Zhejiang Province Key Laboratory of Anti cancer Drug Research

Hangzhou, China

Zhejiang Province Key Laboratory of Anti cancer Drug Research

Hangzhou, China
SEARCH FILTERS
Time filter
Source Type

Xian M.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Cao H.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Cao J.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Shao X.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | And 6 more authors.
International Journal of Cancer | Year: 2017

Osteosarcoma is the most common bone cancer, and chemotherapy is currently indispensable for its treatment. Adriamycin has been claimed to be the most effective agent for osteosarcoma, however, the outcome of adriamycin chemotherapy remains unsatisfactory. Here, we reported a potent combination therapy that bortezomib, a proteasome inhibitor, enhances adriamycin-induced apoptosis to eliminate osteosarcoma cells and we revealed that the activation of p-eIF2α/ATF4/CHOP axis is the underlying associated mechanisms. First, we observed that bortezomib enhances adriamycin-mediated inhibition of cell proliferation and enhances the apoptosis in osteosarcoma cell lines. Moreover, this drug combination produced more potent tumor-growth inhibitory effects in human osteosarcoma cell line KHOS/NP xenografts. Our study showed that reactive oxygen species (ROS) plays an important role in apoptosis induced by adriamycin plus bortezomib, whereas ROS scavenger NAC could almost completely block the apoptosis induced by the combination treatment. Meanwhile, p-eIF2α is remarkably elevated in the combination group. As a result, ATF4 exhibits strong activation which consequently induces the activation of CHOP and leads to the cell death. Finally, 13 primary osteosarcoma cells demonstrated potent response to the combination treatment. In a human osteosarcoma patient-derived xenograft (PDX) model, our finding suggests that when combined with bortezomib, a relatively low dose of adriamycin produced more potent tumor-growth inhibitory effects without increased toxicity. Thus, our findings not only provide a promising combination strategy to overcome osteosarcoma but also shed new light on the strategy of combining increased ROS and inhibited proteasome to open up new opportunities for the clinical development of chemotherapy regimens. © 2017 UICC.


Hu H.-H.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Bian Y.-C.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Liu Y.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Sheng R.,Zhejiang University | And 4 more authors.
International Journal of Pharmaceutics | Year: 2014

2-Phenoxy-indan-1-one derivatives (PIOs) are a series of novel central-acting cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The adequate distribution of PIOs to the central nervous system (CNS) is essential for its effectiveness. However, articles related with their permeability in terms of CNS penetration across the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) have not been found. This study was undertaken to evaluate the in vitro BBB and BCSFB transport of PIOs using Madin-Darby canine kidney (MDCK), MDCK-MDR1 and Z310 cell line models. As a result, the transepithelial transport of PIOs did not differ between MDCK and MDCK-MDR1, and the result suggested that PIOs were not substrates for P-gp, which means that multidrug resistance (MDR) function would not affect PIOs absorption and brain distribution. High permeability of PIOs in Z310 was found and it suggested that PIOs had high brain uptake potential. The experiment also showed that PIOs had inhibitory effects on the MDR1-mediated transport of Rhodamine123 with an IC50 value of 40-54 μM. And we suggested that 5,6-dimethoxy-1-indanone might be the pharmacophoric moiety of PIOs that interacts with the binding site of P-gp. © 2013 Elsevier B.V. All rights reserved.


Chen Z.,Zhejiang Cancer Hospital | Chen Z.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Zheng S.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Li L.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Jiang H.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research
Current Drug Metabolism | Year: 2014

Flavonoids are naturally occurring polyphenols, which are widely taken in diets, supplements and herbal medicines. Epidemiological studies have shown a flavonoid-rich diet is associated with the decrease in incidence of a range of diseases. Pharmacological evidences also reveal flavonoids display anti-oxidant, anti-allergic, anti-cancer, anti-inflammatory, anti-microbial and anti-diarrheal activities. Therefore, it is critical to study the biotransformation and disposition of flavonoids in human. This review summarizes the major metabolism pathways of flavonoids in human. First, lactase-phlorizin hydrolase (LPH) and human intestinal microflora mediate the hydrolysis of flavonoid glycosides, which is recognized as the first and determinant step in the absorption of flavonoids. Second, phase II metabolic enzymes (UGTs, SULTs and COMT) dominate the metabolism of flavonoids in vivo. UGTs are the most major contributors, followed by SULTs and COMT. By contrast, phase I metabolism pathway mediated by CYPs only plays a minor role. Third, the coupling of transporters (such as BCRP and MRPs) and phase II enzymes (UGTs and SULTs) plays an important role in the disposition of flavonoids, especially in the enteroenteric and enterohepatic circulations. Thus, all the above factors should be taken into consideration when studying pharmacokinetics of flavonoids. Here we describe a comprehensive metabolism profile of flavonoids, which will enhance our understanding of the mechanisms underlying the disposition and pharmacological effects of flavonoids in vivo. © 2014 Bentham Science Publishers.


