现货，ABT-263 (Navitoclax)，selleck，美国进口， Bcl-2 YZ剂，CAS号: 923564-51-6 ，目录号S1001_详细资料

规格：		产品价格：	￥2268
规格：	5mg	产品价格：	￥2268

规格：

产品价格：

￥2268

规格：

5mg

产品价格：

￥2268

分子量(MW):	974.61
化学式:	C₄₇H₅₅ClF₃N₅O₆S₃
溶解度:	DMSO ≥195mg/mL Water <1mg/mL Ethanol <1mg/mL
纯度:	>97%
稳定性:	at -20℃ 2 years
CAS号:	923564-51-6

分子量(MW):

974.61

化学式:

C₄₇H₅₅ClF₃N₅O₆S₃

溶解度:

DMSO ≥195mg/mL Water <1mg/mL Ethanol <1mg/mL

纯度:

>97%

稳定性:

at -20℃ 2 years

CAS号:

923564-51-6

	Apoptosis induced by ABT-737 and ABT-263 in purified CLL cells. A, CLL cells freshly isolated from peripheral blood of CLL patients were incubated in RPMI plus 10% FCS with different concentrations of ABT-737 or ABT-263 for 4 hours before apoptosis was assessed by externalization of phosphatidylserine (PS) and staining with AnnexinV–FITC (n = 21; *, P < 0.05).
	The reduced biological activity of ABT-263 is not due to a reduced potency or plasma membrane permeability. A, F-dextran–loaded liposomes were incubated with BAX, N/C-BID, and BCL-XL, and the indicated concentrations of ABT-737 or ABT-263 (0.04, 0.2, 1, or 5 μmol/L) for 2.5 hours at room temperature. Both ABT-737 and ABT-263 reversed BCL-XL–mediated inhibition of BAX and N/C-BID liposome permeabilization (n = 3). B, purified CLL cells were treated with 0.05% digitonin to permeabilize the plasma membrane and the cells were washed and pelleted by centrifugation at 13,000 rpm. The permeabilized cells were incubated with different concentrations of ABT-737 and ABT-263 for 1 hour at 37°C. The release of cytochrome c (Cyt c) from the cell pellet into the supernatant (SN) was assessed after centrifugation by Western blotting.
	Mechanism of cell death induced by ABT-737 and ABT-263. A, CLL cells were incubated with 10 or 100 nmol/L ABT-737 or ABT-263 for 4 hours before staining with 50 nmol/L tetramethylrhodamine ethyl ester (TMRE) and analysis of the loss of mitochondrial membrane potential (n = 3;*, P < 0.05). B, CLL cells were incubated with 10 or 100 nmol/L ABT-737 or ABT-263 for 2 hours before immunoprecipitation (IP) of BCL2. Binding of BAK was detected by Western blotting. C, CLL cells were exposed to 100 nmol/L ABT-263 for 4 hours before electron microscopy. High power magnification shows swollen mitochondria and breaks in the outer mitochondrial membrane (bar, 100 nm). The morphology resembles that previously described for ABT-737. D, murine embryonic fibroblasts (wt or Bax/Bak double knockout, DKO) were exposed to different concentrations of ABT-263 for 48 hours and apoptosis was assessed by externalization of phosphatidylserine (PS) and staining with AnnexinV–FITC.
	Cell density and albumin binding confer resistance to ABT-737 and ABT-263.B,purified CLL cells were incubated at different cell densities in RPMI plus 10% FCS with different concentrations of ABT-263 for 4 hours. Apoptosis was assessed by phosphatidylserine (PS) externalization and staining with AnnexinV–FITC (n = 8). D, CLL cells were incubated at 1 × 106 cells/mL in RPMI with different concentrations of FCS and ABT-263 with or without BSA (3%) for 4 hours. Apoptosis was assessed by PS externalization and AnnexinV–FITC binding (n = 8).
