Frontiers in Pharmacology
·
2023
·
IF 5.6
Zhang Hua,Yan Shu,Zhan Yan,Ma Sheng,Bian Yicong,Li Shaorong,Tian Junjun,Li Guangze,Zhong Dafang,Diao Xingxing,Miao Liyan
SHR6390 (dalpiciclib) is a selective and effective cyclin-dependent kinase (CDK) 4/6 inhibitor and an effective cancer therapeutic agent. On 31 December 2021, the new drug application was approved by National Medical Product Administration (NMPA). The metabolism, mass balance, and pharmacokinetics of SHR6390 in 6 healthy Chinese male subjects after a single oral dose of 150 mg [14C]SHR6390 (150 µCi) in this research. The Tmax of SHR6390 was 3.00 h. In plasma, the t1/2 of SHR6390 and its relative components was approximately 17.50 h. The radioactivity B/P (blood-to-plasma) AUC0-t ratio was 1.81, indicating the preferential distribution of drug-related substances in blood cells. At 312 h after administration, the average cumulative excretion of radioactivity was 94.63% of the dose, including 22.69% in urine and 71.93% in stool. Thirteen metabolites were identified. In plasma, because of the low level of radioactivity, only SHR6390 was detected in pooled AUC0-24 h plasma. Stool SHR6390 was the main component in urine and stool. Five metabolites were identified in urine, and 12 metabolites were identified in stool. Overall, faecal clearance is the main method of excretion.
研究领域:
药理学
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药物代谢动力学
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肿瘤学
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DOI
PubMed
高影响因子
Nanoscale
·
2023
·
IF 6.7
Xia Zhang,Like Ning,Hongshuai Wu,Wenhong Wang,Suisui Yang,Ziyi Hu,Yuandong Cao,Hongliang Xin,Chaoqun You,Fan Lin
Despite aggressive treatments, including surgery, chemo- and radio-therapy, the prognosis of glioblastoma (GBM) remains poor and tumor recurrence is inevitable. The FDA-approved CDK4/6 inhibitor palbociclib (PB) showed interesting anti-GBM effects, but its brain penetration is limited by the blood-brain barrier. The hypothesis of this project is to find whether the cellulose-based hydrogel via in situ injection could provide an alternative route of PB brain delivery and generate sufficient drug exposure in orthotopic GBM. In brief, PB was encapsulated in a cellulose nanocrystal network structure crosslinked by polydopamine via divalent Cu2+ and hexadecylamine. The formed hydrogel (PB@PH/Cu-CNCs) exhibited sustained drug retention and acid-responsive network de-polymerization for controlled release in vivo. Specifically, the released Cu2+ catalyzed a Fenton-like reaction to generate reactive oxygen species (ROS), which was further enhanced by PB, and consequently induced irreversible senescence and apoptosis in GBM cells. Finally, PB@PH/Cu-CNCs demonstrated a more potent anti-GBM effect than those treated with free PB or PH/Cu-CNCs (drug-free hydrogel) in cultured cells or in an orthotopic glioma model. These results prove that the injection of PB-loaded hydrogel in situ is an effective strategy to deliver CDK4/6 inhibitor into the brain and its anti-GBM effect can be further enhanced by combining Cu2+-mediated Fenton-like reaction.
研究领域:
肿瘤学
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药学
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生物医学工程
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神经科学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Yuxiao Fang,Zipeng Zhang,Yang Liu,Tong Gao,Shuang Liang,Qihui Chu,Li Guan,Weiwei Mu,Shunli Fu,Huizhen Yang,Na Zhang,Yongjun Liu
In recent years, therapeutic strategies based on macrophages have been inspiringly developed, but due to the high intricacy and immunosuppression of the tumor microenvironment, the widespread use of these strategies still faces significant challenges. Herein, an artificial assembled macrophage concept (AB@LM) was presented to imitate the main antitumor abilities of macrophages of tumor targeting, promoting the antitumor immunity, and direct tumor-killing effects. The artificial assembled macrophage (AB@LM) was prepared through an extrusion method, which is to fuse the macrophage membrane with abemaciclib and black phosphorus quantum dot (BPQD)-loaded liposomes. AB@LM showed good stability and tumor targeting ability with the help of macrophage membrane. Furthermore, AB@LM reversed the immunosuppressive tumor microenvironment by inhibiting regulatory T cells (Tregs) and stimulating the maturation of antigen-presenting cells to activate the antitumor immune response through triggering an immunogenic cell death effect. More importantly, in the colorectal tumor model in vivo, a strong cooperative therapeutic effect of photo/chemo/immunotherapy was observed with high tumor inhibition rate (95.3 ± 2.05%). In conclusion, AB@LM exhibits excellent antitumor efficacy by intelligently mimicking the abilities of macrophages. A promising therapeutic strategy for tumor treatment based on imitating macrophages was provided in this study.
