FASEB JOURNAL
·
2021
·Vol. 35
·期 10
·e21923
·
IF 5.192
Peiling Wang,Xiangmei Hua,Yang Sun,Hongyu Li,Yuge Han Bryner,Richard P. Hsung,Jun Dai
Our recent studies have shown that haspin, a protein kinase imperative for mitosis, is engaged in the interphase progression of HeLa and U2OS cancer cells. In this investigation, we employed the Fucci reporter system and time-lapse imaging to examine the impact of haspin gene silencing on cell cycle progressions at a single-cell level. We found that the loss of haspin induced multiple cell cycle defects. Specifically, the S/G2 duration was greatly prolonged by haspin gene depletion or inhibition in synchronous HeLa cells. Haspin gene depletion in asynchronous HeLa and U2OS cells led to a similarly protracted S/G2 phase, followed by mitotic cell death or postmitotic G1 arrest. In addition, haspin deficiency resulted in robust induction of the p21 CIP1/WAF1 checkpoint protein, a target of the p53 activation. Also, co-depleting haspin with either p21 or p53 could rescue U2OS cells from postmitotic G1 arrest and partially restore their proliferation. These results substantiate the haspin's capacity to regulate interphase and mitotic progression, offering a broader antiproliferative potential of haspin loss in cancer cells.
研究领域:
癌症生物学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FEBS Open Bio
·
2021
·Vol. 11
·期 5
·1440-1451
·
IF 2.693
Tianyu Wu,Sichun Zhou,Mei Qin,Jing Tang,Xinjian Yan,Lingli Huang,Meiyuan Huang,Jun Deng,Di Xiao,Xin Hu,Jingtao Wu,Xiaoping Yang,Gaofeng Li
Inhibitors of ataxia – telangiectasia mutated (ATM), such as KU-55933 (Ku), represent a promising class of novel anticancer drugs. In addition, the biguanide derivative phenformin exhibits antitumor activity superior to that of the AMPK activator metformin. Herein, we assessed the potential combinatorial therapeutic efficacy of phenformin and Ku when used to inhibit the growth of liver cancer cells, and we assessed the mechanisms underlying such efficacy. The Hep-G2 and SMMC-7721 liver cancer cell lines were treated with phenformin and Ku either alone or in combination, after which the impact of these drugs on cellular proliferation was assessed via 3-(4,5-dimethylthiazol) 2, 5-diphenyltetrazolium and colony formation assays, whereas Transwell assays were used to gauge cell migratory activity. The potential synergy between these two drugs was assessed using the CompuSyn software, while flow cytometry was employed to evaluate cellular apoptosis. In addition, western blotting was utilized to measure p-ATM, p-AMPK, p-mTOR, and p-p70s6k expression, while mitochondrial functionality was monitored via morphological analyses, JC-1 staining, and measurements of ATP levels. Phenformin and Ku synergistically impacted the proliferation, migration, and apoptotic death of liver cancer cells. Together, these compounds were able to enhance AMPK phosphorylation while inhibiting the phosphorylation of mTOR and p70s6k. These data also revealed that phenformin and Ku induced mitochondrial dysfunction as evidenced by impaired ATP synthesis, mitochondrial membrane potential, and abnormal mitochondrial morphology. These findings suggest that combination treatment with phenformin and Ku may be an effective approach to treating liver cancer via damaging mitochondria within these tumor cells.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY
·
2019
·Vol. 30
·期 9
·1814-1824
·
IF 1.335
Zhao Jiao,Zhou Yifang,Zhang Yi,Wang Baoling,Ge Dandan
A novel method for the determination of aflatoxins B1, B2, G1, and G2 (AFB1, AFB2, AFG1, AFG2) in animal feed samples based on magnetic solid-phase cleanup and novel pre-column derivatization has been developed. In this work, synthesized polyvinylpyrrolidone-coated Fe3O4 magnetic nanoparticles were applied as adsorbents for rapid cleanup for extracts of animal feed samples. The purified extract was then derivatized with trifluoroacetic acid coupling ultraviolet irradiation which enabled the weakly fluorescent AFB1 and AFG1 transformed into their highly fluorescent hemiacetals derivatives. Afterward aflatoxins were separated and quantified by reverse phase liquid chromatography with fluorescence detection. The results indicated that four AFs presented excellent linear response with correlation coefficients > 0.996 and recoveries ranged from 86.7 to 108.9% with relative standard deviations (RSDs) from 3.6 to 6.4%. The limits of detection (LODs) were 0.0392, 0.2429, 0.0842, 0.4556 ng mL-1 for AFB1, AFB2, AFG1 and AFG2, respectively.