	ABT-263 has a higher albumin binding affinity than ABT-737. The binding capacity of ABT-737 (solid lines) and ABT-263 (dotted lines) to HSA was investigated using a fluorescence polarization assay. A, to measure binding to site 2 on HSA-IIIA, dansyl sarcosine was used as a probe. In this assay the IC50 was 711 and 37μmol/L for ABT-737 and ABT-263, respectively. B, to measure binding to site 1 on HSA-IIA, dansyl L-glutamate was used as a probe. The IC50 was >1,000 and 145 μmol/L for ABT-737 and ABT-263, respectively.
	Cumulative survival curves for indicated treatments in 4 cancer cell lines: treatment with 1 mmol/L navitoclax (ABT-263) alone (denoted in gray), 150nmol/L paclitaxel alone (red), 150 nmol/L paclitaxel t 1 mmol/L navitoclax (green), 1 mmol/L K5I alone (black), and 1 mmol/L K5I t 1 mmol/L navitoclax (blue). Total number of cells analyzed for each curve ranges from 76 to 120 varied between conditions and cell lines. Individual cells were monitored by phasecontrast and fluorescence time-lapse microscopy, and time from mitotic entry to morphologic death was measured and plotted as cumulative survival curves. The top panel quantified kinetics of all cell death and the bottom panel quantified only death during mitotic arrest.
	HCC cells are resistant to low doses of ABT-263. A. LH86 and B. Huh7 cells were treated with ABT-263 (0–20 mM) for up to 24 h. Apoptosis was measured through Hoechst staining to show apoptotic cells with condensed nuclei as described in ‘materials and methods’.(representative apoptotic cells were marked with white arrows in ABT-263 treatment panel). C. HCC cells were treated with increasing doses of ABT-263 as indicated for up to 24 h. Then cells were harvested and cell lysates were prepared and subjected to Western blotting. Caspase activation was assessed through detecting the cleaved bands of caspase 9 and caspase 3. b-actin protein levels were used as an equal protein loading control.
	YM-155 sensitizes ABT-263-induced apoptosis in HCC cells. A. LH86 and B. Huh7 cells were untreated or treated with ABT-263(1 mM), YM-155(1 mM) or combination of ABT-263(1 mM) and YM-155(1 mM) for up to 6 h. Then apoptotic cells were assessed as in Figure 2A and2B (representative apoptotic cells were marked with white arrows). C. LH86 and D. Huh7 cells were untreated or treated with ABT-263(1 mM), YM-155(1 mM) or combination of ABT-263(1 mM) and YM-155(1 mM) for 6 h. Cells with apoptotic nuclei were counted to determine cell death ratio (p,0.05, *p,0.05). E. LH86 cells and F. Huh7 cells were treated as indicated and cell lysates were prepared and subjected to Western blotting.Apoptosis was evaluated through caspase 3 activation. b-actin was used as an equal protein loading control. G. LH86 cells grown in six-well plate were untreated (control) or treated with different conditions as indicated for 48 h. After rinsed with fresh culture medium for 3 times, cells were cultured for another two weeks. Cell colony formation assays were performed with crystal violet staining. H. colony number were counted to show combination treatment with ABT-263 and YM-155 resulted in reduction of clonogenesis (#p<0.05).