研究领域:
癌症研究
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纳米技术
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免疫学
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药学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
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IF 10.5
Borui Zhao,Xuan Qin,Rui Fu,Maosen Yang,Xin Hu,Shaorong Zhao,Yange Cui,Qingxiang Guo,Wei Zhou
Chemoresistance to cisplatin remains a significant challenge affecting the prognosis of advanced oral squamous cell carcinoma (OSCC). However, the specific biomarkers and underlying mechanisms responsible for cisplatin resistance remain elusive. Through comprehensive bioinformatic analyses, we identified a potential biomarker, BCL2 associated athanogene-1 (BAG1), showing elevated expression in head and neck squamous cell carcinoma (HNSCC). Since OSCC represents the primary pathological type of HNSCC, we investigated BAG1 expression in human tumor tissues and cisplatin resistant OSCC cell lines, revealing that silencing BAG1 induced apoptosis in cisplatin-resistant cells both in vitro and in vivo . This effect led to impaired cell viability of cisplatin resistant OSCC cells and indicated a positive correlation between BAG1 expression and the G1/S transition during cell proliferation. Based on these insights, the administration of a CDK4/6 inhibitor in combination with cisplatin effectively overcame cisplatin resistance in OSCC through the CDK4/6-BAG1 axis. Additionally, to enable simultaneous drug delivery and enhance synergistic antitumor efficacy, we developed a novel supramolecular nanodrug LEE011-FFERGD/CDDP, which was validated in an OSCC orthotopic mouse model. In summary, our study highlights the potential of a combined administration of CDK4/6 inhibitor and cisplatin as a promising therapeutic regimen for treating advanced or cisplatin resistant OSCC.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Sun Chao-Yue,Talukder Milton,Cao Di,Chen Cun-Wu
Abemaciclib is a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor approved for the treatment of metastatic breast cancer. Preclinical studies suggest that abemaciclib has the potential for lung cancer treatment. However, several clinical trials demonstrate that monotherapy with abemaciclib has no obvious superiority than erlotinib to treat lung cancer patients, limiting its therapeutic options for lung cancer treatment. Here, we show that the US Food and Drug Administration (FDA)-approved drug, gilteritinib, enhances the cytotoxicity of abemaciclib through inducing apoptosis and senescence in lung cancer cells. Interestingly, abemaciclib in combination with gilteritinib leads to excessive accumulation of vacuoles in lung cancer cells. Mechanistically, combined abemaciclib and gilteritinib induces complete inactivation of AKT and retinoblastoma (Rb) pathways in lung cancer cells. In addition, RNA-sequencing data demonstrate that combination of abemaciclib and gilteritinib treatment induces G2 phase cell-cycle arrest, inhibits DNA replication, and leads to reduction in homologous recombination associated gene expressions. Of note, abemaciclib-resistant lung cancer cells are more sensitive to gilteritinib treatment. In a mouse xenograft model, combined abemaciclib and gilteritinib is more effective than either drug alone in suppressing tumor growth and appears to be well tolerated. Together, our findings support the combination of abemaciclib with gilteritinib as an effective strategy for the treatment of lung cancer, suggesting further evaluation of their efficacy is needed in a clinical trial.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
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IF 8.7
Qiyuan Luo,Shiqiang Li,Chenglong Zhang,Yijing Chen,Yun Chen
ALP1 is a structurally defined polysaccharide isolated from Amomum villosum T.L. Wu fruits with an average molecular weight of 26.1 kDa. Previous studies have demonstrated that ALP1 promotes growth performance of piglet by regulating proliferation of intestinal epithelial cells. However, the molecular mechanism remains incompletely understood. In the present study, the absorbability of ALP1 by porcine small intestine epithelial cells and regulating mechanism of ALP1 on cell proliferation were investigated. The results showed that ALP1 resists gastrointestinal degradation and is efficiently absorbed by intestinal epithelial cells via endocytosis. Furthermore, ALP1 facilitates cell cycle progression through upregulating expressions of cdk4 and cyclin e , resulting in an increased proportion of cells in the S and G2/M phases. These findings provide insights into the cellular mechanisms underlying the growth-promoting effects of ALP1 and highlight the potential of dietary polysaccharides as functional agents for enhancing animal growth and gut health.
