Apoptosis最新文献_第3页

MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis. MRG15在高脂血症急性胰腺炎中通过抑制有丝分裂促进细胞凋亡

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-11-02 DOI: 10.1007/s10495-024-02034-4

Boyuan Gu, Wenhao Yu, Zhiwei Huang, Junjie Bai, Shenglu Liu, Bingyu Ren, Pengru Wang, Lei Sun, Jian Wen, Yang Zheng, Peng Tan, Wenguang Fu

{"title":"MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis.","authors":"Boyuan Gu, Wenhao Yu, Zhiwei Huang, Junjie Bai, Shenglu Liu, Bingyu Ren, Pengru Wang, Lei Sun, Jian Wen, Yang Zheng, Peng Tan, Wenguang Fu","doi":"10.1007/s10495-024-02034-4","DOIUrl":"https://doi.org/10.1007/s10495-024-02034-4","url":null,"abstract":"Hyperlipidemia is a common cause of acute pancreatitis (AP), often leading to more severe clinical symptoms. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) plays a crucial role in regulating lipid metabolism. Therefore, this study aimed to explore the mechanism of MRG15 in hyperlipidemic acute pancreatitis (HAP). Mendelian randomization, transcriptome analysis, and single-cell analysis were employed to explore the association between MRG15 and AP by utilizing publicly available databases. In vivo, hypertriglyceridemia mouse models were created by intraperitoneal injection of P407 or using APOE-deficient mice. Subsequently, the HAP model was induced by cerulean. In vitro, a cell model of HAP was established by initially exposing cells to palmitic acid to simulate a high-fat environment, followed by cerulein treatment. Subsequently, MRG15-related indicators were measured. Through Mendelian randomization, it was discovered that there is a positive correlation between genetic expression of MRG15 and the risk of AP. Transcriptome and single-cell analysis revealed that elevated MRG15 expression in AP contributes to lipid metabolism disorders and the activation of apoptosis pathways in pancreatic acinar cells. MRG15 is found to be significantly upregulated in cases of HAP. Knocking down MRG15 led to an increase in mitophagy and a decrease in apoptosis in pancreatic cells, and this effect was reversed when the mitochondrial Tu translation elongation factor (TUFM) was simultaneously knocked down. MRG15 inhibits mitophagy by degrading TUFM, ultimately promoting cell apoptosis and worsening the progression of HAP.","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: The extracellular lactate-to-pyruvate ratio modulates the sensitivity to oxidative stress-induced apoptosis via the cytosolic NADH/NAD + redox state 更正：细胞外乳酸与丙酮酸的比率通过细胞膜 NADH/NAD + 氧化还原状态调节对氧化应激诱导的细胞凋亡的敏感性。

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-10-30 DOI: 10.1007/s10495-024-02024-6

Simei Go, Thorquil T. Kramer, Arthur J. Verhoeven, Ronald P. J. Oude Elferink, Jung-Chin Chang

引用次数: 0

The STING signaling pathways and bacterial infection. STING 信号通路与细菌感染

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-10-20 DOI: 10.1007/s10495-024-02031-7

Jiayi You, Ailing Xu, Ye Wang, Guangmin Tu, Rui Huang, Shuyan Wu

{"title":"The STING signaling pathways and bacterial infection.","authors":"Jiayi You, Ailing Xu, Ye Wang, Guangmin Tu, Rui Huang, Shuyan Wu","doi":"10.1007/s10495-024-02031-7","DOIUrl":"https://doi.org/10.1007/s10495-024-02031-7","url":null,"abstract":"As antibiotic-resistant bacteria continue to emerge frequently, bacterial infections have become a significant and pressing challenge to global public health. Innate immunity triggers the activation of host responses by sensing \"non-self\" components through various pattern recognition receptors (PRRs), serving as the first line of antibacterial defense. Stimulator of interferon genes (STING) is a PRR that binds with cyclic dinucleotides (CDN) to exert effects against bacteria, viruses, and cancer by inducing the production of type I interferon and inflammatory cytokines, and facilitating regulated cell death. Currently, drugs targeting the STING signaling pathway are predominantly applied in the fields of modulating host immune defense against cancer and viral infections, with relatively limited application in treating bacterial infections. Given the significant immunomodulatory functions of STING in the interaction between bacteria and hosts, this review summarizes the research progress on STING signaling pathways and their roles in bacterial infection, as well as the novel functions of STING modulators, aiming to offer insights for the development of antibacterial drugs.","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The contributory role of GSK3β in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway. GSK3β 通过调节 OMA1/PGC1α 通路在高血压加剧动脉粥样硬化中的作用。

