EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2014
·
IF 3.432
Ke-Guang Cheng,Chun-Hua Su,Lin-Dong Yang,Jun Liu,Zhen-Feng Chen
Five dimeric oleanolic acids linked at C-28 by 1,6-hexanediamine, or built around the carbon chains of varying lengths between two carboxyl groups were synthesized, to investigate the effect of internal spacer length and species upon the stereochemical features and anti-tumor activity of the resultant bis-oleanolic acids. The IC 50 values of these dimeric compounds for cytotoxicity evaluation in vitro against Hep-G2, A549, BGC-823, MCF-7 and PC-3 tumor cell lines, were mainly under 10.0 μM. This result was much better than the inhibition of proliferation against tested tumor cell lines of the monomer oleanolic acid and the commercial anticancer drug 5-fluorouracil. The cytotoxicity selectivity detection revealed that dimer 11c exhibited low cytotoxicity towards normal human liver cell HL-7702. A combination of fluorescence staining observation and flow cytometric analysis indicated that 11c could induce Hep-G2 cell apoptosis . Molecular mechanism studies suggested that 11c induced apoptosis is mediated through the intrinsic apoptotic pathway with changes in mitochondrial membrane potential by finally activating effector caspase-3/9 to trigger cell apoptosis. Further studies revealed that 11c caused cell cycle arrest at G1 phase in Hep-G2 cells. Taken together, these results suggest that 11c may be a potential candidate for further cancer research.
研究领域:
药理学
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肿瘤学
·
有机化学
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产品关联
DOI
PubMed
高影响因子
Analytical Cellular Pathology
·
2022
·
IF 4.133
Yingru Zhang,Yiyang Zhao,Jingwen Liu,Chunpu Li,Ying Feng,Shasha Jiang,Xiaoting Sun,Xueqing Hu,Yan Wang
Tanshinone IIA (TanIIA) is the main active ingredient in the fat-soluble components isolated from Salvia miltiorrhiza Bunge. Our previous studies have convincingly proved that TanIIA is an effective drug against human colorectal carcinoma cells. In order to further demonstrate the effect of TanIIA on CRC, we carried out exploratory research about it in vivo and in vitro. The results demonstrated that TanIIA were observably more effective than control group in preventing tumor growth, and it has increased the survival time. Cancer cells viability and proliferation were accompanied by concentration and time dependent decline reached with TanIIA. We found that TanIIA altered the morphology of cytoskeleton and it could obviously induce apoptosis of colorectal cancer cells and block the cells in the G0/G1 phase. TanIIA also increased phosphorylation of p38MAPK, upregulated ATF-2 expression and downregulated Transgelin-2 expression, which could be reversed by SB203580, a p38MAPK-specific inhibitor. Our results suggested that TanIIA could induce apoptosis of colorectal cancer and block the cells in G0/G1 phase involved in downregulating the expression of Transgelin-2 through p38MAPK signal pathway.
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oncology Letters
·
2018
·Vol. 15
·期 4
·5250-5256
·
IF 1.664
Jun‑Ming Chen,Jue Zhang,Yong‑Mei Xia,Xiao‑Xia Wang,Jian Li
Steviol is the colonic metabolite of the natural sweetener steviol glycosides. It does not diffuse to the blood and the half maximal inhibitory concentration of steviol is longer compared with that of current chemotherapy agents, including 5‑fluorouracil and doxorubicin. The present study demonstrated that steviol inhibits the proliferation of the human osteosarcoma U2OS cell line in a dose‑ and time‑dependent manner, and that the inhibition rate is comparative with that of doxorubicin and 5‑fluorouracil. The mechanism of this anticancer activity is also investigated. The results indicated that steviol inhibits U2OS cells through inducing G1 phase cell cycle arrest, downregulating the ability of colony formation via a mitochondrial apoptotic pathway, which was indicated by an increase of the Bax/Bcl‑2 ratio and activation of cyclin‑dependent kinase inhibitor 1, tumor protein 53 and cyclin‑dependent kinase; whereas a Survivin and Caspase 3‑independent mechanism was involved. Considering that steviol appears minimally in the plasma during metabolism, and possesses a median lethal dose of 100-fold greater compared with that of 5‑fluorouracil, it may become a potential chemotherapy agent.