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产品关联
DOI
PubMed
高影响因子
Science China-Life Sciences
·
2025
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IF 9.5
Liu Yaqi,Wang Yalei,Zhang Ni,Xiong Haijuan,Zhao Lipan,Qi Ying,Xie Jiping,Duan Xiaofeng,Yue Dongsheng,Qie Shuo
The hyperactivation of cyclin D1-CDK4/6 signaling is correlated with tumour metastasis and poor prognosis in patients with non-small cell lung cancer (NSCLC), suggesting the therapeutic potential of targeting CDK4/6 to treat NSCLC. Our preliminary data indicate CDK4/6 inhibitors are sequestered in lysosomes in NSCLC cells, a phenomenon that is termed lysosomal trapping and is associated with intrinsic drug resistance. It is promising to search for new compounds that could be co-administered with CDK4/6 inhibitors to reduce lysosomal trapping, thereby enhancing the sensitivity of NSCLC cells. Here, we find that metformin reduces the activity of the lysosomal pathway through genome-wide analyses; consistently, metformin reduces lysosomal trapping of CDK4/6 inhibitors in NSCLC cells. Biologically, metformin enhances the suppressive effects of CDK4/6 inhibitors on cell cycle progression, cell proliferation, and colony formation. Mechanistically, metformin suppresses lysosomal trapping by: (i) reducing translocation of TFEB into nuclei that leads to decreased lysosome biogenesis and (ii) disrupting lysosomal acidic environment through reduced V-ATPase activity and decreased interaction between LAMP1/LAMP2 and TMEM175. Clinically, combined treatment with metformin and CDK4/6 inhibitors decreased the growth of mouse xenografts and tumour cell organoids. In conclusion, our study provides a new mechanism for utilizing metformin to treat NSCLC by reducing lysosomal trapping, thereby increasing cellular sensitivity to CDK4/6 inhibitors.
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DOI
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 3
·1228
·
IF 4.9
Ruifang Guo,Yihang Wang,Aiwen Zhang,Siwanon Jirawatnotai,Chen Chu,Lijun Liu
Beyond their canonical role in promoting G1/S progression, the complexes formed by cyclin D and cyclin-dependent kinase (CDK) 4/6 have emerged as contributors to enhanced cell migration. However, a direct link between this complex and cytoskeletal remodeling during cell motility has remained poorly understood. Here, we show that CDK4/6 inhibition in HeLa cells disrupts lamellipodia formation and subsequent focal adhesion assembly, leading to a reduction in cell migration and invasion. Notably, CDK4, but not CDK6, in complex with cyclin D1/D2, localizes to membrane ruffles to facilitate cytoskeletal reorganization. Mechanistically, proteomic and phosphoproteomic analyses revealed that CDK4 inhibition attenuates the transforming growth factor β (TGFβ) pathway via reduced Smad3 phosphorylation at Thr8, downregulating integrin subunits (α5, α6, and β1). Furthermore, CDK4 inhibition significantly decreased focal adhesion kinase (FAK) phosphorylation at Tyr397 and Rac1-GTP levels. Importantly, the resulting migration defect was largely restored by activation of either Rac1 or FAK. Thus, our data support a model in which cyclin D1/D2–CDK4 promotes phosphorylation of Smad3, leading to upregulation of integrin subunits, activation of FAK and Rac1, and consequent lamellipodia formation and cell migration. These findings provide direct evidence that CDK4 regulates actin cytoskeletal reorganization during cell migration and suggest that CDK4/6 inhibitors may dampen cytoskeleton-dependent tumor invasion, in addition to their antiproliferative effects.
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DOI
PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 13
·5047
·
IF 4.6
Yan Wang,Youbin Li,Dong Liu,Danyang Zheng,Xiaogang Li,Chang Li,Caihui Huang,Yun Wang,Xuesong Wang,Qifu Li,Junyu Xu
Glioblastoma (GBM) is a deadly brain tumor characterized by signaling dysregulation and aberrant cell cycle control. The CDK4/6-Rb axis is dysregulated in approximately 80% of all GBM cases. In this study, the anti-GBM effect of a novel pyrimidin-2-amine, LH20 was evaluated in vitro using the primary GBM cell lines U87MG and U251. GBM cells were administered LH20 at concentrations of 0.1, 1, 4, 8, 10, 20, 100, and 200 µM for 24 and 48 h, and the proliferation rate was evaluated using a CCK8 assay. Migration, apoptosis, and cell cycle were also assessed using a wound healing assay, Annexin V-FITC/PI apoptosis assay, and cell cycle staining, respectively. The targets of LH20 were predicted using SwissTargetPrediction and molecular docking. Western blotting analysis was performed to confirm the anti-GBM mechanism of LH20. We found that at concentrations of 4, 8, and 10 µM, LH20 significantly inhibited the proliferation and migration of U87MG and U251 cells, induced late phase apoptosis, promoted tumor cell necrosis, and arrested the G2/M phase of the cell cycle. LH20 also inhibited CDK4 and CDK6 activities by decreasing the phosphorylation of Rb. Our results suggest LH20 as a potential treatment strategy against GBM.Keywords:LH20;glioblastoma;apoptosis;G2/M;mitochondrial;CDKs
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF MATERIALS SCIENCE
