Drug Development Research最新文献

{"title":"Design, synthesis, and evaluation of novel Indole-Based small molecules as sirtuin inhibitors with anticancer activities","authors":"Busra Binarci,&nbsp;Ensar Korkut Kilic,&nbsp;Tunca Dogan,&nbsp;Rengul Cetin Atalay,&nbsp;Deniz Cansen Kahraman,&nbsp;Sultan Nacak Baytas","doi":"10.1002/ddr.70008","DOIUrl":"https://doi.org/10.1002/ddr.70008","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, driven mainly by chronic hepatitis infections and metabolic disorders, which highlights the urgent need for novel therapeutic strategies. Sirtuins, particularly SIRT1 are crucial in HCC pathogenesis, making it a promising drug target. Indole-based molecules show potential as therapeutic agents by interacting with key proteins like sirtuins involved in cancer progression. In this study, we designed and synthesized novel indole-based small molecules and investigated their potential sirtuin inhibitory action and anticancer activity on HCC cell lines. Four of the twenty-eight tested small molecules on different cancer types were selected (<b>4 g</b>, <b>4 h</b>, <b>4o</b>, and <b>7j</b>) based on their structure–activity relationship and studied on a panel of HCC cell lines. Compounds had active drug-target interactions with SIRT1 or SIRT2 based on DEEPScreen DTI predictions and docking studies which confirmed that <b>4o</b>, <b>4 g</b>, and <b>7j</b> were most potent in their interaction with SIRT1. Compound <b>4 g</b> caused the highest sirtuin activity inhibition in vitro and induced G1 arrest and apoptosis in HCC cell lines.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451775","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":"New S-substituted-3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B-RAF signaling pathway","authors":"Safaa E. Seif,&nbsp;Wagnat W. Wardakhan,&nbsp;Rasha A. Hassan,&nbsp;Amr M. Abdou,&nbsp;Zeinab Mahmoud","doi":"10.1002/ddr.70007","DOIUrl":"https://doi.org/10.1002/ddr.70007","url":null,"abstract":"<p>Novel 3-phenyltetrahydrobenzo[4,5]thieno[2,3-<i>d</i>]pyrimidine derivatives were synthesized and screened for their antiproliferative activity against a panel of 60 cancer cell lines. Derivatives <b>5b</b>, <b>5f</b>, and <b>9c</b> showed significant antitumor activity at a single dose with mean growth inhibition of 55.62%, 55.79%, and 71.40%, respectively. These compounds were further investigated against HCT-116, colon cancer cell line, and FHC, normal colon cell line. Compound <b>9c</b> showed the highest activity with IC₅₀ = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC₅₀ = 2.556 ± 0.09 µM and SI = 6.19. Compound <b>9c</b> was also the most potent against B-RAF^WT and mutated B-RAF^V600E with IC₅₀ = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC₅₀ = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively. The cell cycle analysis showed that <b>9c</b> increased the cell population and induced an arrest in the cell cycle of HCT-116 cancer cells at the G0-G1 stage with 1.23-fold. Apoptosis evaluation showed that compound <b>9c</b> displayed an 18.18-fold elevation in total apoptosis of HCT-116 cancer cells in comparison to the control. Compound <b>9c</b> increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of <b>9c</b> with the B-RAF active site.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451285","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":"Downregulation of short-stature homeobox protein 2 suppresses gastric cancer cell growth and stemness in vitro and in vivo via inactivating wnt/β-catenin signaling","authors":"Xiangyu Chen,&nbsp;Shuai Li,&nbsp;Binghua Sun","doi":"10.1002/ddr.70006","DOIUrl":"https://doi.org/10.1002/ddr.70006","url":null,"abstract":"<p>Gastric cancer (GC) a prevalent form of cancer globally. Previous research suggests that SHOX2 may have a role in promoting cancer progression. However, the role of SHOX2 in GC is not well understood. Based on data from TCGA_GC data set, SHXO2 levels were examined in