BV6 is an IAP antagonist with Kd values of o.46nM and 1.3nM for c-IAP and XIAP, respectively. Treatment with BV-6 could cause time (5μM, 2-60min)-dependent c-IAP1 and c-IAP2 ubiquitin degradation in MDA-MB-231 cells. The loss of XIAP can be observed at 8h post treatment. BV-6 led induced caspase-dependent cell death in EVSAT and A2058 cells at concentration ranging in 8-1000nM for 24h concentration-dependently, as well as cell death in MDA-MB-231 at concentration<20nM. And this cell death by BV-6 was TNF dependent. BV-6 at 5μM induced a 15- to 30-fold increase in TNFα mRNA levels and further activated its downstream, both of canonical and noncanonical NF-κB pathways, as the phosphorylation and subsequent proteasomal degradation of IκB, time-dependent increased p52 and p100 and inhibited destabilization of NIK by BV-6 can be observed[1]. After treatment with 10mg/kg BV6, i.p., for 4 weeks could significantly reduce the total number of lesions, the average weight and the surface area of lesions in endometriosis-like model[2].
作用机制
BV-6 can bind to the BIR domains of IAP proteins and then lead to rapid ubiquitination and proteasomal degradation of cIAPs.[1]
BV6 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Acute lymphoblastic leukemia cells
300 nM
24 hours
Induces necroptotic cell death
Cell Death Differ. 2017 Jan;24(1):83-97.
HT29 cells
2 µM
1, 2, 4 hours
Induction of necroptosis in HT29 cells, stimulating RIP1 ubiquitination within the necrosome
Cell Death Differ. 2017 Jan;24(1):26-37.
GBM9 cells
0.6 µM
10 days
BV6 stimulates morphological changes in GBM9 cells and increases GFAP expression, indicating that BV6 induces astrocytic differentiation of GBM9 cells.
Cell Death Differ. 2014 May;21(5):735-47.
A172 glioblastoma cells
2 µM
120 hours
BV6 enhances TMZ-induced apoptosis, and upregulation of IFNβ is a critical event in BV6/TMZ-induced apoptosis.
Cell Death Dis. 2015 Sep 17;6(9):e1888.
T98G glioblastoma cells
4 µM
120 hours
BV6 enhances TMZ-induced apoptosis, and upregulation of IFNβ is a critical event in BV6/TMZ-induced apoptosis.
Cell Death Dis. 2015 Sep 17;6(9):e1888.
L929 cells
1 µM
2 hours
BV6 treatment greatly sensitized L929 cells to TNF-induced necrosis, but not to necrotic death induced by anti-Fas, poly(I:C), or oxidative stress.
Cell Death Differ. 2011 Apr;18(4):656-65.
Mouse embryonic fibroblasts
5 µM
24 hours
Protects cells from BV6/Dexa-induced cell death
Cell Death Differ. 2017 Jan;24(1):83-97.
HCC193
1 µM
24 hours
BV6 significantly enhanced the radiosensitivity of HCC193 cells, DER=1.38 (p<0.05).
J Thorac Oncol. 2011 Nov;6(11):1801-9.
FADD-deficient Jurkat T cells
1 µM
24 hours
BV6 treatment sensitized FADD-deficient Jurkat T cells to TNF-induced necrosis.
Cell Death Differ. 2011 Apr;18(4):656-65.
T98G cells
2.5 µM
24 hours
BV6 at non-toxic concentrations triggers cell elongation, migration, and invasion, and causes profound depletion of cIAP1 protein.
Cell Death Dis. 2013 Mar 28;4(3):e564.
U87MG cells
2.5 µM
24 hours
BV6 at non-toxic concentrations triggers cell migration and invasion, and causes degradation of cIAP1 and XIAP proteins.
Cell Death Dis. 2013 Mar 28;4(3):e564.
LN229 cells
2.5 µM
24 hours
BV6 at non-toxic concentrations triggers cell migration and invasion, and causes degradation of cIAP1 and XIAP proteins.
Cell Death Dis. 2013 Mar 28;4(3):e564.
GBM1 cells
1 µM
24 hours
BV6 at non-toxic concentrations triggers cell elongation, migration, and invasion, and causes profound depletion of cIAP1 protein.
Cell Death Dis. 2013 Mar 28;4(3):e564.
GBM2 cells
0.8 µM
24 hours
BV6 at non-toxic concentrations triggers cell elongation, migration, and invasion, and causes profound depletion of cIAP1 protein.
Cell Death Dis. 2013 Mar 28;4(3):e564.
AsPc-1
5 µM
48 hours
To investigate whether BV6 combined with 2′3′-cGAMP can induce necroptosis in apoptosis-deficient pancreatic cancer cells, the results showed that BV6 combined with 2′3′-cGAMP significantly increased cell death, and this death could be reduced by Nec-1s inhibition of RIPK1, indicating RIPK1-dependent necroptotic cell death.
Cell Death Dis. 2021 Aug 30;12(9):816.
BxPc-3
5 µM
48 hours
To investigate whether BV6 combined with 2′3′-cGAMP can induce necroptosis in apoptosis-deficient pancreatic cancer cells, the results showed that BV6 combined with 2′3′-cGAMP significantly increased cell death, and this death could be reduced by Nec-1s inhibition of RIPK1, indicating RIPK1-dependent necroptotic cell death.
Cell Death Dis. 2021 Aug 30;12(9):816.
