CANCER LETTERS
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2026
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IF 11.8
Yi-Yang Gao,Kang-Liang Lou,Lin-Ling Lin,Cheng-Xi Li,Sheng-Jie Lin,Yi-Xin Chen,Hong-Yu Chen,Jing-Wen Bai,Guo-Jun Zhang
The evaluation of therapeutic response to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer currently relies on anatomical imaging, which suffers from significant delays. To enable early and direct visualization of drug activity, we developed a near-infrared-II (NIR-II) fluorescent molecular probe, HSA-ICi, by conjugating a CDK4/6 inhibitor (Palbociclib or Ribociclib) with ICG and facilitating its self-assembly with human serum albumin. This probe demonstrated specific targeting to the CDK4/6-cyclin D complex, excellent biocompatibility, and high tumor accumulation in preclinical models. Crucially, HSA-ICi allowed non-invasive monitoring of pharmacodynamic response: a significant decrease in tumor fluorescence signal was detected via NIR-II imaging as early as one week after treatment initiation, preceding any measurable change in tumor volume by caliper or magnetic resonance imaging (MRI). This early signal reduction correlated with decreased pRB and Ki-67 expression in tumor tissues. Furthermore, the probe could distinguish between CDK4/6 inhibitor-sensitive and -resistant tumors, with resistant models showing a consistently low baseline signal. Our findings establish HSA-ICi as a promising tool for the early assessment of therapeutic efficacy and the identification of resistance, potentially facilitating timely treatment adaptation for patients with HR+/HER2- breast cancer.
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高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2022
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IF 5.062
Yan Wang,Chen Zhang,Meng Xiao,Kumar Ganesan,Fei Gao,Qingqing Liu,Zhen Ye,Yue Sui,Feng Zhang,Kunhua Wei,Yaobin Wu,Jianmin Wu,Bing Du,Cong Xu,Yan Li,Peng Li,Jinming Zhang,Jianping Chen
Treatment of aggressive triple-negative breast cancer (TNBC) is still challenging. Isoliquiritigenin (ISL) is a water-insoluble bioactive compound possessing high anti-TNBC capacity with less toxicity. The present study aimed to develop a safe and effective oral drug delivery system to improve the oral efficacy of ISL for TNBC therapeutics. ISL-loaded zein phosphatidylcholine hybrid nanoparticles ( [email protected] NPs) were constructed by a one-step solvent evaporation method. Optimization and characterization of [email protected] NPs were performed. Cellular uptake in vitro and biodistribution of ZLH NPs in vivo were investigated. The pharmacokinetics of [email protected] NPs in terms of ISL content in the plasma, organs, and tumor tissues were validated, and the anti-TNBC efficacy was evaluated. Encapsulation efficiency (96.75 ± 1.41%) and drug loading efficiency (6.56 ± 0.83%) were found in [email protected] NPs. [email protected] NPs were able to enhance the absorption of ISL in the tumor sites. Moreover, the upregulation of p27 and downregulation of EGFR and CDK4 were observed in [email protected] NPs treated tumors. Collectively, oral intake of [email protected] NPs would be translated into a potential clinical therapy strategy against TNBC.
研究领域:
肿瘤学
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药剂学
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纳米技术
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分子生物学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
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IF 5.4
Yifei Wang,Xiaolong Wang,Wenhao Li,Hanwen Huang,Chenyu Di,Qifeng Yang
Ethnopharmacological relevance Trametes robiniophila Murr (Huaier), a traditional Chinese medicine (TCM), has shown promising effects as a complementary therapy in the treatment of multiple kinds of cancers. Aim of the study This study aimed to systematically evaluate whether Huaier could enhance the antitumor effects of palbociclib, a highly selective CDK4/6 inhibitor. Materials and methods A breast cancer xenograft mouse model was constructed to assess the anticancer effects of Huaier and palbociclib. Transcriptomic analysis was performed to identify the differentially expressed genes and associated pathways. Flow cytometry, immunofluorescence and immunohistochemical staining were then conducted to observe the infiltration of immune cells in the tumor microenvironment (TME). The composition of the gut microbiota was explored through 16S rDNA sequencing, and a pseudosterile mouse model was established to verify the contribution of the gut microbiota to the antitumor effects of Huaier and palbociclib. Results Oral administration of Huaier enhanced the antitumor effects of palbociclib in breast cancer. Transcriptomic analysis of tumor tissues revealed that the differentially expressed genes were related to immune functions. Indeed, the addition of Huaier to palbociclib therapy further increased the ratio of CD8 + /CD3 + T cells and the abundance of GzmB + CD8 + T cells in the TME. Mechanistically, sequencing of 16S rDNA revealed that Huaier reshaped the gut microbiota composition in favor of Akkermansia , which positively modulated antitumor immune responses. The pseudosterile mouse model verified the necessity of the gut microbiota for the synergistic effect of Huaier on palbociclib. Furthermore, butyrate, a metabolite of Akkermansia , synergized with palbociclib to suppress tumor progression and promote the infiltration of CD8 + T cells in the TME. Conclusions Our data suggested that Huaier augmented the antitumor effects of palbociclib by increasing the abundance of Akkermansia in gut microbiota, which contributed to the enhancement of anti-tumor immunity. Consequently, combining palbociclib with Huaier may serve as a promising strategy for the treatment of breast cancer.