normal and GC tissues. Patients in the TCGA_GC cohort were divided into high- and low-SHOX2 level groups for analysis of overall survival (OS), functional enrichment, and immune infiltration. Furthermore, experiments were conducted to investigate the impact of SHOX2 on GC cell function through gain- and loss-of-function experiments. Utilizing data from public databases, SHOX2 mRNA levels were found to be elevated in GC tissues compared to normal control, this finding was confirmed by RT-qPCR, western blot analysis, and immune-histochemical analyses. Elevated SHOX2 levels could serve as an independent indicator of poor prognosis in GC patients. Furthermore, SHOX2 levels had a negative correlation with CD8 T cells and CD4 memory activated T cells, and a positive correlation with of M0 macrophages in GC patients. Functional analyses revealed that SHOX2 deficiency notably suppressed GC cell proliferation, migration, and invasion. Additionally, SHOX2 deficiency was shown to suppress stemness in GC cells in vitro and in vivo via inactivating wnt/β-catenin signaling. Collectively, SHOX2 may serve as a prognostic marker for GC patients, and downregulation of SHOX2 could effectively impede GC cell growth and stemness by inactivating the wnt/β-catenin signaling pathway. These findings underscore the potential of SHOX2 as a promising therapeutic target for GC.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447480","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 and advance of ubiquitination and deubiquitination in depression pathogenesis and treatment","authors":"Xiaoru Yan,&nbsp;Yunhui Ma,&nbsp;Junting Yang,&nbsp;Xiaoqi Chang,&nbsp;Shuxuan Shi,&nbsp;Guohua Song","doi":"10.1002/ddr.70005","DOIUrl":"https://doi.org/10.1002/ddr.70005","url":null,"abstract":"<p>Depression is a common neuropsychiatric disease that is characterized by long-term, repeated low mood, pain and despair, pessimism, and even suicidal tendencies. Increasing evidence has shown that ubiquitination and deubiquitination are closely related to the occurrence of depression, including pathological morphogenesis, neuroplasticity, synaptic transmission, neuroinflammation, and so forth. The development of depression is regulated by intracellular proteins that undergo various posttranslational modifications, including ubiquitination, which falls under the epigenetics category. Although there have been studies and reviews of literature on epigenetics and depression, a systematic review of ubiquitination modification and depression has not been reported. In addition, with the deepening of research on depression and ubiquitination, the development of drugs targeting the ubiquitin system has gradually increased, but it is still not mature, so there is an urgent need to find new antidepressant drug targets. E3 ubiquitin ligases and deubiquitinating enzymes can regulate the occurrence and development of depression in a variety of ways, which may be a direction for the treatment of depression in the future. Therefore, this review describes the latest progress of ubiquitination and deubiquitination in the regulation of depression, summarizes the published signal pathways of ubiquitination and deubiquitination involved in depression, emphasizes the targets and mechanisms of E3 ubiquitin ligases and deubiquitinase in the regulation of depression, and further discusses the therapeutic targets of targeting ubiquitination modification systems to regulate depression.