PLoS One
·
2014
·Vol. 9
·期 4
·e92962
·
IF 3.534
Yunhai Dai,Xiaopeng Xiong,Gang Huang,Jianjun Liu,Shile Sheng,Hongjian Wang,Wenxin Qin
A unique bioenergetic feature of cancer, aerobic glycolysis is considered an attractive therapeutic target for cancer therapy. Recently, dichloroacetate (DCA), a small-molecule metabolic modulator, was shown to reverse the glycolytic phenotype, induce reactive oxygen species (ROS) generation, and trigger apoptosis in various tumor cells. In this work, the capacity of DCA to enhance Adriamycin (ADM) efficacy in hepatoma cells by modulating glucose metabolism and redox status was evaluated. Two human hepatoma (HCC-LM 3 and SMMC-7721) and a normal liver (LO 2 ) cell lines were treated with DCA or ADM alone, or in combination. Exposure of hepatoma cells to DCA/ADM combination resulted in significantly decreased cell viability and increased percentage of apoptotic cells as well as intracellular ROS levels, in comparison with treatment with DCA or ADM alone. However, simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC, 10 mmol/L) reduced the elevated ROS levels and protected hepatoma cells from the cytotoxic effects of DCA/ADM combination. L-buthionine-[S,R]-sulfoximine, an inhibitor of glutathione synthesis, enhanced hepatoma cell sensitivity to DCA/ADM combination. Interestingly, treatment with DCA/ADM combination did not significantly increase cytotoxicity in normal hepatocytes in comparison with the drugs administered individually. Finally, DCA reduced tumor growth and enhanced ADM efficacy on HCC-LM 3 hepatoma in mice. Overall, our data suggest that DCA enhances ADM cytotoxicity in hepatoma cells by increasing intracellular ROS levels and provide a strong biochemical rationale for the use of DCA in combination with ADM for treatment of hepatoma.
研究领域:
肿瘤学
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生物化学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Conglian Yang,Tingting Wu,Yuting Qin,Yan Qi,Yu Sun,Miao Kong,Xue Jiang,Xianya Qin,Yaqi Shen,Zhiping Zhang
Background Doxorubicin (DOX) is an effective chemotherapeutic agent but severe side effects limit its clinical application. Nanoformulations can reduce the toxicity while still have various limitations, such as complexity, low drug loading capability and excipient related concerns.Methods An amphiphilic conjugate, doxorubicin-dichloroacetate, was synthesized and the corresponding nanoparticles were prepared. The in vitro cytotoxicity and intracellular uptake, in vivo imaging, antitumor effects and systemic toxicities of nanoparticles were carried out to evaluate the therapeutic efficiency of tumor.Results Doxorubicin-dichloroacetate conjugate can self-assemble into nanoparticles with small amount of DSPE-PEG2000, leading to high drug loading (71.8%, w/w) and diminished excipient associated concerns. The nanoparticles exhibited invisible systemic toxicity and high maximum tolerated dose of 75 mg DOX equiv./kg, which was 15-fold higher than that of free DOX. It also showed good tumor targeting capability and enhanced antitumor efficacy in murine melanoma model.Conclusion This work provides a promising strategy to simplify the drug preparation process, increase drug loading content, reduce systemic toxicity as well as enhance antitumor efficiency.
研究领域:
药剂学
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肿瘤学
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纳米医学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF FOOD SCIENCE
·
2021
·Vol. 86
·期 12
·5495-5502
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IF 3.167
Liangting Shao,Yue Qin,Xinglian Xu,Huhu Wang
Sodium hypochlorite (NaClO) has been widely used at 100 ppm concentration during poultry slaughter to reduce carcass microorganism loads. However, its use in poultry processing is restricted owing to the potential risks of disinfection by-products (DBPs) that can be produced by the reaction of NaClO with poultry meat components. This study assessed whether dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), as primary DBP representatives, were produced when NaClO was used as a disinfectant in various methods during broiler prechilling. Headspace gas chromatography-mass spectrometry for the quantitative determination of DCAA and TCAA in 180 prechilling water samples and 30 broiler meat samples, obtained from large standard slaughterhouses equipped with an online monitoring system to control the NaClO concentration between 50 and 100 ppm, showed that neither DCAA nor TCAA were detected. In simulation assays, haloacetic acids (HAAs) were not detected when the concentration of the NaClO solution was less than 200 ppm with low frequency addition; however, more than 0.1 mg/L of DCAA and TCAA were detected on applying 200, 300, 400, 500, and 1000 ppm NaClO at high frequency. These findings indicated that adding high concentrations of NaClO and frequently adding low levels pose a potential risk of DBP formation. This investigation provides a basis for the establishment of food risk and the scientific use of NaClO in poultry processing, and contributes to the evaluation of DBPs in poultry slaughter. Practical Application This study confirmed the occurrences of DCAA and TCAA during broiler chilling processing, indicating that formation of HAAs in simulation systems was correlated with NaClO levels and validated the absence of DCAA and TCAA with less than 200 ppm, providing a basic study for food safety standards and regulations on the disinfectants used in food processing.