研究领域:
肿瘤学
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药理学
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免疫学
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微生物学
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中医学
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转录组学
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PubMed
高影响因子
Frontiers in Oncology
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2022
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IF 5.738
Li Tian,Zhou An-Di,Bai Li-Fei,Zhang Xiao-Yang,Zhou Yu-Ting,Yang Hai-Li,Xu Le-Tian,Guo Xin-Qin,Zhu Xi-Yu,Wang Dong-Jin,Gu Hong-Wei,Wang Xiao-Ming
Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives.
研究领域:
肿瘤学
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药物化学
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药物设计
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高影响因子
OncoTargets and Therapy
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2022
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IF 4.345
Yue Jing,Gang Wang,Ying Ge,Minjie Xu,Shuainan Tang,Zhunan Gong
Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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高影响因子
LABORATORY INVESTIGATION
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2022
·Vol. 102
·期 5
·494-504
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IF 5.502
Tao Lianyuan,Li Deyu,Mu Sengmao,Tian Guanjing,Yan Guoyi
We explored the biological role of long non-coding RNA (lncRNA) MAPKAPK5_AS1 (MAAS) and the mechanism of its differential expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Differentially expressed lncRNAs in HBV-related HCC were determined using bioinformatics analysis. Gain-of-function experiments were conducted to evaluate the effect of MAAS on cell proliferation. A xenograft model was established for in vivo experiments. Dual-luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and methylated RNA immunoprecipitation were performed to elucidate the underlying molecular mechanisms. MAAS was upregulated in HBV-related HCC cancerous tissues and its high expression was closely related to the poor survival probability of patients. Functional assays revealed that MAAS overexpression facilitated the proliferation of HBV + HCC cells in vitro and in vivo. Mechanistically, MAAS promoted the MYC proto-oncogene (c-Myc)-induced transcriptional activation of cyclin-dependent kinase 4 (CDK4), CDK6, and S-phase kinase associated protein 2 via stabilizing c-Myc protein, thereby facilitating G1/S transition. The latter contributed to the paradoxical proliferation of HBV + HCC cells. Although MAAS was upregulated in HBV-related HCC cancerous tissues, it was highly expressed in M2 macrophages, a major phenotype of tumor-associated macrophages in HBV-related HCC, instead of in HBV + HCC cells. HBeAg, an HBV-associated antigen, further elevated the MAAS level in M2 macrophages by enhancing the methyltransferase-like 3-mediated N6-methyladenosine modification of MAAS. The increased MAAS in the M2 macrophages was then transferred to HBV + HCC cells through the M2 macrophage-derived exosomes, promoting cell proliferation. Our findings show that HBV + HCC cell-secreted HBeAg upregulates MAAS expression in M2 macrophages by affecting its m 6 A modification. The upregulated MAAS is then transferred to HBV + HCC cells via exosomes, facilitating the proliferation of HBV + HCC cells by targeting c-Myc.
研究领域:
分子生物学
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肿瘤学
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病毒学
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细胞生物学
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2018
·Vol. 42
·期 1
·61-70
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IF 2.784
Yuhuan Ma,Wenwei Zheng,Houhuang Chen,Xiang Shao,Pingdong Lin,Xianxiang Liu,Xihai Li,Hongzhi Ye
The present study investigated the mechanism underlying the effects of glucosamine (GlcN) on the proliferation of chondrocytes isolated from the knee cartilage of Sprague‑Dawley rats. Chondrocytes were treated with various concentrations of GlcN or without GlcN. The effects of GlcN on chondrocyte proliferation were determined using reverse transcription‑polymerase chain reaction, western blot analysis and immunohistochemistry. The results indicated that GlcN significantly improved chondrocyte viability, accelerated G1/S transition during progression of the cell cycle and promoted the expression of cell cycle regulatory proteins, including cyclin D1, cyclin‑dependent kinase (CDK)4 and CDK6, thus indicating that GlcN may promote chondrocyte proliferation. Furthermore, GlcN upregulated the expression levels of Wnt‑4, Frizzled‑2 and β‑catenin, and downregulated the expression of glycogen synthase kinase‑3. GlcN also promoted β‑catenin translocation; β‑catenin is able to activate numerous downstream target genes, including cyclin D1. To determine the role of the Wnt/β‑catenin signaling pathway in chondrocyte proliferation, the Wnt/β‑catenin signaling pathway was inhibited using Dickkopf‑1 (DKK‑1), after which chondrocytes were treated with GlcN. The results demonstrated that the expression levels of β‑catenin and cyclin D1 were decreased in chondrocytes treated with DKK‑1 and GlcN. These results suggested that GlcN may promote chondrocyte proliferation via the Wnt/β‑catenin signaling pathway.
