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Kai-Sheng Liu,
Yi Zhang,
Wei-Chao Ding,
Shao-Xiang Wang,
Yang-Fei Xiang,
Pan Yang,
Zhen-Ping Chen,
Kai Zheng,
Zhong Liu, Min Xia,
Yi-Fei Wang
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ABSTRACT: BJ-B11 is a selective heat shock protein 90 (Hsp90) inhibitor that has been reported to possess significant antitumor activity in multiple types of cancer cells; however, the mechanism of action needs to be further clarified. We investigated, for the first time, the antitumor activity and the molecular mechanism underlying growth inhibition in Eca-109 cells. The results revealed that BJ-B11 inhibited the proliferation of Eca-109 cells in a time- and concentration-dependent manner, with 50% inhibitory concentration (IC50) values of 0.31±0.01 µM after 48-h incubation. BJ-B11 induced concentration-dependent G2/M cell cycle arrest and apoptosis. The cleavage of caspase 3 and PARP signals detected might originate from mitochondrial dysfunction, which was supported by the results of reactive oxygen species (ROS) production, cytochrome c release and the mitochondrial membrane potential (MMP) reduction. The general caspase inhibitor Z-VAD-fmk did not completely abolish BJ-B11-induced cell death. Furthermore, inhibition of the Akt/mTOR/p70S6K signaling pathway might be involved in the process of BJ-B11-induced autophagy, which was characterized by the production of autophagic vacuoles and upregulation of LC3-II protein in a time- and concentration-dependent manner. Meanwhile, the general autophagy inhibitor 3-MA decreased the apoptotic ratio. Furthermore, BJ-B11 induced the polymerization of cytoskeleton β-tubulin and F-actin. Taken together, our results suggest that the growth inhibition of Eca-109 cells induced by BJ-B11 may result from the induction of G2/M cell cycle arrest, apoptosis and autophagy.
International Journal of Oncology 10/2012; · 2.40 Impact Factor
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ABSTRACT: After the widespread use of the acyclic purine nucleoside analogues for therapy of herpes simplex virus (HSV) infection since the 1980s, new antiviral strategies are urgently needed to counter the emergence of drug-resistant clinical isolates. In this report, we define the anti-HSV efficacies of three optimized 2-aminobenzamide derivatives in vitro and in vivo. The synthetic analogues SNX-25a, SNX-2112 and SNX-7081, which selectively bind to the N-terminal ATP pocket of heat shock protein 90 (HSP90), exhibited significant anti-HSV-1 and HSV-2 activities at non-cytotoxic concentrations in Vero cells, with EC(50) values close to that of acyclovir (ACV). The in vivo antiviral potentials were then confirmed using a herpes simplex keratitis (HSK) rabbit model, where eye gels containing 0.1% or 0.025% SNX-25a displayed the highest efficacies against HSV-1 infection, which were better than that obtained with 0.1% ACV. SNX-2112 and SNX-7081 gels were also effective against HSV-1 with different magnitude of activities. Our results for the first time confirmed the anti-HSV efficacies of these 2-aminobenzamide derivatives and suggest that with alternative mechanisms of action these novel HSP90 inhibitors, especially SNX-25a, could be potent as new anti-HSV clinical trial candidates.
Bioorganic & medicinal chemistry letters 05/2012; 22(14):4703-6. · 2.65 Impact Factor
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ABSTRACT: SNX-2112 is an Hsp90 inhibitor which is currently undergoing multiple phase 1 clinical trials; however, its mechanism of action needs to be further elaborated. Here we investigated the effects of SNX-2112 in A-375 cells. SNX-2112 induced the degradation of multiple Hsp90 client proteins, activated both the mitochondrial-mediated and death receptor-mediated apoptotic pathways, downregulated Bcl-2 and Bcl-xL, upregulated Bid, cleaved caspase-9, caspase-7, caspase-3 and PARP, and activated caspase-8. The general caspase inhibitor, z-VAD-fmk, did not completely abolish SNX-2112-induced cell death. SNX-2112 induced autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induces significant apoptosis and autophagy in human melanoma A-375 cells, and may be an effective targeted therapy agent.