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-10-19 DOI: 10.1007/s10495-024-02029-1

Hongjia Bao, Changyuan Wang, Yue Jin, Qiang Meng, Jingjing Wu, Qi Liu, Huijun Sun

{"title":"The contributory role of GSK3β in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway.","authors":"Hongjia Bao, Changyuan Wang, Yue Jin, Qiang Meng, Jingjing Wu, Qi Liu, Huijun Sun","doi":"10.1007/s10495-024-02029-1","DOIUrl":"https://doi.org/10.1007/s10495-024-02029-1","url":null,"abstract":"Atherosclerosis is closely related to endothelial dysfunction and hypertension. GSK3β is a critical regulator in atherosclerosis. This study was carried out to investigate the effects of GSK3β on hypertension exacerbating atherosclerosis in vitro and in vivo. L-NAME + HFD-ApoE-/- mice were used for this study for 12 weeks, and their endothelial dysfunction and inflammation were analyzed. Oil red O and H&E staining revealed that treatment with LiCl, an inhibitor of GSK3β, reduced atherosclerotic lesions and lipid accumulation. The levels of lipid homeostasis and oxidation stress were attenuated following LiCl administration. LiCl-treated ApoE-/- mice showed lowered blood pressure. LiCl also suppressed the expressions of Drp1, Bax, ICAM1, VCAM1 and TNF-α compared to HFD + L-NAME induced mice and oxLDL + L-NAME-treated Human aorta endothelial cell line(HAECs). LiCl treatment increased the expressions of MFN2 and Bcl2. Mitotracker-red, MitoSOX and JC-1 staining indicated that LiCl treatment reduced mitochondrial division and ROS production, increased mitochondrial ΔΨm compared to oxLDL + L-NAME-treated HAECs. The expression of OMA1 was decreased by LiCl treatment, while PGC1α expression was increased. In HAECs, we found that OMA1 knockdown increased mitochondrial function and the expression of PGC1α. We also demonstrated LiCl increased OMA1 ubiquitination compared with the Control group, thus decreased OMA1 expression. Furthermore, siOMA1 antagonized the increased protein expressions of ICAM1, VCAM1, TNF-α, Bax and Drp1, decreased the protein expressions of Bcl2 and MFN2 by siPGC1α. Taken together, we demonstrated that GSK3β could play a contributory role in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway and inhibiting mitochondrial function.","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combination of magnetic hyperthermia and gene therapy for breast cancer. 磁热疗与基因疗法相结合治疗乳腺癌。

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-10-19 DOI: 10.1007/s10495-024-02026-4

Kubra Solak, Seyda Yildiz Arslan, Melek Acar, Fatma Turhan, Yagmur Unver, Ahmet Mavi