研究领域:
肿瘤学
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药理学
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代谢
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DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Jingyu Wang,Jun Zhang,Longsheng Xu,Ying Zheng,Danyan Ling,Zhiping Yang
The hepatocyte nuclear factor 4 gamma (HNF4G), a member of orphan nuclear receptors, is up-regulated and functions as an oncoprotein in bladder cancer. In the present study, we observed that HNF4G expression was elevated in lung cancer tissues as compared to adjacent normal lung tissues. The expression of HNF4G protein was correlated with the tumor size and the prognosis of patients. Transfection with a small interference RNA (siRNA) targeting HNF4G in two lung cancer cell lines (H358 and H292 cells) significantly inhibited cell proliferation via arresting cells at G1 phase and inducing cell apoptosis. In addition, HNF4G siRNA reduced cell proliferation in a xenograft tumor-bearing model. Moreover, A549 cells, which had relative lower level of HNF4G, were ectopic expressed with HNF4G and treated with an AKT inhibitor (MK-2206). MK-2206 exposure not only attenuated the promoting effects of HNF4G overexpression on cell proliferation and cell cycle progression, but also suppressed the inhibitory effects of HNF4G overexpression on cell apoptosis. These data suggested that AKT signaling pathway was a potential upstream mediator of HNF4G. Collectively, our data indicate that HNF4G exerts as an oncogenic role in lung cancer by promoting cell proliferation and that HNF4G expression is a potential prognosis factor for lung cancer.
研究领域:
肿瘤学
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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
ENVIRONMENTAL TOXICOLOGY
·
2019
·Vol. 34
·期 5
·666-673
·
IF 2.649
Xia Wang,Chenqian Zhou,Bingnan He,Baida Kong,Lai Wei,Rong Wang,Jiajia Lin,Yiyan Shao,Jianbo Zhu,Yuanxiang Jin,Zhengwei Fu
Fluorotelomer alcohols (FTOHs) are fluorinated intermediates used in manufacturing specialty polymer and surfactants, with 8:2 FTOH the homologue of largest production. FTOHs were found to pose acute toxicity, hepatotoxicity, nephrotoxicity, developmental toxicity and endocrine-disrupting risks, whereas research regarding immunotoxicity and its underlying mechanism, especially on specific immune cells is limited. Here, we investigated the immunotoxicity of 8:2 FTOH on immature immune cells in an in vitro system. We observed that exposure of HL-60 cells, a human promyelocytic leukemic cell line, to 8:2 FTOH reduced cell viability in a dose- and time-dependent manner. In addition, 8:2 FTOH exposure caused G1 cell cycle arrest in HL-60 cells, while it showed no effect on apoptosis. Exposure to 8:2 FTOH inhibited the mRNA expression of cell cycle-related genes, including CCNA1 , CCNA2 , CCND1 , and CCNE2 . Moreover, exposure to 8:2 FTOH inhibited the mRNA expression of granulocytic differentiation-related genes of CD11b , CSF3R , PU.1 , and C/EPBε in HL-60 cells . Furthermore, 8:2 FTOH exhibited no effect on intracellular ROS level, while hydralazine hydrochloride (Hyd), one reactive carbonyl species (RCS) scavenger, partially blocked 8:2 FTOH-caused cytotoxicity in HL-60 cells. Overall, the results obtained in the study show that 8:2 FTOH poses immunotoxicity in immature immune cells and RCS may partially underline its mechanism.