研究领域:
食品安全
·
分析化学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2015
·
IF 3.65
Lejiao Jia,Zhenyu Li,Jingyi Shen,Dandan Zheng,Xiaona Tian,Hejian Guo,Ping Chang
The objective of the study is to fabricate multifunctional mesoporous silica nanoparticles for achieving co-delivery of conventional antitumor drug paclitaxel (PTX) and the multidrug resistance reversal agent tetrandrine (TET) expecting to overcome multidrug resistance of MCF-7/ADR cells. The nanoparticles were facile to prepare by self-assemble in situ drug loading approach. Namely, PTX and TET were solubilized in the cetyltrimethylammonium bromide (CTAB) micelles and simultaneously silica resources hydrolyze and condense to form nanoparticles. The obtained nanoparticles, denoted as PTX/TET-CTAB@MSN, exhibited pH-responsive release property with more easily released in the weak acidic environment. Studies on cellular uptake of nanoparticles demonstrated TET could markedly increase intracellular accumulation of nanoparticles. Furthermore, the PTX/TET-CTAB@MSN suppressed tumor cells growth more efficiently than only delivery of PTX (PTX-CTAB@MSN) or the free PTX. Moreover, the nanoparticle loading drugs with a PTX/TET molar ratio of 4.4:1 completely reversed the resistance of MCF-7/ADR cells to PTX and the resistance reversion index was 72.3. Mechanism research showed that both TET and CTAB could arrest MCF-7/ADR cells at G1 phase; and besides PTX arrested cells at G2 phase. This nanocarrier might have important potential in clinical implications for co-delivery of multiple drugs to overcome MDR.
研究领域:
纳米技术
·
药物科学
·
癌症研究
·
药物递送系统
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2014
·
IF 4.787
Yuling Bao,Yuanyuan Guo,Xiangting Zhuang,Dan Li,Bolin Cheng,Songwei Tan,Zhiping Zhang
To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ∼140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration–time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.
研究领域:
药学
·
肿瘤学
·
药物递送系统
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2023
·
IF 3.5
Guiying Wu,Hui Zhong,Ying Wang,Li Chen,Jianbo Sun
A number of NO-releasing quinoline derivatives have been designed and synthesized by introducing NO donor to quinoline carboxylic acid fragment. The anti-proliferation of all target compounds was evaluated against human cancer cell lines (HCT-116, MCF-7, and A549), MCF-7/ADR and normal cell (MCF-10A). Most compounds showed cytotoxic activity on cancer cells and drug-resistant cells with IC 50 values in the range of 0.62–5.51 μM. Importantly, these compounds showed low toxicity to normal cells (4.21–34.08 μM). Further mechanism studies showed that the most potent compound 9 could release high concentration of NO and inhibit the activity of topoisomerase I. In addition, 9 regulated apoptosis-related proteins, generated ROS and blocked MCF-7 cells in G2/M phase to induce cell apoptosis. Furthermore, the P-gp-mediated transport was also influenced by 9 . And 9 could significantly inhibit the growth of tumor in vivo without observable organ-related toxicities. Overall, as a novel NO-releasing quinoline derivative, 9 was worthy for further in-depth study.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2017
·
IF 4.3
Wen-Ting Zhu,Sheng-Yao Liu,Lei Wu,Hua-Li Xu,Jun Wang,Guo-Xin Ni,Qing-Bing Zeng
Background It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future. Materials and methods In this study, CUR-loaded methoxy polyethylene glycol–polylactide (CUR/mPEG–PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently. Results The average size of CUR/mPEG–PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067–0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG–PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG–PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG–PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG–PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax. Conclusion The mPEG–PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG–PLA micelles have promising clinical potential in treating NSCLC.