{"title":"Combination of magnetic hyperthermia and gene therapy for breast cancer.","authors":"Kubra Solak, Seyda Yildiz Arslan, Melek Acar, Fatma Turhan, Yagmur Unver, Ahmet Mavi","doi":"10.1007/s10495-024-02026-4","DOIUrl":"https://doi.org/10.1007/s10495-024-02026-4","url":null,"abstract":"This study presented a novel breast cancer therapy model that uses magnetic field-controlled heating to trigger gene expression in cancer cells. We created silica- and amine-modified superparamagnetic nanoparticles (MSNP-NH2) to carry genes and release heat under an alternating current (AC) magnetic field. The heat-inducible expression plasmid (pHSP-Azu) was designed to encode anti-cancer azurin and was delivered by magnetofection. MCF-7 cells demonstrated over 93% cell viability and 12% transfection efficiency when exposed to 75 µg/ml of MSNP-NH2, 3 µg of DNA, and PEI at a 0.75 PEI/DNA ratio (w: w), unlike non-tumorigenic cells (MCF-10 A). Magnetic hyperthermia (MHT) increased azurin expression by heat induction, leading to cell death in dual ways. The combination of MHT and heat-regulated azurin expression induced cell death, specifically in cancer cells, while having negligible effects on MCF-10 A cells. The proposed strategy clearly shows that simultaneous use of MHT and MHT-induced azurin gene expression may selectively target and kill cancer cells, offering a promising direction for cancer therapy.","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pulsed electromagnetic fields inhibit IL-37 to alleviate CD8+ T cell dysfunction and suppress cervical cancer progression 脉冲电磁场可抑制 IL-37，从而缓解 CD8+ T 细胞功能障碍并抑制宫颈癌的进展。

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-10-15 DOI: 10.1007/s10495-024-02006-8

Ke Jin, Dan Zhao, Jun Zhou, Xun Zhang, Yujue Wang, Zhao Wu

{"title":"Pulsed electromagnetic fields inhibit IL-37 to alleviate CD8+ T cell dysfunction and suppress cervical cancer progression","authors":"Ke Jin, Dan Zhao, Jun Zhou, Xun Zhang, Yujue Wang, Zhao Wu","doi":"10.1007/s10495-024-02006-8","DOIUrl":"10.1007/s10495-024-02006-8","url":null,"abstract":"<div>Pulsed electromagnetic field (PEMF) therapy is a potential non-invasive treatment to modulate immune responses and inhibit tumor growth. Cervical cancer (CC) is influenced by IL-37-mediated immune regulation, making PEMF therapy a potential strategy to impede CC progression. This study aimed to elucidate the effects of PEMF on IL-37 regulation and its molecular mechanisms in CC. CC cell-xenografted mouse models, including IL-37 transgenic (IL-37tg) mice, were used to assess tumor growth through in vivo fluorescence imaging and analyze CC cell apoptosis via flow cytometry. TCGA-CESC transcriptome and clinical data were analyzed to identify key inflammation and immune-related genes. CD8+ T cell models were stimulated with PEMF, and apoptosis, oxidative stress, and inflammatory factor expression were analyzed through RT-qPCR, Western blot, and flow cytometry. PEMF treatment significantly inhibited IL-37 expression (p < 0.05), promoted inflammatory factor release (TNF-α and IL-6), and activated oxidative stress, leading to increased CC cell apoptosis (p < 0.05). IL-37 interaction with SMAD3 impacted the p38/NF-κB signaling pathway, modulating CD8+ T cell activity and cytotoxicity. Co-culture of Hela cells with CD8+ T cells under PEMF treatment showed reduced proliferation (by 40%), migration, and invasion (p < 0.05). In vivo experiments with CC-bearing mice demonstrated that PEMF treatment downregulated IL-37 expression (p < 0.05), enhanced CD8+ T cell function, and inhibited tumor growth (p < 0.05). These molecular mechanisms were validated through RT-qPCR, Western blot, and immunohistochemistry. Thus, PEMF therapy inhibits CC progression by downregulating IL-37 and improving CD8+ T cell function via the SMAD3/p38/NF-κB signaling pathway.</div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"29 11-12","pages":"2108 - 2127"},"PeriodicalIF":6.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SHCBP1 promotes cisplatin resistance of ovarian cancer through AKT/mTOR/Autophagy pathway. SHCBP1通过AKT/mTOR/Autophagy途径促进卵巢癌的顺铂耐药性。

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-10-13 DOI: 10.1007/s10495-024-02027-3

Gonghua Qi, Hanlin Ma, Kai Teng, Panpan Gai, Yanmin Gong, Jingying Chen, Xia Luo, Beihua Kong