研究领域:
食品安全
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环境科学
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食品科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2019
·Vol. 15
·期 24
·1901156
·
IF 10.856
Lei Sun,Yurui Xu,Ya Gao,Xinyu Huang,Shujun Feng,Jianmei Chen,Xuekun Wang,Leilei Guo,Meng Li,Xia Meng,Jikang Zhang,Junliang Ge,Xueying An,Dang Ding,Yadong Luo,Yu Zhang,Qing Jiang,Xinghai Ning
Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal–organic framework (MOF)-Fe 2+ (MD@Lip) has been developed, which can efficiently stimulate ROS-mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF-Fe 2+ , but also generate an acidic microenvironment to activate a MOF-Fe 2+ -based Fenton reaction. Importantly, MD@Lip promotes DCA-mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H 2 O 2 ), which can be consequently converted to highly cytotoxic hydroxyl radicals (•OH) via MOF-Fe 2+ , leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome-based combination therapy of DCA and MOF-Fe 2+ provides a promising oxidative stress–associated antitumor strategy for the management of malignant tumors.
研究领域:
医学
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生物化学
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肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF APPLIED POLYMER SCIENCE
·
2023
·Vol. 140
·期 12
·e53638
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IF 3
Yao-Shen Guo,Cheng Chen,Chun-Er Lin,Li-Ping Zhu,Hong-Xing Liu
Dichloroacetic acid (DCAA), one of the disinfection by-products in water, has showed critical harm to human health since it can cause cancer, teratogen and mutagen. Herein, a quaternized hollow fiber membrane was fabricated by ring-open reaction via a facile one-step immersion method, which could fast adsorb DCAA by flow-through adsorption. The obtained membrane with a sponge pore structure, which was quaternized at 60°C in an alkaline solution, exhibited excellent adsorption performance with removal percentage of 100%, life span up to 100 L and treating capacity of 24.8 mg m −2 . Meanwhile, the optimal membrane exhibited the exceptional performance in a neutral test solution compared with acid or alkaline test solution. It was concluded that electrostatic attraction between positively charged quaternary ammonium groups and negatively charged DCAA was responsible for the adsorption mechanism. Additionally, fitting results indicated that the adsorption of DCAA onto the membrane was mainly dominated by homogeneous monolayer adsorption. This work developed a facile approach to prepare a novel quaternized membrane with outstanding adsorption performance, which demonstrated huge potentials in the molecular separation and water purification fields.
研究领域:
环境科学
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材料科学
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水处理技术
✓ 已验证
产品关联
DOI
高影响因子
ChemPhotoChem
·
2024
·
IF 3
Zhenyan Zhou,Lei Wang,ShouCai Yan,Ziang Liu,Rensong Sun,Yuan Qiao,Engin Umut Akkaya
Cancer cells change their glucose metabolism towards lactic acid production for various defensive and proliferative advantages. Dichloroacetate (DCA) is an inhibitor of a key enzyme and thus, changes back the OX-PHOS to glycolysis ratio. We designed and synthesized a singlet oxygen triggered source of dichloroacetate which releases this inhibitor during photodynamic singlet oxygen generation. Synergistic action of DCA and singlet oxygen results in significant enhancement of photocytotoxicity. The results suggest that this approach could offer significant improvement in the therapeutic outcome of PDT.