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447481","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":"RecQ protein-like 4 drives cisplatin chemosensitivity of cervical cancer cells by modulating annexin A2","authors":"Ruixue Wang,&nbsp;Yunyan Zhang","doi":"10.1002/ddr.70003","DOIUrl":"https://doi.org/10.1002/ddr.70003","url":null,"abstract":"<p>Cervical cancer is a common malignant tumor in women with high morbidity and mortality. Chemotherapy drugs such as cisplatin (DDP) are easy to cause chemotherapy resistance and affect the therapeutic effect. Hence, it is critical to design new therapies that can reverse chemotherapy resistance and increase sensitivity to chemotherapy drugs. This study investigated the function of RecQ protein-like 4 (RECQL4) in DDP-resistant cervical cancer cells and its regulatory mechanism. By constructing DDP-resistant Hela and CaSki cell lines, it was found that RECQL4 expression was elevated. RECQL4 knockdown is able to promote apoptosis, DNA damage, and increase the DDP sensitivity in cervical cancer cells. In vivo experiments have demonstrated that knockdown of RECQL4 suppresses tumor growth and promotes tumor apoptosis. Next, we investigated the potential regulatory relationship of RECQL4 to Annexin A2 (ANXA2). The results demonstrated that RECQL4 binds to ANXA2. Knockdown of RECQL4 downregulates the ANXA2 expression via promoting ubiquitination. Furthermore, we also found that ANXA2 overexpression partially abolished the role of RECQL4 knockdown in promoting apoptosis and DNA damage of cervical cancer cells, suggesting that RECQL4 plays a role in DDP sensitivity of cervical cancer cells by mediating ANXA2. In conclusion, the present study suggests that knocking down RECQL4 reduces DDP sensitivity in cervical cancer cells by modulating ANXA2. Targeting RECQL4 therapy may be a new strategy to improve chemosensitivity of cervical cancer cells.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435716","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":"EGCG enhances antitumor effect of apatinib in nonsmall cell lung cancer by targeting VEGF signaling to inhibit glycolysis","authors":"Yue Zhou,&nbsp;Liqing Qin,&nbsp;Chengpeng Li,&nbsp;Danxue Zhu,&nbsp;Bo Liu","doi":"10.1002/ddr.22239","DOIUrl":"https://doi.org/10.1002/ddr.22239","url":null,"abstract":"<p>Nonsmall cell lung cancer (NSCLC), one of the most aggressive malignancies globally, is characterized by poor prognosis and limited life expectancy. Epigallocatechin-3-gallate (EGCG), a natural polyphenol found in green tea, has emerged as a promising anticancer agent due to its potent antitumor properties. However, the role and the underlying mechanisms of EGCG in NSCLC remain poorly understood. Hence, this research aimed to explore the effect of EGCG on the antitumor effect of apatinib in NSCLC through vascular endothelial growth factor (VEGF)-regulated glycolysis. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine staining, wound healing, transwell, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and flow cytometry assays were carried out to evaluate the proliferation, migration, invasion, and apoptosis of H1299 cells, respectively. Furthermore, western blot analysis was used to detect the expressions of VEGF, p-vascular endothelial growth factor receptor-2, hypoxia-inducible factor 1α, neuropilin-1, phosphorylated-phosphatidylinositol 3-kinase, and phosphorylated-AKT. The transfection efficiency of H1299 cells with VEGF overexpression plasmid was also assessed by western blot analysis. Glycolysis was analyzed by estimating extracellular acidification rate, lactate concentration, glucose uptake, and the expressions of lactate dehydrogenase A, pyruvate kinase M2, and hexokinase 2. The results demonstrated that VEGF activated glycolysis in NSCLC cells. EGCG alone and apatinib alone or in combination inhibited cell viability, proliferation, invasion, migration, and glycolysis whereas promoted apoptosis in NSCLC cells. EGCG regulated glycolysis levels in NSCLC through VEGF overexpression, and enhanced the antitumor effect of apatinib in NSCLC through VEGF-regulated glycolysis. Taken together, EGCG strengthened the protective effects of apatinib in NSCLC through glycolysis mediated by VEGF.