研究领域:
毒理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-12
·
IF 3.8
Song Yang,Zhang Hui,Geng Jie,Chen Haoran,Bo Yang,Lu Xuechun
Patients with multiple myeloma (MM) experience relapse and drug resistance; therefore, novel treatments are essential. Clotrimazole (CTZ) is a wide-spectrum antifungal drug with antitumor activity. However, CTZ’s effects on MM are unclear. We investigated CTZ’s effect on MM cell proliferation and apoptosis induction mechanisms. CTZ’s effects on MM.1S, NCI- H929, KMS-11, and U266 cell growth were investigated using Cell Counting Kit-8 (CCK-8) assay. The apoptotic cell percentage was quantified with annexin V-fluorescein isothiocyanate/7-amino actinomycin D staining. Mitochondrial membrane potential (MMP) and cell cycle progression were evaluated. Reactive oxygen species (ROS) levels were measured via fluorescence microscopy. Expression of apoptosis-related and nuclear factor (NF)-κB signaling proteins was analyzed using western blotting. The CCK-8 assay indicated that CTZ inhibited cell proliferation based on both dose and exposure time. Flow cytometry revealed that CTZ decreased apoptosis and MMP and induced G0/G1 arrest. Immunofluorescence demonstrated that CTZ dose-dependently elevated in both total and mitochondrial ROS production. Western blotting showed that CTZ enhanced Bax and cleaved poly ADP-ribose polymerase and caspase-3 while decreasing Bcl-2, p-p65, and p-IκBα. Therefore, CTZ inhibits MM cell proliferation by promoting ROS-mediated mitochondrial apoptosis, inducing G0/G1 arrest, inhibiting the NF-κB pathway, and has the potential for treating MM.
研究领域:
肿瘤学
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药理学
·
细胞生物学
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分子生物学
✓ 已验证
DOI
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Qingqing Zhang,Yuying Liu,Jie Zhang,Yanchen Li,Jin Wang,Nanxin Liu,Jie Zhang,Xiaoyan Pan
Proteolysis targeting chimeras (PROTAC) are bifunctional chimeric molecules capable of directly degrading binding proteins through the ubiquitin-proteasome pathway. PROTACs have demonstrated significant potential in overcoming drug resistance and targeting previously untreatable targets. However, several limitations still need to be addressed, including their high molecular weight resulting in poor membrane permeability and bioavailability. In this study, we proposed that cancer-targeted penetrating peptides could enhance the cell permeability of PROTACs. We developed 26 novel targeted penetrating peptides for leukemia and lymphoma cells, among which C9C-f(3Bta) and Cyclo-C9C–R exhibited superior membrane permeability, targetability, and stability. By combining C9C-f(3Bta) and Cyclo-C9C–R with IMA-PROTAC, we effectively enhanced the anti-proliferative activity of IMA-PROTAC, facilitated degradation of Bcr-Abl protein in K562 cells, and reduced downstream STAT5 phosphorylation. Furthermore, the combined application promoted cell apoptosis while blocking G1 phase progression. HPLC-MRM-MS revealed that the combination of C9C-f(3Bta) or Cyclo-C9C–R with IMA-PROTAC significantly enhanced intracellular IMA-PROTAC content. In summary, our proof-of-concept study validated the hypothesis that combining PROTACs with targeted penetrating peptides can improve protein degradation efficiency as well as anti-proliferative capabilities.