	Survivin down-regulation sensitizes ABT-263-induced apoptosis in HCC cells. A. LH86 cells were treated as indicated and cell lysates were prepared for Western blotting. Pro-apoptotic proteins: Bax, Bad, and Bak and anti-apoptotic proteins Bcl-xL and Mcl-1 were assessed with specific antibodies respectively. b-actin was detected and served as an equal protein loading control. B. LH86 cells were untreated or treated with ABT-263 (1 mM), YM-155 (1 mM) or combination of ABT-263 (1 mM) and YM155 (1 mM) for up to 6 h as indicated. Then cells were harvested and cell lysates were prepared for Western blotting. Anti-survivin and anti-Bcl-xL polyclonal antibodies were used to assess protein levels for survivin and Bcl-xL respectively. b-actin was used as an equal protein loading control. The band intensities of survivin, Bcl-xL, and b-actin was qualified with Image J software. C. LH86 cells were transiently transfected with synthesized random siRNA (control) or survivin specific siRNA duplexes, and 48 h posttransfection, cells were subjected to Western blotting analysis with anti-survivin polyclonal antibody. b-actin was used as an equal protein loading control. D. LH86 cells were transfected with synthesized random control siRNA or survivin specific siRNA, and 48 h post-transfection, cells were untreated or treated with ABT-263 (1 mM) for 24 h and then subjected to Hoechst staining to show apoptotic cells with condensed nuclei (representative apoptotic cells were marked with white arrows). E. LH86 cells were treated as in Figure 4D and apoptosis was measured as in Figure 2A. Statistical analysis was performed for apoptosis ratio by counting the number of cells with apoptotic nuclei (*p,0.05). F. LH86 cells treated as in Figure 4D were harvested and cell lysates were prepared and subjected to Western blotting. Apoptosis was determined through caspase 3 activation. b-actin was used as an equal protein loading control.
	ABT-263 induces activation of ERK and survivin up-regulation in HCC cells. A. LH86 cells were treated with different doses of ABT-263 as indicated for 1 h. Cells were harvested and cell lysates were prepared for Western blotting. Phospho-ERK and ERK protein levels were examined with specific antibodies. b-actin was assessed and served as an equal protein loading control. B, LH86 cells were untreated or treated with ABT-263 (1 mM) for 1 h. Cells were harvested and cell lysates were prepared for Western blotting. Survivin expression level was examined with specific antibodies. b-actin was assessed and served as an equal protein loading control. C. LH86 cells were not treated (control) or treated with ABT-263(1 mM), ERK specific inhibitor PD98059 (50 mM), or pre-treated with PD98059 (50 mM) for 1 h followed by ABT-263 (1 mM) for 24 h. Apoptosis was determined by Hoechst staining to show cells with apoptotic nuclei (representative apoptotic cells were labeled with white arrows; PD: PD98059). D. LH86 cells were treated as in Figure 6C, apoptosis was assessed by nuclear staining and cells with apoptotic nuclei were counted as described in ‘materials and methods’ (*p,0.05). E. LH86 cells were untransfected or transiently transfected with synthesized random siRNA (control) or ERK specific siRNA duplexes, and 48 h post-transfection, cells were subjected to Western blotting analysis with anti-ERK polyclonal antibody. b-actin was used as an equal protein loading control. F. LH86 cells were transfected with synthesized random control siRNA or ERK specific siRNA, and 48 h posttransfection, cells were untreated or treated with ABT-263 (1 mM) for 24 h and then subjected to Hoechst staining to show apoptotic cells with condensed nuclei (representative apoptotic cells were marked with white arrows).