研究领域:
药学
·
肿瘤学
·
纳米技术
·
药物递送系统
✓ 已验证
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
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Naihan Huang,Xiao-Yan Tang,Wei Meng,Ye-Hua Lai,Xuan Zhou,Xue-Zhao Yu,Wen-Hua Zhang,Jin-Xiang Chen
Due to the immunosuppressive tumor microenvironment (TME) and weak radiation absorption, the immune response triggered by radiation therapy (RT) is limited. Herein, a core–shell nanosensitizer UiO@MnS (denoted as UM) was genuinely constructed for the amplification of RT efficacy and induction of immunogenicity via integrating MnS-reprogrammed TME with Hf-based UiO-sensitized RT. The acid-sensitive MnS would produce H2S under acidic TME to improve oxygenation through inhibition mitochondrial respiration and reducing metabolic oxygen consumption, leading to decreased HIF-1α expression and enhanced radiosensitization. In addition, the generated H2S inhibited the catalase activity to increase the H2O2 level, which subsequently enhanced the Mn2+-mediated Fenton-like reaction, resulting in G2/M cell cycle arrest to improve the cellular sensitivity for radiation. This impressive tumor oxygenation, cell cycle arrest, and radiosensitization procedure boosted RT efficacy and resulted in strong antitumor immunogenicity. Taken together, combining the immunosuppressive TME modulation with a sensitizing radiation strategy shows great promise for magnifying immunogenic RT outputs.
研究领域:
癌症研究
·
纳米技术
·
放射肿瘤学
·
免疫治疗
·
肿瘤微环境
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
·
IF 16.744
Xiaoyang Liang,Ping Liu,Wen Li,Long Binh Vong,Tingting Wang,Lujing Geng,Yue Zhou,Siyu Wang,Qiang Lu,Fengping Tan,Xinxing Wang,Nan Li
Reactive oxygen species (ROS)-mediated cell cycle arrest mechanism shows distinguished potential for the inhibiting of cancer cells. However, poly ADP-ribose polymerase (PARP), an enzyme which can contribute to the repair of single-strand DNA nicks, largely limited the efficiency in cell cycle arrest. Here, polydopamine (PDA)/hyaluronic acid (HA) decorated and protein translation inhibitor homoharringtonine (HHT) loaded tellurium (Te)-prussian blue (PB) nanorods ( [email protected] @PDA-HA/HHT NRs) were synthesized for boosted G2 cell cycle arrest to realize tumor ablation. Under NIR-II irradiation, Te and Fe elements can collectively generate ROS and deplete GSH due to the fenton-like reaction and metal-reducing reaction under tumor microenvironment (TME), thus disturbing the DNA structure to induce cell cycle arrest. More importantly, HHT suppresses PARP production to induce DNA repair dysfunction, thereby boosting DNA oxidative damage. Remarkably, this nanoplatform degrades into ionic form under acid condition, illustrating inherently TME-responsive biodegradability. The anti-tumor evaluation illustrated that [email protected] @PDA-HA/HHT NRs could notably destroy tumor cells in both cellular experiments and mouse models. This study made a successful attempt in boosted cell cycle arrest and encouraged more biological explorations on biodegradation nanomaterials, especially in combating cancers.
研究领域:
癌症生物学
·
纳米技术
·
生物医学工程
·
药学
✓ 已验证
产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 7.088
Xing-Rong Wang,Shuai Wang,Hong-Xia Mu,Kai-Yan Xu,Xue-Ting Wang,Jian-Tao Shi,Qi-Hang Cui,Li-Wen Zhang,Shi-Wu Chen
VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro , as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC 50 : 0.084 ± 0.04 μM, D max : 73.7%) and HUVEC cells (DC 50 : 0.51 ± 0.10 μM, Dmax: 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G 2 /M phase cycle arrest and apoptosis . All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SYNTHETIC COMMUNICATIONS
·
2023
·
IF 2.1
Jun Yang,Guang-Ping Liang,Xiong-Li Liu
To investigate the effects and mechanisms of 4-(1H-indol-1-yl)-4-oxobutanoic acid spliced podophyllotoxin derivatives (3a–3l) on tumor cells. The MTT method was adopted to evaluate (3a–3l) antitumor activity in vitro against A549 cells, A549/DDP cells, MCF-7 cells. The results showed that compound 3l had the most prominent inhibitory effect and high selectivity with IC50 18.53 ± 1.51 µM against A549/DDP cells. Meanwhile, the effects of compound 3l on the nuclear state, cell cycle and apoptosis of A549/DDP cells showed that compound 3l induced apoptosis by delaying the G2/M phase of A549/DDP cell cycle. In addition, molecular docking of compound 3l also showed that it could form a good hydrogen bond with ARG-158 (d = 2.6, 2.7 Å) and HIS-406 (d = 2.5 Å) at the colchicine site of tubulin. Compound 3l could provide lead compound for the development of new multi-drug resistant anti-tumor drugs.
研究领域:
药理学
·
肿瘤学
·
化学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）