Ma L.,Zhejiang Province Key Laboratory of Anti cancer Drug Research | Qin Y.,Zhejiang Province Key Laboratory of Anti cancer Drug Research | Shen Z.,Zhejiang Province Key Laboratory of Anti cancer Drug Research | Hu H.,Zhejiang Province Key Laboratory of Anti cancer Drug Research | And 4 more authors.
Biological and Pharmaceutical Bulletin | Year: 2015

We previously showed that anthraquinones (including rhein, emodin, aloe-emodin, chrysophanol and physcion) were inhibitors of human organic anion transporter 1 (hOAT1) and hOAT3, causing transporter-mediated drug-drug interactions in rats. In this study, the time-dependent inhibition (TDI) of hOAT1 and hOAT3 by anthraquinones was investigated. Madin-Darby canine kidney (MDCK)-hOAT1, HEK293- hOAT3 and their parental cells were used. Preincubation with chrysophanol or physcion for 30 min significantly increased the inhibition of hOAT1, but preincubation with rhein, emodin, aloe-emodin or probenecid had no effect on hOAT1 activity. By contrast, preincubation of hOAT3 with emodin, aloe-emodin, chrysophanol or physcion for 30 min significantly increased its inhibition, but preincubation with rhein or probenecid had no effect on activity. As the incubating time lengthened, from 0 to 60 min, both the inhibition of hOAT1 by chrysophanol and physcion and the inhibition of hOAT3 by emodin, aloe-emodin, chrysophanol and physcion were observed to increase in a time-dependent manner. In conclusion, our results suggest that some anthraquinones contribute to the TDI of hOAT1 and hOAT3. An inhibition study without the preincubation procedure may underestimate the inhibitory potential of anthraquinones against hOAT1 and hOAT3. The underlying mechanisms of TDI of hOAT1 and hOAT3 need to be further investigated. © 2015 The Pharmaceutical Society of Japan.


Zheng S.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Ma Z.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Song F.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Ye J.,Conba Pharmaceutical Co. | And 6 more authors.
Bioanalysis | Year: 2015

Background: Deficiency or imbalance of unsaturated fatty acids will promote the pathogenesis of many diseases. In order to monitor the exposure of unsaturated fatty acids, the method based on LC-MS/MS was developed. Results: Standard calibration curves for α-linolenic acid, linoleic acid, palmitoleic acid and oleic acid were linear (r ≥0.99). The intra-and interbatch accuracy (RE%) ranged from -4.5 to 8.6%, while the intra- and interbatch precisions (RSD%) were ≤8.7%. The extraction recovery varied from 85.4 to 99.6%, and no obvious matrix effect was observed. Conclusion: The method offers a simple approach for measuring 4 unsaturated fatty acids in 1 μl rat plasma within 3.95 min. © 2015 Future Science Ltd.


Chen Q.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Bian Y.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research | Zeng S.,Zhejiang Province Key Laboratory of Anti Cancer Drug Research
Drug Metabolism and Pharmacokinetics | Year: 2014

Caco-2 is a widely used cell model in drug absorption and P-glycoprotein (P-gp, MDR1) substrate identification. Long-term vinblastine treatment of Caco-2 cells could increase the expression of P-gp; thus, the vinblastine resistant Caco-2 (Caco-2 vbl) cells can be used as a rapid and sensitive alternative model in identifying P-gp substrates. The mechanism of P-gp induction in this model is not clear; this study was therefore intended to clarify the possible factors involved in P-gp up-regulation in Caco-2 vbl cells. Since vinblastine is the inducer of both activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB), we investigated the role of AP-1 and NF-κB in the regulation of MDR1 gene expression. Our results indicated that the AP-1 and NF-κB luciferase activity was higher in Caco-2 vbl cells than that in Caco-2 cells according to reporter gene assay. The mRNA expression of AP-1 subunit c-Jun and NF-κB was increased in Caco-2 vbl cells. The c-Jun inhibitor SP600125 and NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) suppressed the expression of MDR1 mRNA in Caco-2 vbl cells. In conclusion, this study provides the evidence that AP-1 and NF-κB are involved in the P-gp induction in Caco-2 vbl cells. Copyright © 2014 by the Japanese Society for the Study of Xenobiotics (JSSX).


PubMed | Zhejiang University and Zhejiang Province Key Laboratory of Anti Cancer Drug Research
Type: Journal Article | Journal: International journal of pharmaceutics | Year: 2014

2-Phenoxy-indan-1-one derivatives (PIOs) are a series of novel central-acting cholinesterase inhibitors for the treatment of Alzheimers disease (AD). The adequate distribution of PIOs to the central nervous system (CNS) is essential for its effectiveness. However, articles related with their permeability in terms of CNS penetration across the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) have not been found. This study was undertaken to evaluate the in vitro BBB and BCSFB transport of PIOs using Madin-Darby canine kidney (MDCK), MDCK-MDR1 and Z310 cell line models. As a result, the transepithelial transport of PIOs did not differ between MDCK and MDCK-MDR1, and the result suggested that PIOs were not substrates for P-gp, which means that multidrug resistance (MDR) function would not affect PIOs absorption and brain distribution. High permeability of PIOs in Z310 was found and it suggested that PIOs had high brain uptake potential. The experiment also showed that PIOs had inhibitory effects on the MDR1-mediated transport of Rhodamine123 with an IC50 value of 40-54 M. And we suggested that 5,6-dimethoxy-1-indanone might be the pharmacophoric moiety of PIOs that interacts with the binding site of P-gp.

Loading Zhejiang Province Key Laboratory of Anti cancer Drug Research collaborators
Loading Zhejiang Province Key Laboratory of Anti cancer Drug Research collaborators