices confirming enhanced antiproliferation. Moreover, this combination markedly suppressed colony formation and cell migration. SAMA/cisplatin induced subG1 accumulation and G2/M arrest, elevated cellular and mitochondrial ROS, and promoted apoptosis, as evidenced by increased annexin V positivity and caspase‑3, -8, and -9 activation, while DNA damage markers γH2AX and 8‑OHdG were also markedly elevated. In contrast, normal oral S‑G cells showed minimal cytotoxic damage and mechanical changes, suggesting selectivity. Mechanistically, JNK inhibition rescued the antiproliferative response and suppressed apoptosis, caspase activation, and DNA damage. Pretreatment with the ROS scavenger NAC attenuated all test effects, confirming ROS dependence. Together, these findings demonstrate that SAMA synergizes with cisplatin to selectively enhance oxidative stress, apoptosis, and DNA damage in oral cancer cells via ROS‑dependent JNK signaling, highlighting its potential as a cisplatin adjunct.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 4","pages":"e70327"},"PeriodicalIF":4.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148028185","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}

引用次数: 0

Sustainable One-Pot Synthesis of Novel Triazolopyrimidine Derivatives as Selective CDK4 Inhibitors for Breast Cancer Therapy. 新型三唑嘧啶衍生物选择性CDK4抑制剂在乳腺癌治疗中的可持续一锅合成。

IF 4.2 4区医学

Drug Development Research Pub Date : 2026-06-01 DOI: 10.1002/ddr.70322

Doaa A Elsayed, Wesam S Shehab, Maysa M Mohamed, Abdulrahman E Mesbah, Gehan T El-Bassyouni, Sahar M Mousa, Omnia M Abo Elenin, Mohammed G Assy, Eman S Tantawy

{"title":"Sustainable One-Pot Synthesis of Novel Triazolopyrimidine Derivatives as Selective CDK4 Inhibitors for Breast Cancer Therapy.","authors":"Doaa A Elsayed, Wesam S Shehab, Maysa M Mohamed, Abdulrahman E Mesbah, Gehan T El-Bassyouni, Sahar M Mousa, Omnia M Abo Elenin, Mohammed G Assy, Eman S Tantawy","doi":"10.1002/ddr.70322","DOIUrl":"10.1002/ddr.70322","url":null,"abstract":"A sustainable and effective one-pot synthesis of new 4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile derivatives was accomplished using Mn₃O₄ nanoparticles as a recyclable nanocatalyst under moderate and environmentally benign conditions. The approach provided outstanding yields and adheres to sustainable chemical principles. Analysis revealed CDK4 as a possible therapeutic target linked to breast cancer growth, therefore elucidating its biological potential. In silico molecular docking validated the robust binding affinities of the synthesized derivatives to the CDK4 active site, especially compound 4, which demonstrated the greatest interaction energy and stable orientation inside the binding pocket. In vitro cytotoxic studies on MCF-7 and MDA-MB-231 breast cancer cell lines demonstrated that compound 4 had the highest antiproliferative activity (IC₅₀ = 5.80 and 6.44 µM, respectively), equivalent to doxorubicin and sorafenib. Compound 3 had significant effects, whereas compounds 9 and 10 showed modest efficacy. Notably, compound 4 exhibited little toxicity to WI-38 normal fibroblasts (IC₅₀ = 51.61 µM), suggesting selectivity for cancer cells. Flow cytometric analyses demonstrated that compound 4 produced G₀/G₁ cell-cycle arrest (82.77%) and initiated apoptosis (35.19%) with little necrosis, therefore validating its CDK4-dependent mechanism. These results together identify compound 4 as a powerful, selective, and environmentally friendly synthetic CDK4 inhibitor, serving as a viable candidate for the future development of tailored anti-breast cancer therapies.","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 4","pages":"e70322"},"PeriodicalIF":4.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148028273","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}

引用次数: 0

Molecular Boomerangs Against Cancer: Design, Synthesis, Biological Evaluation, and In Silico Study of Novel Dual PARP-1/EGFR Inhibitors 抗癌分子飞弹：新型PARP-1/EGFR双抑制剂的设计、合成、生物学评价和计算机研究。

IF 4.2 4区医学

Drug Development Research Pub Date : 2026-05-28 DOI: 10.1002/ddr.70325

Haytham O. Tawfik, Amr Tayel, Salma M. Hefny, Tarfah Al-Warhi, Nada K. Sedky, Anwar A. El-Hamaky, Nourhan A. Khattab, Ahmed K. B. A. W. Farouk, Moataz A. Shaldam, Wagdy M. Eldehna, Mohamed S. Nafie