研究领域:
肿瘤学
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药理学
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生物医学工程
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细胞生物学
✓ 已验证
产品关联
DOI
高影响因子
CHINESE JOURNAL OF CHEMISTRY
·
2011
·Vol. 29
·期 4
·778-782
·
IF 0.773
Haining Shi,Zonghua Wang,Hui Wang,Rui Zhao,Mingyu Ding
An anion-exchange chromatography method combined solid phase extraction (SPE) was developed for the simultaneous analysis of glycolate acid (GL), monochloroacetic acid (MCA) and dichloroacetic acid (DCA) in synthetical betaine products. The analytes and unknown anionic impurities were well separated on a Metrosep A supp5 anion-exchange column (150 mm×4 mm) with 2.0 mmol/L Na 2 CO 3 +2.0 mmol/L NaHCO 3 solution as eluent. Suppressed conductivity detection was used. A strong cation exchange (SCX) solid phase extraction (SPE) cartridge was used to reduce the concentration of matrix betaine and a Cleanert IC-Ag pretreatment cartridge was used to remove high Cl − concentration. The detection limits of GL, MCA and DCA were 0.09, 0.017 and 0.05 µg/L, respectively. The relative standard deviations (RSDs) of the retention times and peak areas were less than 0.09% and 0.49%, respectively. The recoveries of the three analytes were between 90.6% and 100.8%. The analytical results showed that GL and DCA were present in high concentration and no MCA was found when the proposed ion chromatography method was applied to three synthetical betaine samples. The proposed method is simple, sensitive and timesaving, and is also suitable for routine analysis in quality control of synthetical betaine products.
研究领域:
分析化学
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药物质量控制
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分离科学
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环境分析
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食品化学
✓ 已验证
DOI
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2016
·
IF 3.42
Fangrong Zhang,Min Li,Yujie Su,Jianping Zhou,Wei Wang
Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers, and chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor, without apparent toxicity in normal tissues. Combining DCA and p53 gene could be an effective way to treat tumors. The progress towards broad applications of DCA/p53 combination requires the development of safe and efficient vectors that target to specific cells. In this study, we developed a DSPE-PEG-AA (1,2-distearoryl- sn -glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide) modified reconstituted high-density lipoprotein-based DCA/p53-loaded nanoparticles (DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes), which was fabricated as a drug/gene dual-targeting co-delivery system for potential cancer therapy. Here, DCA-PEI was utilized to effectively condense the p53 plasmid, to incorporate the plasmid into rHDL and to act as an antitumor drug to inhibit tumor cell growth. The DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes exhibited desirable and homogenous particle size, neutral surface charge and low cytotoxicity for normal cells in vitro . The results of confocal laser scanning microscopy (CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug delivery and gene transfection in human lung adenocarcinoma cell line A549. And in vivo investigation on nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes possessed specific tumor targeting and strong antitumor activity. The work described here demonstrated that the DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes might offer a promising tool for effective cancer therapy.
研究领域:
肿瘤学
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药剂学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR LIQUIDS
·
2022
·
IF 6.633
Wang Jun,Zhu Tianlong,Deng Ziwen,Liu Haicheng,Huang Chunxiang,Li Na,Sun Xueni,Shao Hui,Qi Lv
Isobaric vapour-liquid equilibrium (VLE) data for binary systems containing methyl chloroacetate (MC) + methyl 2-chloropropionate (M2C), MC + methyl dichloroacetate (MDC), and M2C + MDC at 101.33 kPa and the saturated vapour pressure data of these components were measured by using a modified Othmer still. The VLE data showed that these binary systems were all slightly positive deviation solutions compared with the ideal system. Herington area and point tests were used to confirm the thermodynamic consistency for these binary systems, and the results showed good thermodynamic consistency. The interaction energy ( E inter ) between these components was calculated by molecular simulation to explain the normal boiling point and VLE behavior. The simulation results showed weak hydrogen bonds between these chlorinated esters. In addition, the binary VLE experimental data were correlated by the Wilson, NRTL, and UNIQAC models. The correlated results agreed well with the experimental values.