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
✓ 已验证
DOI
PubMed
高影响因子
Nanomaterials
·
2023
·Vol. 13
·期 11
·1779
·
IF 5.3
Shunyu Zhang,Jinxia Li,Liang Yan,Yue You,Feng Zhao,Jixing Cheng,Limin Yang,Yanqi Sun,Qingchao Chang,Ru Liu,Yunhui Li
Telomerase is constitutively overexpressed in the majority of human cancers and telomerase inhibition provides a promising broad-spectrum anticancer therapeutic strategy. BIBR 1532 is a well-known synthetic telomerase inhibitor that blocks the enzymatic activity of hTERT, the catalytic subunit of telomerase. However, water insolubility of BIBR 1532 leads to low cellular uptake and inadequate delivery and thus, limits its anti-tumor effects. Zeolitic imidazolate framework-8 (ZIF-8) is considered as an attractive drug delivery vehicle for improved transport, release and anti-tumor effects of BIBR 1532. Herein, ZIF-8 and BIBR[email protected]were synthesized, respectively, and the physicochemical characterizations confirmed the successful encapsulation of BIBR 1532 in ZIF-8 coupled with an improved stability of BIBR 1532. ZIF-8 could alter the permeability of lysosomal membrane probably by the imidazole ring-dependent protonation. Moreover, ZIF-8 encapsulation facilitated the cellular uptake and release of BIBR 1532 with more accumulation in the nucleus. BIBR 1532 encapsulation with ZIF-8 triggered a more obvious growth inhibition of cancer cells as compared with free BIBR 1532. A more potent inhibition on hTERT mRNA expression, aggravated G0/G1 arrest accompanied with an increased cellular senescence were detected in BIBR[email protected]cancer cells. Our work has provided preliminary information on improving the transport, release and efficacy of water-insoluble small molecule drugs by using ZIF-8 as a delivery vehicle.Keywords:ZIF-8;drug loading;transport;protonation effect;telomerase inhibitor
研究领域:
药学
·
癌症研究
·
药物递送系统
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2017
·Vol. 16
·期 2
·2211-2216
·
IF 1.692
Xuefeng Yang,Handong Huang,Maijian Wang,Xingbin Zheng,Jie Xu,Ming Xie
Nonylphenol (NP) is a well-known endocrine-disrupting chemical (EDC), which can enhance the progression of cancer by functioning as an estrogen‑like factor. In the present study, the effects of different concentrations of NP on COLO205 colorectal cancer (CRC) cells were examined. The results of flow cytometric analysis revealed that NP significantly decreased the proportion of cells in the G0/G1 phase in a dose‑dependent manner, which was accompanied by a marginal increase in the proportions of cells in S and G2/M phases. NP did not induce apoptosis, whereas estradiol (E2) did induce apoptosis. To elucidate the mechanisms underlying the action of NP on COLO205 cells, the transcriptional levels of extracellular signal‑regulated kinase (ERK)1, ERK2 and phosphoinositide 3‑kinase (PI3K) were assessed using reverse transcription‑quantitative polymerase chain reaction analysis. The expressions levels of ERK1, ERK2 and PI3K were increased by treatment with NP in a dose‑dependent manner. On examining protein levels, the expression of PI3K p38 was increased by NP and E2, and the expression of ERK1/2 was increased by NP. The phosphorylation of the ERK protein was significantly increased by treatment with NP at a high concentration (10‑4 M; P<0.01), but significantly decreased by E2 (P<0.01). Two key proteins in the transforming growth factor (TGF)β pathway (c‑Fos and SnoN) were selected for analysis using western blot analysis in the COLO205 cells treated with NP and E2. The expression levels of c‑Fos and SnoN were significantly increased by treatment with E2 (10‑7 M; P<0.01) and NP (10‑7‑10‑4 M; P<0.01). Taken together, these results indicated that NP affected the development of CRC via the ERK signaling pathway and TGFβ pathway.
研究领域:
肿瘤学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Science and Human Wellness
·
2024
·
IF 5.6
Ruijie Xu,Zhijie Yao,Hao Zhang,Haitao Li,Wei Chen
Loss of susceptibility to anoikis signals is a crucial step in metastasis. Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management. In this study, we have conducted a rationalized screening to search for novel leading anoikis sensitizer from daily foods. Among 19 tested dietary phytochemicals, the best results were obtained with apigenin, a natural component of celery. Phenotypically, apigenin sensitized breast cancer cells to anoikis, lowered the number of circulating tumor cells, and protected against breast cancer metastasis to lung in mice. Mechanistically, we demonstrated that the thromboxane A 2 (TXA 2 )-TXA 2 receptor (TP) axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway. Blockage of TXA 2 signaling up-regulated p53 as well as its target gene p21, caused a G1 phase arrest, and finally led to apoptosis in breast cancer cells. TXA 2 level was positively correlated with breast cancer cell anoikis rate, and apigenin significantly inhibited TXA 2 biosynthesis in vitro and in vivo. Collectively, we identified apigenin as a potent anoikis sensitizer with anti-metastatic properties in a mouse model of breast cancer, and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