Cancer letters 12/2011; 318(2):180-8. · 4.86 Impact Factor
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Shao-Xiang Wang,
Huai-Qiang Ju,
Kai-Sheng Liu,
Jia-Xuan Zhang,
Xiao Wang,
Yang-Fei Xiang,
Rui Wang,
Jin-Yun Liu,
Qiu-Ying Liu, Min Xia,
Guo-Wen Xing,
Zhong Liu,
Yi-Fei Wang
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ABSTRACT: SNX-2112 is a heat shock protein 90 (Hsp90) inhibitor with anticancer properties currently in clinical trials. This study investigated the effects of SNX-2112 on inhibition of cell growth, the cell cycle, and apoptosis in MCF-7 human breast cancer cells, in addition to the various molecular mechanisms. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis suggest that SNX-2112 inhibits cell growth in a time- and dose-dependent manner more potently than 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), a traditional Hsp90 inhibitor, probably as a result of cell-cycle arrest at the G2/M phase and the induction of apoptosis. Downregulation of Bcl-2 and Bcl-xL, upregulation of Bax, cleavage of caspase-9 and poly (ADP-ribose) polymerase (PARP), and degradation of the breast cancer-related Hsp90 client proteins human epidermal growth factor receptor-2 (HER2), Akt, Raf-1, and nuclear factor kappa-B kinase (IKK) were observed in SNX-2112 treated cells by Western blot assay. These findings suggest that the molecular mechanisms of cell-growth inhibition by SNX-2112 involve activation of the mitochondrial apoptotic pathway and the degradation of breast cancer-related proteins.
Bioscience Biotechnology and Biochemistry 08/2011; 75(8):1540-5. · 1.28 Impact Factor
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Huai-Qiang Ju,
Shao-Xiang Wang,
Yang-Fei Xiang,
Zhong Liu,
Jin-Yun Liu,
Zhen-Ping Chen,
Fan-Li Zeng, Min Xia,
Zong-Hua Liu,
Guo-Wen Xing,
Sha-Yan Wang,
Yi-Fei Wang
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ABSTRACT: In the past few years heat shock protein 90 (Hsp90) inhibitors have been reported to possess significant antitumor activity. We investigated, for the first time, the antitumor activity of a novel Hsp90 inhibitor 2-(4-acetyloxycyclohexylamino)-4-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-1H-indazol-1-yl)-benzamide (BJ-B11) and the molecular mechanism underlying the apoptosis it induces in human chronic myeloid leukemia K562 cells. The results revealed that BJ-B11 triggered growth inhibition in K562 cells and other malignant cell lines in vitro with only minor toxicity in a normal human cell line. BJ-B11 inhibited the proliferation of K562 cells in a concentration- and time-dependent manner, with IC(50) values of 1.1 ± 0.2 μM and 0.4 ± 0.1 μM after 48 and 72 h incubations respectively. This most likely results from cell cycle arrest at the G(0)/G(1) phase and the induction of apoptosis. In addition, BJ-B11 degraded the Hsp90 client proteins Bcr-Abl and Akt, induced activation of caspase-9 and caspase-3, and subsequent cleavage of PARP. The caspase signals may originate from mitochondrial dysfunction, which is supported by the finding of cytochrome c release. In addition, inactivation of the Akt signaling pathway may be involved in the process of BJ-B11-induced apoptosis. Taken together, our data provide a putative molecular mechanism for the anticancer effect of BJ-B11 on K562 cells, and suggest a potential application for BJ-B11 in chronic myeloid leukemia therapy.