Apoptosis induced by ABT-737 and ABT-263 in purified CLL cells. A, CLL cells freshly isolated from peripheral blood of CLL patients were incubated in RPMI plus 10% FCS with different concentrations of ABT-737 or ABT-263 for 4 hours before apoptosis was assessed by externalization of phosphatidylserine (PS) and staining with AnnexinV–FITC (n = 21; *, P < 0.05).

The reduced biological activity of ABT-263 is not due to a reduced potency or plasma membrane permeability. A, F-dextran–loaded liposomes were incubated with BAX, N/C-BID, and BCL-XL, and the indicated concentrations of ABT-737 or ABT-263 (0.04, 0.2, 1, or 5 μmol/L) for 2.5 hours at room temperature. Both ABT-737 and ABT-263 reversed BCL-XL–mediated inhibition of BAX and N/C-BID liposome permeabilization (n = 3). B, purified CLL cells were treated with 0.05% digitonin to permeabilize the plasma membrane and the cells were washed and pelleted by centrifugation at 13,000 rpm. The permeabilized cells were incubated with different concentrations of ABT-737 and ABT-263 for 1 hour at 37°C. The release of cytochrome c (Cyt c) from the cell pellet into the supernatant (SN) was assessed after centrifugation by Western blotting.

Mechanism of cell death induced by ABT-737 and ABT-263. A, CLL cells were incubated with 10 or 100 nmol/L ABT-737 or ABT-263 for 4 hours before staining with 50 nmol/L tetramethylrhodamine ethyl ester (TMRE) and analysis of the loss of mitochondrial membrane potential (n = 3;*, P < 0.05). B, CLL cells were incubated with 10 or 100 nmol/L ABT-737 or ABT-263 for 2 hours before immunoprecipitation (IP) of BCL2. Binding of BAK was detected by Western blotting. C, CLL cells were exposed to 100 nmol/L ABT-263 for 4 hours before electron microscopy. High power magnification shows swollen mitochondria and breaks in the outer mitochondrial membrane (bar, 100 nm). The morphology resembles that previously described for ABT-737. D, murine embryonic fibroblasts (wt or Bax/Bak double knockout, DKO) were exposed to different concentrations of ABT-263 for 48 hours and apoptosis was assessed by externalization of phosphatidylserine (PS) and staining with AnnexinV–FITC.

Cell density and albumin binding confer resistance to ABT-737 and ABT-263.B,purified CLL cells were incubated at different cell densities in RPMI plus 10% FCS with different concentrations of ABT-263 for 4 hours. Apoptosis was assessed by phosphatidylserine (PS) externalization and staining with AnnexinV–FITC (n = 8). D, CLL cells were incubated at 1 × 106 cells/mL in RPMI with different concentrations of FCS and ABT-263 with or without BSA (3%) for 4 hours. Apoptosis was assessed by PS externalization and AnnexinV–FITC binding (n = 8).

ABT-263 has a higher albumin binding affinity than ABT-737. The binding capacity of ABT-737 (solid lines) and ABT-263 (dotted lines) to HSA was investigated using a fluorescence polarization assay. A, to measure binding to site 2 on HSA-IIIA, dansyl sarcosine was used as a probe. In this assay the IC50 was 711 and 37μmol/L for ABT-737 and ABT-263, respectively. B, to measure binding to site 1 on HSA-IIA, dansyl L-glutamate was used as a probe. The IC50 was >1,000 and 145 μmol/L for ABT-737 and ABT-263, respectively.

Cumulative survival curves for indicated treatments in 4 cancer cell lines: treatment with 1 mmol/L navitoclax (ABT-263) alone (denoted in gray), 150nmol/L paclitaxel alone (red), 150 nmol/L paclitaxel t 1 mmol/L navitoclax (green), 1 mmol/L K5I alone (black), and 1 mmol/L K5I t 1 mmol/L navitoclax (blue). Total number of cells analyzed for each curve ranges from 76 to 120 varied between conditions and cell lines. Individual cells were monitored by phasecontrast and fluorescence time-lapse microscopy, and time from mitotic entry to morphologic death was measured and plotted as cumulative survival curves. The top panel quantified kinetics of all cell death and the bottom panel quantified only death during mitotic arrest.

HCC cells are resistant to low doses of ABT-263. A. LH86 and B. Huh7 cells were treated with ABT-263 (0–20 mM) for up to 24 h. Apoptosis was measured through Hoechst staining to show apoptotic cells with condensed nuclei as described in ‘materials and methods’.(representative apoptotic cells were marked with white arrows in ABT-263 treatment panel). C. HCC cells were treated with increasing doses of ABT-263 as indicated for up to 24 h. Then cells were harvested and cell lysates were prepared and subjected to Western blotting. Caspase activation was assessed through detecting the cleaved bands of caspase 9 and caspase 3. b-actin protein levels were used as an equal protein loading control.

YM-155 sensitizes ABT-263-induced apoptosis in HCC cells. A. LH86 and B. Huh7 cells were untreated or treated with ABT-263(1 mM), YM-155(1 mM) or combination of ABT-263(1 mM) and YM-155(1 mM) for up to 6 h. Then apoptotic cells were assessed as in Figure 2A and2B (representative apoptotic cells were marked with white arrows). C. LH86 and D. Huh7 cells were untreated or treated with ABT-263(1 mM), YM-155(1 mM) or combination of ABT-263(1 mM) and YM-155(1 mM) for 6 h. Cells with apoptotic nuclei were counted to determine cell death ratio (*p,0.05, **p,0.05). E. LH86 cells and F. Huh7 cells were treated as indicated and cell lysates were prepared and subjected to Western blotting.Apoptosis was evaluated through caspase 3 activation. b-actin was used as an equal protein loading control. G. LH86 cells grown in six-well plate were untreated (control) or treated with different conditions as indicated for 48 h. After rinsed with fresh culture medium for 3 times, cells were cultured for another two weeks. Cell colony formation assays were performed with crystal violet staining. H. colony number were counted to show combination treatment with ABT-263 and YM-155 resulted in reduction of clonogenesis (#p<0.05).