CARBOHYDRATE POLYMERS
·
2020
·
IF 7.182
Zhao Zhao,Mei Ji,Qianqing Wang,Nannan He,Yue Li
Off-target drug delivery, together with multidrug resistance (MDR), are two keys obstacles that account for the disappointing outcome in clinical chemotherapy of cancer. To solve these dilemmas, Herein, we constructed cancer cell membrane (CCM) modified silica (CS) nanoparticles (CCM/CS) to co-deliver Ca 2+ channel siRNA with doxorubicin (DOX) to construct a platform (CCM/CS/R-D) for the efficient therapy of cervical cancer. It was demonstrated that the optimal CCM/CS/R-D was spherical nanoparticles with size at 122.39 ± 4.69 nm and the surface charge of -27.76 ± 3.12 mV. In addition, the CCM/CS/R-D showed acid responsive drug release while high stability under physiological conditions with negligible hemolysis. The CCM/CS/R-D showed CCM mediated cellular uptake and efficient endosomal escape as well as siRNA transfection potential (comparable to that of PEI 25 K) on MDR cervical cancer cells (HeLa/DOX). Most importantly, the MDR of cancer cells was conquered through modulation of T-type Ca 2+ (Cav) channels. It was observed that the Cav channel siRNA could negatively regulate the level of cytosolic Ca 2+ concentration which triggered G0/G1 phase cell cycle arrest and elevated intracellular drug retention in HeLa/DOX cells without significantly affect the expression of P-glycolprotein (P-gp). The in vitro and in vivo experiments revealed that CCM/CS/R-D exerted greatly enhanced tumor targetability and therapeutic effect on HeLa/DOX, which was superior than CS/R-D or mono delivery system (CCM/CS/R or CCM/CS/D).
研究领域:
癌症研究
·
纳米医学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Qi Lai,Chun-Ju Yang,Qi zhang,Min Zhuang,Yan-Hua Ma,Cheng-Yuan Lin,Guang-Zhi Zeng,Jun-Lin Yin
Liver cancer belongs to Gastrointestinal (GI) malignancies which is a common clinical disease, a thorny public health problem, and one of the major diseases that endanger human health. Molecules from natural products (NPs) or their derivatives play an increasingly important role in various chronic diseases such as GI cancers. The chemical composition of the Alstonia yunnanensis Diels roots was studied using silica column chromatography, gel chromatography, recrystallization, and HPLC, and the compounds were structurally identified by modern spectral analysis using mass spectrometry (MS) and nuclear magnetic resonance ( 1 H-, 13 C-, HMQC-, HMBC-, and 1 H- 1 HCOSY-NMR), ultraviolet and visible spectrum (UV), and electronic Circular Dichroism (ECD). Acetoxytabernosine (AC), an indole alkaloid with antitumor activity, was isolated from Alstonia yunnanensis Diels root. The current study aimed to investigate the influence of AC on the cell proliferation of BEL-7402 and SMMC7721 and to elucidate the underlying mechanism. The absolute configuration of AC was calculated by ECD (electronic circular dichroism). The effects of AC on the viability of different tumor cell lines were studied by the SRB method. The death mode of human hepatoma cells caused by AC was studied by TUNEL cell apoptosis detection and AnnexinV-FITC/PI double staining image. Mitochondrial membrane potential was detected by JC-1. The effects of AC on the expression of apoptosis-related proteins (Caspase9, Caspase3, and Parp-1) in SMMC7721 and BEL-7402 cells were detected by western blot. It was found that the absolute configuration of AC is 19(s), 20(s)-Acetoxytabernosine. AC could induce apoptosis of SMMC7721 and BEL-7402, and block the replication of DNA in the G1 phase. Under the treatment of AC, the total protein expression of apoptosis-related proteins (Caspase9, Caspase3, and Parp-1) significantly decreased in SMMC7721 and BEL-7402. The results suggested that AC induced apoptosis through a caspase-dependent intrinsic pathway in SMMC7721 and BEL-7402, and natural product-based drug development is an important direction in antitumor drug discovery and research.
研究领域:
药理学
·
肿瘤学
·
天然产物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）