研究领域:
化学工程
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物理化学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Wenyan She,Tingting Liu,Haimei Li,Zichen Wang,Zhibin Guo,Yi Liu,Yujiao Liu
In many types of cancers, pyruvate dehydrogenase kinase (PDK) is abnormally overexpressed and has become a promising target for cancer therapy. However, few highly effective inhibitors of PDK have been reported to date. Herein, we designed and synthesized a series of PDK inhibitors based on dichloroacetate (DCA) and arsenicals. Of the 27 compounds, 1f demonstrated PDK inhibition with high efficiency at a cellular level (IC50 = 2.0 μM) and an enzyme level (EC50 = 68 nM), far more effective than that of DCA. In silico, in vitro, and in vivo studies demonstrated that 1f inhibited PDK, shifted the energy metabolism from aerobic glycolysis to oxidative phosphorylation, and induced cell apoptosis. Moreover, new 1f-loaded nanoparticles were developed, and the administration of high-drug-loading nanoparticles (0.15 mg/kg) caused up to 90% tumor shrinkage without any apparent toxicity. Hence, this study provided a novel metabolic therapy for cancer treatment.
研究领域:
肿瘤学
·
药理学
·
生物技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Theranostics
·
2024
·
IF 12.4
Zhiyong Shi,Miaomiao Liu,Xiaowen Zhang,Jingyang Wang,Junwei Zhang,Zeyan Peng,Li Meng,Ruijing Wang,Lihong Guo,Qiang Zhang,Jing Li,Liang Yang,Jie Liu,Yang Xu,Jie Yan,Jianlin Cui,Shan Ren,Yang Gao,Yanming Wang,Zhi Qi
Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo . Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Animal Nutrition
·
2022
·
IF 5.285
Yuan Luo,Wenhao Zhou,Ruixin Li,Samwel M. Limbu,Fang Qiao,Liqiao Chen,Meiling Zhang,Zhen-Yu Du
Pyruvate dehydrogenase kinases (PDKs)-pyruvate dehydrogenase E1α subunit (PDHE1α) axis plays an important role in regulating glucose metabolism in mammals. However, the regulatory function of PDKs-PDHE1α axis in the glucose metabolism of fish is not well known. This study determined whether PDKs inhibition could enhance PDHE1α activity, and improve glucose catabolism in fish. Nile tilapia fingerlings (1.90 ± 0.11 g) were randomly divided into 4 treatments in triplicate (30 fish each) and fed control diet without dichloroacetate (DCA) (38% protein, 7% lipid and 45% corn starch) and the control diet supplemented with DCA, which inhibits PDKs through binding the allosteric sites, at 3.75 (DCA3.75), 7.50 (DCA7.50) and 11.25 g/kg (DCA11.25), for 6 wk. The results showed that DCA3.75, DCA7.50 and DCA11.25 significantly increased weight gain, carcass ratio and protein efficiency ratio ( P < 0.05) and reduced feed efficiency ( P < 0.05) of Nile tilapia. To investigate the effects of DCA on growth performance of Nile tilapia, we selected the lowest dose DCA3.75 for subsequent analysis. Nile tilapia fed on DCA3.75 significantly reduced the mesenteric fat index, serum and liver triglyceride concentration and total lipid content in whole fish, and down-regulated the expressions of genes related to lipogenesis ( P < 0.05) compared to the control. The DCA3.75 treatment significantly improved glucose oxidative catabolism and glycogen synthesis in the liver, but significantly reduced the conversion of glucose to lipid ( P < 0.05). Furthermore, the DCA3.75 treatment significantly decreased the PDK2/4 gene and protein expressions ( P < 0.05), accordingly stimulated PDHE1α activity by decreasing the phosphorylated PDHE1α protein level. In addition, DCA3.75 treatment significantly increased the phosphorylated levels of key proteins involved in insulin signaling pathway and glycogen synthase kinase 3β ( P < 0.05). Taken together, the present study demonstrates that PDK2/4 inhibition by using DCA promotes glucose utilization in Nile tilapia by activating PDHE1α and improving insulin sensitivity. Our study helps to understand the regulatory mechanism of glucose metabolism for improving dietary carbohydrate utilization in farmed fish.
研究领域:
水产养殖
·
代谢
·
营养
·
分子生物学
✓ 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）