·
2019
·Vol. 55
·期 4
·1702-1714
·
IF 3.442
Shao Qi,Feng Yechen,Wang Wenwu,Wang Min,Li Binbin,El Tahchi Mario,Yin Yixia
Chemotherapeutic drugs have shown some limitations in anti-tumor treatment, such as drug resistance, high toxicity and limited regime of clinical uses. Natural products have attracted extensive attention as potential source of unmodified chemical compounds for disease treatment. Withaferin A (WA) has the potential to inhibit multiple human tumors, but it is hardly available for oral administration due to its low water solubility and its side effects. We developed a methoxy poly(ethylene glycol) (mPEG) conjugated poly( d , l -lactide- co -glycolide) (PLGA) drug carrier particles to encapsulate WA for pancreatic cancer treatment. The results showed that WA does not lose its physicochemical properties after encapsulation, and our drug carriers are completely degraded within 1 month. We used the WA-loaded mPEG–PLGA particles for pancreatic cancer cell treatment where it exhibited stronger inhibition than free drug (WA) at the early treatment stage. Our formulation of the drug carriers provides an efficient encapsulation of WA that allows it bonding with heat shock proteins, thereby reducing the expression of AKT and CDK4 proteins to induce apoptosis in cancer cells. Together, our data demonstrate that mPEG–PLGA loaded with WA can achieve the design goals for cancer therapy given its advantages of sustained release and degradation property to reduce the side effect of WA, which provides a possibility for WA to be used in clinical applications.
研究领域:
药学
·
肿瘤学
·
生物医学工程
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产品关联
DOI
高影响因子
Molecular Metabolism
·
2025
·
IF 6.6
Zheng Ge,Zitian Liu,Shuohui Dong,Xiang Zhao,Guangwei Yang,Ao Yu,Wei Guo,Xiang Zhang,Qunzheng Wu,Kexin Wang
High-fat diet (HFD) promotes adipose tissue senescence, which in turn disrupts insulin-mediated glycemic homeostasis. The underlying mechanisms remain unclear. Through clinical survey data, animal models, and primary adipose-derived mesenchymal stem cells (ADSC), we investigated how dietary patterns influence adipocyte senescence. We found that elevated fatty acid levels enhance the interaction between the E3 ubiquitin ligase TRIP12 and Cyclin-dependent kinase 4 (CDK4) in ADSCs, triggering CDK4 ubiquitination and degradation. As a process associated with this disruption in cell cycle progression, cellular senescence may represent a key outcome. Consequently, senescent ADSC-derived mature adipocytes (ADSC-MA) exhibit impaired insulin-stimulated GLUT4 membrane translocation and reduced glucose uptake. In contrast, within an HFD setting, dietary fiber supplementation is associated with the reversal of cellular senescence. The gut microbiota–short-chain fatty acids (SCFAs) axis may be involved in the restoration of cell cycle progression and the amelioration of ADSC senescence, correlating with a partial recovery of glucose uptake capacity in ADSC-MAs. Our study highlights potential strategies to reverse cellular senescence and identifies promising therapeutic targets for impaired glucose tolerance.
研究领域:
内分泌学
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细胞生物学
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代谢学
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分子生物学
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营养科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY
·
2024
·
IF 3.9
Shao-Liang Jiang,Wang-Cai Chen,Yu-Ting Wu,Huan-Yu Sui,Dong Chen,Li Li,Tao Wu,Jie-Hua Shi
Ribociclib (RIB), a tyrosine kinase inhibitor, exhibits promising antitumor efficacy and controlled toxicity in HR+/HER2- breast cancer patients, which is closely related to the binding with plasma proteins. This study utilized a combination of spectroscopic techniques including UV spectroscopy, fluorescence spectroscopy, and circular dichroism (CD) as well as molecular docking and molecular dynamic simulation to clarify the binding mechanism between bovine serum albumin (BSA) and RIB. The findings demonstrated that RIB produced a 1:1 stoichiometric complex with BSA, which quenched BSA's fluorescence in the manner of the static quenching mechanism. Site labelling experiments pinpointed Site III on BSA as the primary binding site for RIB, a finding validated by molecular docking. Van der Waals forces and hydrogen bonding interactions as key drivers in the formation of RIB-BSA complexes, a conclusion supported by molecular docking. Molecular simulation studies suggested that the insertion of RIB into the hydrophobic cavity (Site III) of BSA induced subtle conformational changes in the BSA protein, and CD measurements confirmed alterations in BSA secondary structure content. Synchronous and three-dimensional fluorescence spectroscopy further demonstrated that RIB decreased the hydrophobicity of the microenvironment surrounding tyrosine and tryptophan residues. These findings offer valuable insights into the pharmacokinetics and structural modifications of RIB.
研究领域:
药理学
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生物化学
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计算生物学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）