Survivin down-regulation sensitizes ABT-263-induced apoptosis in HCC cells. A. LH86 cells were treated as indicated and cell lysates were prepared for Western blotting. Pro-apoptotic proteins: Bax, Bad, and Bak and anti-apoptotic proteins Bcl-xL and Mcl-1 were assessed with specific antibodies respectively. b-actin was detected and served as an equal protein loading control. B. LH86 cells were untreated or treated with ABT-263 (1 mM), YM-155 (1 mM) or combination of ABT-263 (1 mM) and YM155 (1 mM) for up to 6 h as indicated. Then cells were harvested and cell lysates were prepared for Western blotting. Anti-survivin and anti-Bcl-xL polyclonal antibodies were used to assess protein levels for survivin and Bcl-xL respectively. b-actin was used as an equal protein loading control. The band intensities of survivin, Bcl-xL, and b-actin was qualified with Image J software. C. LH86 cells were transiently transfected with synthesized random siRNA (control) or survivin specific siRNA duplexes, and 48 h posttransfection, cells were subjected to Western blotting analysis with anti-survivin polyclonal antibody. b-actin was used as an equal protein loading control. D. LH86 cells were transfected with synthesized random control siRNA or survivin specific siRNA, and 48 h post-transfection, cells were untreated or treated with ABT-263 (1 mM) for 24 h and then subjected to Hoechst staining to show apoptotic cells with condensed nuclei (representative apoptotic cells were marked with white arrows). E. LH86 cells were treated as in Figure 4D and apoptosis was measured as in Figure 2A. Statistical analysis was performed for apoptosis ratio by counting the number of cells with apoptotic nuclei (*p,0.05). F. LH86 cells treated as in Figure 4D were harvested and cell lysates were prepared and subjected to Western blotting. Apoptosis was determined through caspase 3 activation. b-actin was used as an equal protein loading control.

ABT-263 induces activation of ERK and survivin up-regulation in HCC cells. A. LH86 cells were treated with different doses of ABT-263 as indicated for 1 h. Cells were harvested and cell lysates were prepared for Western blotting. Phospho-ERK and ERK protein levels were examined with specific antibodies. b-actin was assessed and served as an equal protein loading control. B, LH86 cells were untreated or treated with ABT-263 (1 mM) for 1 h. Cells were harvested and cell lysates were prepared for Western blotting. Survivin expression level was examined with specific antibodies. b-actin was assessed and served as an equal protein loading control. C. LH86 cells were not treated (control) or treated with ABT-263(1 mM), ERK specific inhibitor PD98059 (50 mM), or pre-treated with PD98059 (50 mM) for 1 h followed by ABT-263 (1 mM) for 24 h. Apoptosis was determined by Hoechst staining to show cells with apoptotic nuclei (representative apoptotic cells were labeled with white arrows; PD: PD98059). D. LH86 cells were treated as in Figure 6C, apoptosis was assessed by nuclear staining and cells with apoptotic nuclei were counted as described in ‘materials and methods’ (*p,0.05). E. LH86 cells were untransfected or transiently transfected with synthesized random siRNA (control) or ERK specific siRNA duplexes, and 48 h post-transfection, cells were subjected to Western blotting analysis with anti-ERK polyclonal antibody. b-actin was used as an equal protein loading control. F. LH86 cells were transfected with synthesized random control siRNA or ERK specific siRNA, and 48 h posttransfection, cells were untreated or treated with ABT-263 (1 mM) for 24 h and then subjected to Hoechst staining to show apoptotic cells with condensed nuclei (representative apoptotic cells were marked with white arrows).

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