{"title":"SHCBP1 promotes cisplatin resistance of ovarian cancer through AKT/mTOR/Autophagy pathway.","authors":"Gonghua Qi, Hanlin Ma, Kai Teng, Panpan Gai, Yanmin Gong, Jingying Chen, Xia Luo, Beihua Kong","doi":"10.1007/s10495-024-02027-3","DOIUrl":"https://doi.org/10.1007/s10495-024-02027-3","url":null,"abstract":"Ovarian cancer caused the highest cancer-related mortality among female reproductive system malignancies. Platinum-based chemotherapy is still the footstone of the chemotherapy for ovarian cancer. However, the molecular mechanisms underlying cisplatin insensitivity and resistance remain unclear. SHC SH2 domain-binding protein 1 (SHCBP1) plays critical roles in the progression and drug resistance of different types of cancer. However, the biological function of SHCBP1 in ovarian cancer progression and cisplatin resistance remains obscure. In this study, we found that SHCBP1 was upregulated in ovarian cancer and the upregulated SHCBP1 has growth-promoting effect on ovarian cancer cells. Furthermore, SHCBP1 silencing sensitize ovarian cancer cells to cisplatin (hereafter referred to as CDDP). Mechanism analysis revealed that SHCBP1 activated the Akt/mTOR pathway and further inhibited autophagy in ovarian cancer cells. Meanwhile, autophagy inhibitors combined with SHCBP1 knockdown enhances CDDP sensitivity. In addition, knockdown of SHCBP1 restricted the proliferation of tumors and increased the cisplatin sensitivity in vivo. These findings suggested that upregulated SHCBP1 promoted the proliferation and CDDP resistance of ovarian cancer. The combination of SHCBP1 inhibition and cisplatin treatment might lead to substantial progress in ovarian cancer targeted therapy.","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phosphatidylserine-mediated uptake of extracellular vesicles by hepatocytes ameliorates liver ischemia-reperfusion injury. 磷脂酰丝氨酸介导的肝细胞吸收细胞外囊泡可改善肝脏缺血再灌注损伤。

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-10-13 DOI: 10.1007/s10495-024-02030-8

Rongrong Li, Chen Wang, Xiaoniao Chen, Enze Fu, Kaiyue Zhang, Hongyan Tao, Zhibo Han, Zhong-Chao Han, Zongjin Li

{"title":"Phosphatidylserine-mediated uptake of extracellular vesicles by hepatocytes ameliorates liver ischemia-reperfusion injury.","authors":"Rongrong Li, Chen Wang, Xiaoniao Chen, Enze Fu, Kaiyue Zhang, Hongyan Tao, Zhibo Han, Zhong-Chao Han, Zongjin Li","doi":"10.1007/s10495-024-02030-8","DOIUrl":"https://doi.org/10.1007/s10495-024-02030-8","url":null,"abstract":"Compelling evidence suggests that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) promote regeneration in animal models of liver injury by delivering signaling molecules. However, their target cells and uptake mechanism remain elusive. In this study, MSC-EVs were intravenously administered in a mouse model of liver ischemia-reperfusion injury (IRI). Our results revealed that MSC-EVs exhibit enhanced liver targeting in IRI mice, and injured hepatocytes display a greater capacity for MSC-EV uptake. We found that phosphatidylserine (PS) displayed on the exterior of injured hepatocytes promotes MSC-EV internalization, possibly by binding to MFGE8, a protein expressed on the MSC-EV membrane. Furthermore, the therapeutic effect of MSC-EVs on liver IRI is highly dependent on this PS-mediated uptake pathway. Our findings provide evidence that MSC-EVs preferentially target injured hepatocytes, relying on a PS-dependent uptake route to exert hepatoprotective effects, which are critical for the future design of EV-based therapeutic strategies for liver IRI.","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IGF2BP3 boosts lactate generation to accelerate gastric cancer immune evasion IGF2BP3 促进乳酸生成，加速胃癌免疫逃避。

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-10-13 DOI: 10.1007/s10495-024-02020-w