European journal of pharmacology 05/2011; 666(1-3):26-34. · 2.59 Impact Factor
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Huai-Qiang Ju,
Yang-Fei Xiang,
Bao-Juan Xin,
Ying Pei,
Jia-Xin Lu,
Qiao-Li Wang, Min Xia,
Chui-Wen Qian,
Zhe Ren,
Sha-Yan Wang,
Yi-Fei Wang,
Guo-Wen Xing
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ABSTRACT: In this study, a novel Hsp90 inhibitor BJ-B11, was synthesized and evaluated for in vitro antiviral activity against several viruses. Possible anti-HSV-1 mechanisms were also investigated. BJ-B11 displayed no antiviral activity against coxsackievirus B(3) (CVB(3)), human respiratory syncytial virus (RSV) and influenza virus (H1N1), but exhibited potent anti-HSV-1 and HSV-2 activity with EC(50) values of 0.42±0.18 μM and 0.60±0.21 μM, respectively. Additionally, the inhibitory effects of BJ-B11 against HSV-1 were likely to be introduced at early stage of infection. Our results indicate that BJ-B11 with alternative mechanisms of action is potent as an anti-HSV clinical trial candidate.
Bioorganic & medicinal chemistry letters 01/2011; 21(6):1675-7. · 2.65 Impact Factor
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Qian-Qian Zhai,
Guo-Qin Gong,
Yong Luo,
Qing-Duan Wang, Min Xia,
Guo-Wen Xing,
Yi-Cheng Li,
Jin-Hua Jiang,
Zhong Liu,
Qiu-Ying Liu,
Yi-Fei Wang
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ABSTRACT: A sensitive and specific reversed-phase high-performance liquid chromatography method with ultraviolet detection has been developed and validated for the identification and quantification of SNX-2112 in rat plasma. Following sample preparation using liquid-liquid extraction, the analytes were separated by the mobile phase acetonitrile-water (40:60, v/v) with an Agilent RP-HPLC column (ZORBAX SB-C18, 5 microm, 4.6 mm x 250 mm) at a flow rate of 1 ml/min, column temperature of 30 degrees C and detection wavelength of 251 nm. The retention time of SNX-2112 was 11.2 min. A good linear relationship was obtained in the concentration range studied (0.07-21 microg/ml, R(2)>0.9982), and the LLOD and LLOQ for SNX-2112 were 0.02 and 0.07 microg/ml, respectively. The mean absolute recovery of SNX-2112 in plasma ranged from 88.58 to 99.61% at the studied concentrations. The intra- and inter-batch relative standard deviations were 1.7-3.5 and 1.9-4.4%, respectively. This method was successfully applied to pharmacokinetic studies in rats after intravenous administration of SNX-2112.
Journal of pharmaceutical and biomedical analysis 12/2010; 53(4):1048-52. · 2.45 Impact Factor
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Lin Jin,
Chuan-Le Xiao,
Chun-Hua Lu, Min Xia,
Guo-Wen Xing,
Sheng Xiong,
Qiu-Ying Liu,
Hui Liu,
Yi-Cheng Li,
Feng Ge,
Qing-Duan Wang,
Qing-Yu He,
Yi-Fei Wang
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ABSTRACT: SNX-2112, a novel inhibitor of Hsp90 currently used as an anti-tumor drug, induces apoptosis in multiple tumor cell lines. It destabilizes specific client proteins, but the molecular mechanism of the apoptosis effect of SNX-2112 is poorly understood. Here, we analyzed the apoptotic effect of SNX-2112 on human chronic myeloid leukemia (CML) K562 cells. Transcriptomic and proteomic approaches further revealed that caspase signals originated from mitochondria dysfunction, mediated by Akt signaling pathway inactivity. Additionally, SNX-2112 prolonged the survival time of NOD/SCID mice inoculated with K562 tumor cells. Our results demonstrated the therapeutic potential of SNX-2112 against human CML.
FEBS letters 06/2009; 583(12):1859-66. · 3.54 Impact Factor