{"title":"Molecular Boomerangs Against Cancer: Design, Synthesis, Biological Evaluation, and In Silico Study of Novel Dual PARP-1/EGFR Inhibitors","authors":"Haytham O. Tawfik, Amr Tayel, Salma M. Hefny, Tarfah Al-Warhi, Nada K. Sedky, Anwar A. El-Hamaky, Nourhan A. Khattab, Ahmed K. B. A. W. Farouk, Moataz A. Shaldam, Wagdy M. Eldehna, Mohamed S. Nafie","doi":"10.1002/ddr.70325","DOIUrl":"10.1002/ddr.70325","url":null,"abstract":"<div>\u0000 \u0000 A possible method for improving anti-cancer efficacy is the combination of the inhibition of epidermal growth factor receptor (EGFR) and poly (ADP-ribose) polymerase-1 (PARP-1). This work describes the rational design, synthesis, and complete characterization of a novel class of boomerang-shaped dual PARP-1/EGFR inhibitors (3a–o). HepG-2 and MDA-MB-231 cancer cell lines were used to test the synthesized compounds’ antiproliferative potential; MDA-MB-231 cells showed greater sensitivity. Compounds 3h, 3i, and 3j had the strongest cytotoxic effects among the series, with IC50 values of 0.23, 0.90, and 1.40 µM, respectively, against MDA-MB-231 cells. Compared with the reference medications erlotinib and olaparib, compound 3h showed the highest dual inhibition (EGFR IC50 = 1.62 µM and PARP-1 IC50 = 0.36 µM) in enzymatic experiments, demonstrating that these compounds effectively inhibited both EGFR and PARP-1. Compound 3h strongly promoted apoptosis in MDA-MB-231 cells, increasing the total apoptotic population to 20.04% and causing G1-phase cell-cycle arrest, as determined by mechanistic studies. In vivo tumor growth inhibition trials showed a tumor inhibition rate (TIR%) of 41.4% for compound 3h compared to 48.8% for doxorubicin (DOX). Liver function biomarkers and hematological parameters remained within the acceptable levels following compound 3h treatment. The dual-target activity of compound 3h was further validated by molecular docking and molecular dynamics simulations, which demonstrated persistent binding contacts within the active sites of PARP-1 and EGFR.\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053504","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}

引用次数: 0

Unveiling Remyelinating Properties of Roflumilast in CPZ-Induced Neuronal Demyelination in Mice 揭示罗氟司特在cpz诱导的小鼠神经元脱髓鞘中的再生特性。

IF 4.2 4区医学

Drug Development Research Pub Date : 2026-05-28 DOI: 10.1002/ddr.70329

Ahmed S. Kamel, Israa Sameh, Mohamed A. Khattab, Ayman E. El-Sahar, Hala F. Zaki, Osama A. Badary, Sama M. Farrag

{"title":"Unveiling Remyelinating Properties of Roflumilast in CPZ-Induced Neuronal Demyelination in Mice","authors":"Ahmed S. Kamel, Israa Sameh, Mohamed A. Khattab, Ayman E. El-Sahar, Hala F. Zaki, Osama A. Badary, Sama M. Farrag","doi":"10.1002/ddr.70329","DOIUrl":"10.1002/ddr.70329","url":null,"abstract":"<div>\u0000 \u0000 Multiple sclerosis (MS) is a demyelinating disorder characterized by oligodendrocyte apoptosis, microglial activation at demyelination sites, with ROS production. These pathological processes are closely associated with phosphodiesterase-4 (PDE-4) activity. Roflumilast (ROFL), a selective PDE-4 inhibitor, has demonstrated neuroprotective effects in various central nervous system disorders. However, its specific role in MS pathogenesis remains to be fully elucidated. This study aims to investigate the effects of ROFL on oligodendrocyte maturation, microglial polarization and the impact on protein kinase A/cAMP-response element binding protein pathway. An MS model was induced in mice via dietary administration of cuprizone (CPZ) for 7 days, starting with 0.7% (w/w), followed by 0.2% for 5 weeks. Beginning in week 5, mice received ROFL (5 mg/kg/day, p.o) for 2 weeks. ROFL improved the motor abnormalities in the rotarod and open field tests. Together, ROFL downregulated the PDE4/cAMP-dependent pathway, exerting anti-inflammatory effects by suppressing NF-κB and TNF-α. Additionally, microglial polarization shifted toward the anti-inflammatory M2 phenotype, with CD163 increment, in contrast to the pro-inflammatory M1 marker CD83. Furthermore, ROFL's antioxidant capacity was evidenced by reduced malondialdehyde levels, replenishment of glutathione levels, and reduced phosphorylation of ERK1/2. Oligodendrocyte differentiation and maturation were enhanced, as indicated by elevated levels of proteolipid protein, myelin-associated glycoprotein, CNPase, and myelin basic protein. Remyelination was confirmed through Luxol fast blue staining, accompanied by reduced apoptotic marker, caspase-3, in oligodendrocytes. Collectively, these findings suggest that ROFL exerts neuroprotective effects and highlight the therapeutic potential of PDE-4 inhibition as a strategy for MS treatment.\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053454","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}

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IF 4.2 4区医学

Drug Development Research Pub Date : 2026-05-27

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IF 4.2 4区医学

Drug Development Research Pub Date : 2026-05-26

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IF 4.2 4区医学

Drug Development Research Pub Date : 2026-05-26

引用次数: 0

IF 4.2 4区医学

Drug Development Research Pub Date : 2026-05-26