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435330","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":"Trifolirhizin targets PTK6 to induce autophagy and exerts antitumor effects in nasopharyngeal carcinoma","authors":"Yong Wang,&nbsp;Yang Fang","doi":"10.1002/ddr.70000","DOIUrl":"10.1002/ddr.70000","url":null,"abstract":"<p>Trifolirhizin, a natural flavonoid glycoside, has been proved to exert antitumor activities in various human malignant tumors. PTK6 was identified as a direct target of trifolirhizin based on public database SuperPred (https://prediction.charite.de/). Overexpressed PTK6 in a variety of tumors is closely associated with the malignant development of tumors. Herein, this present research was formulated to elaborate the effects of trifolirhizin on the biological behaviors of nasopharyngeal carcinoma (NPC) cells and to probe into the intrinsic mechanisms. The current study firstly elucidated the tumor-inhibiting functions of trifolirhizin in NPC malignant progression from the perspective of targeting inhibition of PTK6. In this work, CCK-8 for cell viability, EdU staining for cell proliferation, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining for cell apoptosis and immunofluorescence staining for LC3 expression were performed. Besides, levels of proliferation-related, apoptosis-related and autophagy-related proteins were detected by western blot analysis. Moreover, molecular docking of trifolirhizin with PTK6 was conducted to seek the compound-protein binding potential. It was demonstrated that trifolirhizin treatment inhibited the proliferation and promoted the apoptosis of NPC cells as well as strengthened autophagy in NPC cells. Furthermore, it was verified that trifolirhizin targeted PTK6 and negatively regulated PTK6 expression. The suppressive effects of trifolirhizin on the malignant behaviors of NPC cells and the enhancing effect of trifolirhizin on autophagy in NPC cells were partly abolished upon upregulation of PTK6. To conclude, findings suggested that trifolirhizin may downregulate PTK6 expression to induce autophagy and exert the antitumor activities in NPC.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399696","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":"Tropisetron attenuates high glucose-induced oxidative stress and inflammation in ARPE-19 cells in vitro via regulating SIRT1/ROCK1 signaling","authors":"Mingxia Tang,&nbsp;Wei Liu","doi":"10.1002/ddr.70002","DOIUrl":"10.1002/ddr.70002","url":null,"abstract":"<p>Diabetic retinopathy (DR) is the leading cause of acquired blindness in diabetic patients. Tropisetron (TRO) exerts potent therapeutic effects against diabetic tissues. The present study aimed to investigate the effects of TRO on retinal injury under diabetic condition. Human retinal pigment epithelial cell line ARPE-19 was treated with high glucose (HG) for 48 h to mimic hyperglycemia-induced retinal damage and subsequently treated with multiple concentrations of TRO for therapeutic intervention. Cell viability and lactate dehydrogenase (LDH) release were detected to assess cell damage. The production of inflammatory cytokines and oxidative stress-related factors was evaluated by corresponding commercial kits. Cell apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression of inflammation-, apoptosis-, and SIRT1/ROCK1-related proteins was examined using western blot analysis. Additionally, ARPE-19 cells were transfected with over-express ROCK1 (Ov-ROCK1) or pretreatment with SIRT1 inhibitor EX527 to perform the rescue experiments. TRO alleviated cell damage in HG-induced ARPE-19 cells through elevating cell viability and reducing LDH release. HG-caused excessive production of TNF-α, IL-1β and IL-6, ROS, malondialdehyde and decreased superoxide dismutase activity were partly inhibited by TRO treatment. HG-induced cell apoptosis, accompanied with the upregulation of proapoptotic proteins and the downregulation of antiapoptotic proteins, was hindered by TRO treatment. HG led to the loss of SIRT1 and an elevation of ROCK1 in ARPE-19 cells, which was reversed following TRO treatment. Furthermore, pretreatment with EX527 or transfected with Ov-ROCK1 partially abolished the protective role of TRO against inflammation, oxidative stress and cell apoptosis in HG-challenged ARPE-19 cells. TRO exerted a protective role against HG-caused ARPE-19 cells inflammation, oxidative stress and cell apoptosis by regulating SIRT1/ROCK1 axis, suggesting that TRO might be therapeutic agent for alleviating retinal pigment epithelial cell damage in DR.