研究领域:
药理学
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细胞生物学
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分子生物学
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高影响因子
CHEMOSPHERE
·
2023
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IF 8.8
Zhen-Ning Zhang,Dan-Lei Yang,Hai Liu,Jue Bi,Ya-Bo Bao,Jiao-Yang Ma,Qin-Xiang Zheng,Dao-Lei Cui,Wei Chen,Ping Xiang
Tris(2-chloroisopropyl) phosphate (TCPP) and Tris(2-chloroethyl) phosphate (TCEP) are the widely used organophosphorus flame retardants indoors and easily accessible to the eyes as the common adhesive components of dust and particle matter, however, hardly any evidence has demonstrated their corneal toxicity. In this study, the adverse effects of TCPP, TCEP, and TCPP + TCEP exposure on human corneal epithelial cells (HCECs) were investigated. The cell viability and morphology, intracellular reactive oxygen species (ROS), cell cycle, and the expressions of cell cycle and pyroptosis-related genes were assessed to explain the underlying mechanisms. Compared to individual exposure, co-exposure to TCPP 20 +TCEP 20 showed higher cytotoxicity with a sharp decrease of >30% in viability and more serious oxidative damage by increasing ROS production to 110.92% compared to the control group. Furthermore, the cell cycle arrested at the S phase (36.20%) was observed after combined treatment, evidenced by the upregulation of cyclin D1 , CDK2 , CDK4 , CDK6 , p21, and p27 . Interestingly, pyroptosis-related genes GSDMD , Caspase-1 , NLRP3 , IL-1β , IL-18 , NLRP1, and NLRC4 expressions were promoted with cell swelling and glowing morphology. Oxidative stress and cell cycle arrest probably acted as a key role in TCPP 20 +TCEP 20 -induced cytotoxicity and pyroptosis in HCECs. Our results suggested that TCPP 20 +TCEP 20 co-exposure induced severer corneal damage, further illustrating its significance in estimating indoor health hazards to humans.
研究领域:
毒理学
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细胞生物学
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眼科学
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环境健康
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高影响因子
ACS Nano
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2022
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IF 18.027
Xue-Feng Bai,Ying Chen,Mei-Zhen Zou,Chu-Xin Li,Yu Zhang,Min-Jie Li,Si-Xue Cheng,Xian-Zheng Zhang
Recent advances in tumor immunotherapy mainly tend to remodel the immunosuppressive tumor microenvironment (TME) for immune enhancement. However, the complexity of TME makes it unlikely to achieve satisfactory therapeutic effects with any single intervention alone. Here, we focus on exposing intrinsic features of tumor cells to trigger direct pleiotropic antitumor immunity. We develop a photosensitive nanointerferer that is engineered with a nanoscale metal–organic framework decorated with tumor cell membranes for targeted delivery of a photosensitizer and small interfering RNA, which is used to knock down cyclin-dependent kinase 4 (Cdk4). Cdk4 blockade can arrest the cell cycle of tumor cells to facilitate antigen exposure and increase the expression level of programmed cell death protein ligand 1 (PD-L1). Under laser irradiation, photodynamic damage triggered by the nanointerferer induces the release of tumor antigens and recruitment of dendritic cells (DCs), thereby promoting the antitumor activity of CD8+ T cells in combination with anti-PD-L1 antibodies. Ultimately, these events markedly retard tumor progression in a mouse model of ectopic colon tumor with negligible adverse effects. This study provides an alternative treatment for effective antitumor immunity by exciting the intrinsic potential of tumor cells to initiate immune responses while reducing immune-related toxicities.
研究领域:
癌症免疫疗法
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纳米技术
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光动力治疗
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分子生物学
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免疫学
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高影响因子
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