Capan-1
5 µM
48 hours
To investigate whether BV6 combined with 2′3′-cGAMP can induce necroptosis in apoptosis-deficient pancreatic cancer cells, the results showed that BV6 combined with 2′3′-cGAMP significantly increased cell death, and this death could be reduced by Nec-1s inhibition of RIPK1, indicating RIPK1-dependent necroptotic cell death.
Cell Death Dis. 2021 Aug 30;12(9):816.
DanG
5 µM
48 hours
To investigate whether BV6 combined with 2′3′-cGAMP can induce necroptosis in apoptosis-deficient pancreatic cancer cells, the results showed that BV6 combined with 2′3′-cGAMP significantly increased cell death, and this death could be reduced by Nec-1s inhibition of RIPK1, indicating RIPK1-dependent necroptotic cell death.
Cell Death Dis. 2021 Aug 30;12(9):816.
H460
5 µM
48 hours
BV6 significantly enhanced the radiosensitivity of H460 cells, DER=1.42 (p<0.05).
J Thorac Oncol. 2011 Nov;6(11):1801-9.
UoCB6
66.1 nM
48 hours
BV6 induced cell death, primarily through TNF-α-dependent apoptosis
Cell Death Dis. 2016 Jan 14;7(1):e2052.
REH
251.1 nM
48 hours
BV6 induced cell death, primarily through TNF-α-dependent apoptosis
Cell Death Dis. 2016 Jan 14;7(1):e2052.
GBM10 cells
1 µM
7 days
BV6 stimulates morphological changes in GBM10 cells and increases GFAP expression, indicating that BV6 induces astrocytic differentiation of GBM10 cells.
Cell Death Differ. 2014 May;21(5):735-47.
Non-malignant neural stem cells (NSCs)
1 µM
7 days
BV6 does not alter cell morphology, differentiation, or expression of stemness markers in NSCs.
Cell Death Differ. 2014 May;21(5):735-47.
A172 glioblastoma cells
5 µM
72 hours
To investigate the mechanism of BV6-induced apoptosis, it was found that BV6 upregulates DR5 expression in an NF-κB-dependent manner, thereby promoting apoptosis.
Cell Death Dis. 2013 Nov 28;4(11):e936.
MDA-MB-231 breast carcinoma cells
50 nM
72 hours
To investigate the mechanism of BV6-induced apoptosis, it was found that BV6 induces apoptosis through the TNFα/TNFR1 autocrine/paracrine signaling pathway.
Cell Death Dis. 2013 Nov 28;4(11):e936.
MDA-MB-231 cells
50 nM
72 hours
To evaluate BV6-induced cell death, results showed that IRF1 knockdown significantly reduced BV6-induced cell death.
Cell Death Dis. 2014 Dec 11;5(12):e1562.
T24 cells
100 nM
72 hours
To evaluate BV6-induced cell death, results showed that IRF1 knockdown significantly reduced BV6-induced cell death.
Cell Death Dis. 2014 Dec 11;5(12):e1562.
SK-N-AS cells
50 nM
72 hours
To evaluate BV6-induced cell death, results showed that IRF1 knockdown significantly reduced BV6-induced cell death.
Cell Death Dis. 2014 Dec 11;5(12):e1562.
Kym1 cells
100 nM
72 hours
To evaluate BV6-induced cell death, results showed that IRF1 knockdown significantly reduced BV6-induced cell death.
Cell Death Dis. 2014 Dec 11;5(12):e1562.
H1299 cells
1 µM
various time periods
To evaluate the effect of BV6 on cIAP1 and cIAP2 protein levels, results showed that cIAP2 degradation was protected in H1299 cells
Cell Death Differ. 2015 Sep;22(9):1463-76.
BV6 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Athymic Nude mice
Orthotopic and subcutaneous GBM models
Injection
0.6 mM
Single injection, observed until clinical symptoms appeared
BV6 treatment reduces clonogenicity and tumorigenicity of GBM CSLCs in vivo and significantly increases the survival of mice.
Cell Death Differ. 2014 May;21(5):735-47.
Nude mice
Xenograft tumor model
Intraperitoneal injection
10 mg/kg
Every 4 days, total four treatments
To evaluate the tumor suppressive effect of BV6, results showed that USP11 downregulation enhanced the antitumor activity of BV6 and TRAIL
Cell Death Differ. 2015 Sep;22(9):1463-76.
NOD/SCID mice
HuALL model
Intraperitoneal injections
10 mg/kg
Twice per week for 2 weeks
BV6 significantly reduced leukemia load and prolonged leukemia-free survival, and this effect was dependent on TNF-α
Cell Death Dis. 2016 Jan 14;7(1):e2052.
Chicken embryos
Chicken chorioallantoic membrane model
Implantation on the chicken chorioallantoic membrane
2.5 µM
Single administration, lasting 4 days
Pre-treatment with BV6 significantly increased the infiltrative growth of GBM cells, indicating that BV6 enhances the invasiveness of GBM cells in vivo.
Cell Death Dis. 2013 Mar 28;4(3):e564.
WT and Ccr2−/− mice
Acute sclerosing cholangitis model
Intrabiliary injection
single intrabiliary injection
Single injection, continued for 5 days
Inhibition of monocyte/macrophage recruitment by genetic or pharmacological depletion of CCR2 reduces biliary injury and fibrosis
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