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388855","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":"89Zr-Labeled DFO@Durvalumab-HSA nanoparticles: In vitro potential for triple-negative breast cancer","authors":"Fatma Yurt,&nbsp;Derya Özel,&nbsp;Şeyma Karagül,&nbsp;Ayça Tunçel,&nbsp;Kübra Durkan,&nbsp;Emin İlker Medine","doi":"10.1002/ddr.22266","DOIUrl":"10.1002/ddr.22266","url":null,"abstract":"<p>This study presents the development and evaluation of a DFO@mAb-NP (DFO@Durvalumab-HSA-DTX nanoparticle) nanoplatform for imaging in triple-negative breast cancer (TNBC). The nanoplatform demonstrated significant changes postconjugation with DFO, evidenced by increased particle size from 178.1 ± 5 nm to 311 ± 26 nm and zeta potential alteration from −31.9 ± 3 mV to −40.5 ± 0.8 mV. Fourier-transform infrared spectroscopy and ultraviolet spectral analyses confirmed successful DFO conjugation, with notable shifts in peak wavelengths. High labeling efficiency was achieved with ⁸⁹Zr, as indicated by thin layer radio chromatography and high-performance liquid radio chromatography results, with labeling efficiencies of 98 ± 2% for ⁸⁹Zr-DFO@mAb and 96 ± 3% for ⁸⁹Zr-DFO@mAb-NP. The nanoplatforms maintained stability over 24 h, showing less than 5% degradation. Lipophilicity assays revealed logP values of 0.5 ± 0.03 for ⁸⁹Zr-DFO@mAb-NP and 0.98 ± 0.2 for ⁸⁹Zr-DFO@mAb, indicating a higher lipophilic tendency in the radiolabeled Durvalumab. Cell uptake experiments showed an initial high uptake in MDA-MB-468 cells (45.1 ± 3.2%), which decreased over time, highlighting receptor-specific interactions. These comprehensive findings suggest the promising potential of the DFO@mAb-NP nanoplatform for targeted imaging in TNBC, with implications for improved diagnostic accuracy and treatment strategies.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371292","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":"Sm(Ⅲ), Gd(Ⅲ), and Eu(Ⅲ) complexes with 8-hydroxyquinoline derivatives as potential anticancer agents via inhibiting cell proliferation, blocking cell cycle, and inducing apoptosis in NCI-H460 cells","authors":"Kun Yang,&nbsp;Huan-Qing Li,&nbsp;Mei-Qi Hu,&nbsp;Meng-Xue Ma,&nbsp;Yun-Qiong Gu,&nbsp;Qi-Yuan Yang,&nbsp;Muhammad Iqbal Choudhary,&nbsp;Hong Liang,&nbsp;Zhen-Feng Chen","doi":"10.1002/ddr.22265","DOIUrl":"10.1002/ddr.22265","url":null,"abstract":"<p>Four lanthanide complexes with 8-hydroxyquinoline-2-aldehyde-2-hydrazinopyridine (H-L¹), 8-hydroxyquinoline-2-aldehyde-2-hydrazimidazole (H-L²): [Sm(L¹)₂][Sm(L¹)(NO₃)₃]<b>·</b>CHCl₃<b>·</b>2CH₃OH (<b>1</b>), [Gd(L¹)₂][Gd(L¹)(NO₃)₃]<b>·</b>CHCl₃<b>·</b>2CH₃OH (<b>2</b>), [Sm(L²)(NO₃)₂]₂<b>·</b>CH₃OH (<b>3</b>), and [Eu(L²)(NO₃)₂]₂<b>·</b>CH₃OH (<b>4</b>) were synthesized and characterized. In vitro cytotoxicity evaluation showed that the ligands and four lanthanide complexes exhibited cytotoxicity to the five tested tumor cell lines. Among them, complex <b>1</b> showed the best antiproliferative activity against NCI-H460 tumor cells. Mechanistic studies demonstrated that complex <b>1</b> arrested the cell cycle of NCI-H460 cells in G1 phase and induced mitochondria-mediated apoptosis, which resulted in the loss of mitochondrial membrane potential, enhanced intracellular Ca²⁺ levels and reactive oxygen species generation. In addition, complex <b>1</b> affected the expression levels of intracellular apoptosis-related proteins and activated the caspase-3/9 in NCI-H460 cells. Therefore, complex <b>1</b> is a potential anticancer agent.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364788","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}