Kai Lin, Xiufeng Lin, Fan Luo

{"title":"IGF2BP3 boosts lactate generation to accelerate gastric cancer immune evasion","authors":"Kai Lin, Xiufeng Lin, Fan Luo","doi":"10.1007/s10495-024-02020-w","DOIUrl":"10.1007/s10495-024-02020-w","url":null,"abstract":"<div>The CD8+ T cells mediated antitumor immunity plays a critical function on gastric cancer (GC) immunotherapy. However, the mechanism of N6-methyladenosine (m6A) and lactate in GC immune microenvironment are still unclear. Here, present research investigated the role of Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) in GC and its in-depth mechanisms in the antitumor immunity. Data illustrated that high IGF2BP3 level was associated to GC poor prognosis and tumor infiltration. Functional assays demonstrated that IGF2BP3 overexpression could promote the lactate accumulation, and impair the CD8+ T cells’ antitumor immunity activity in co-culture system. Correspondingly, IGF2BP3 silencing enhanced the CD8+ T cells’ antitumor immunity activity towards co-cultured GC cells. Mechanistically, IGF2BP3 could bind the m6A site on LDHA mRNA, thereby promoting its mRNA stability. Rescue assays elucidated that IGF2BP3/LDHA axis impaired the CD8+ T cells antitumor immunity by triggering lactate excess tumor microenvironment. In conclusion, our findings demonstrate that IGF2BP3 impairs the CD8+ T cells antitumor immunity by targeting LDHA/lactate axis, providing a novel therapeutic insight for GC immunotherapy.</div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"29 11-12","pages":"2147 - 2160"},"PeriodicalIF":6.1,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel dual inhibitor targeting CDC25 and HDAC for treating triple-negative breast cancer 针对 CDC25 和 HDAC 的新型双重抑制剂，用于治疗三阴性乳腺癌。

IF 6.1 2区生物学

Apoptosis Pub Date : 2024-10-12 DOI: 10.1007/s10495-024-02023-7

Bidyadhar Sethy, Richa Upadhyay, Iin Narwanti, Zih-Yao Yu, Sung-Bau Lee, Jing-Ping Liou

{"title":"Novel dual inhibitor targeting CDC25 and HDAC for treating triple-negative breast cancer","authors":"Bidyadhar Sethy, Richa Upadhyay, Iin Narwanti, Zih-Yao Yu, Sung-Bau Lee, Jing-Ping Liou","doi":"10.1007/s10495-024-02023-7","DOIUrl":"10.1007/s10495-024-02023-7","url":null,"abstract":"<div>Triple-negative breast cancer (TNBC) presents a significant challenge for treatment due to its aggressive nature and the lack of effective therapies. This study developed dual inhibitors against cell division cycle 25 (CDC25) and histone deacetylases (HDACs) for TNBC treatment. CDC25 phosphatases are crucial for activating cyclin-dependent kinases (CDKs), the master regulators of cell cycle progression. HDACs regulate various biological processes by deacetylating histone and non-histone proteins, affecting gene expression, chromatin structure, cell differentiation, and proliferation. Dysregulations of HDAC and CDC25 are associated with several human malignancies. We generated a group of dual inhibitors for CDC25 and HDAC by combining the molecular structures of CDC25 (quinoline-5,8-dione) and HDAC (hydroxamic acid or benzamide) pharmacophores. The newly developed compounds were evaluated against various solid-tumor, leukemia, and non-malignant breast epithelial cells. Among the synthesized compounds, 18A emerged as a potent inhibitor, demonstrating significant cytotoxicity against TNBC cells, superior to its effects on other cancer types while sparing non-malignant cells. 18A possessed similar HDAC inhibitory activity as MS-275 and potently suppressed CDC25 activity in vitro and the CDK1 dephosphorylation in cells. Additionally, 18A hindered the progression of S and G2/M phases, triggered DNA damage, and induced apoptosis. These findings underscore the potential of 18A as a targeted therapy for TNBC and warrants further preclinical development.<h3>Graphical Abstract</h3><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"29 11-12","pages":"2047 - 2073"},"PeriodicalIF":6.1,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0