The ubiquitin-specific peptidases (USPs) are the main members of the deubiquitinase(DUB) family. b-AP15 is an inhibitor of 19S proteasome deubiquitinase (DUB) with IC50 value of 6.5 μM[3]. In vitro, b-AP15 induced time- and dose-dependent apoptosis of the human multiple myeloma cell lines RPM18226 and U266. b-AP15 triggered processing of pro-caspase-3 and cleavage of ploy (ADP-ribose) polymerase in the human multiple myeloma cell. b-AP15 also induced caspase-independent apoptosis in primary human natural killer cells[4]. In vivo, administration of b-AP15 at 4 mg/kg once daily for 14 days was well tolerated, inhibited tumor growth, and prolong survival in human multiple myeloma xenograft models[5]. Treatment with b-AP15 at dose of 5 mg/kg inhibited tumor growth in SCID mice with FaDu human tumor xenograft and C57BL/6J mice with Lewis lung carcinomas (LLCs). Treatment with b-AP15 at dose of 2.5 mg/kg also inhibited tumor growth in BALB/c mice with orthotopic breast carcinoma. In addition, b-AP15 can inhibited organ infiltration in an acute myeloid leukemia model[6].
作用机制
b-AP15 blocks the DUB activity of the 19S regulatory particle (19S RP) without inhibiting the proteolytic activities of the 20S core particle (20S CP), and inhibits two proteasome-associated DUBs, USP14 and UCHL5, resulting in a rapid accumulation of high molecular weight ubiquitin conjugates and a functional proteasome shutdown[7].
b-AP15 细胞实验
Cell Line
Concentration
Treated Time
Description
References
RT4
up to 2000 nM
24 hours
Induced ER stress and apoptosis
Mol Ther Oncolytics. 2022 Aug 5;26:387-398.
IMR-32
107.8 nM (IC50)
72 hours
Inhibits cell proliferation and induces apoptosis
Mol Cancer Ther. 2019 Jun;18(6):1045-1056.
LAN-6
127.8 nM (IC50)
72 hours
Inhibits cell proliferation and induces apoptosis
Mol Cancer Ther. 2019 Jun;18(6):1045-1056.
MelJuSo UbG76V-YFP cells
1 µM
1-3 hours
To study the effect of b-AP15 on proteasome function, it was found that b-AP15 inhibited proteasome function and led to cell death.
Antioxid Redox Signal. 2014 Dec 10;21(17):2271-85.
HeLa cells
10 µM
2 hours
Immunoblot analysis showed that b-AP15 induced the formation of high molecular weight complexes with USP14.
J Med Chem. 2020 Apr 9;63(7):3756-3762.
UMSCC1 cells
250 nM
24 hours
B-AP15 significantly inhibited the growth and colony formation capacity of UMSCC1 cells.
Cell Death Differ. 2023 May;30(5):1382-1396.
BFTC905
up to 2000 nM
24 hours
Induced ER stress and apoptosis
Mol Ther Oncolytics. 2022 Aug 5;26:387-398.
T24
up to 2000 nM
24 hours
Induced ER stress and apoptosis
Mol Ther Oncolytics. 2022 Aug 5;26:387-398.
T24/R
up to 2000 nM
24 hours
Induced ER stress and apoptosis
Mol Ther Oncolytics. 2022 Aug 5;26:387-398.
Monocyte-derived dendritic cells
10 nM, 100 nM, 500 nM, 1000 nM
24 hours
Comparative analysis of effects of bortezomib and b-AP15 on dendritic cell phenotype and function, finding that b-AP15 had no compromising effects on these DC features.
Neoplasia. 2019 Jul;21(7):653-664.
MCF-7
0.5, 1, 2, 5 µM
24, 48, 72 hours
To evaluate the effect of b-AP15 on the growth of ER+ breast cancer cells, results showed that b-AP15 significantly inhibited cell viability.
Oncogenesis. 2018 Sep 24;7(9):75.
T47D
0.5, 1, 2, 5 µM
24, 48, 72 hours
To evaluate the effect of b-AP15 on the growth of ER+ breast cancer cells, results showed that b-AP15 significantly inhibited cell viability.
Oncogenesis. 2018 Sep 24;7(9):75.
PK-15 cells
0–1 µM
24–48 hours
To evaluate the inhibitory effect of b-AP15 on PRV-GFP proliferation, results showed that b-AP15 significantly inhibited PRV-GFP proliferation.
Autophagy. 2022 Aug;18(8):1801-1821.
3D4/21 cells
0–1 µM
24–48 hours
To evaluate the inhibitory effect of b-AP15 on PRV-GFP proliferation, results showed that b-AP15 significantly inhibited PRV-GFP proliferation.
Autophagy. 2022 Aug;18(8):1801-1821.
HNSCC cells
250 nM
48 hours
B-AP15 significantly reduced the proliferation and survival of HNSCC cells and induced apoptosis.
Cell Death Differ. 2023 May;30(5):1382-1396.
SU-DHL-4
0.205 µM
48 hours
B-AP15 inhibited the proliferation and induced apoptosis in GCB-DLBCL cells.
J Exp Clin Cancer Res. 2019 Nov 6;38(1):453.
SU-DHL-2
0.296 µM
48 hours
B-AP15 inhibited the proliferation and induced apoptosis in ABC-DLBCL cells.
J Exp Clin Cancer Res. 2019 Nov 6;38(1):453.
RKO
1-5 µM
48 hours
B-AP15 significantly reduced the viability of RKO cells, with an IC50 value of 1.649 μM.
Acta Pharmacol Sin. 2023 Dec;44(12):2537-2548.
RKO-R
1-5 µM
48 hours
B-AP15 significantly reduced the viability of RKO-R cells, with an IC50 value of 0.987 μM.
Acta Pharmacol Sin. 2023 Dec;44(12):2537-2548.
HCT-15
1-5 µM
48 hours
B-AP15 significantly reduced the viability of HCT-15 cells, with an IC50 value of 1.453 μM.
Acta Pharmacol Sin. 2023 Dec;44(12):2537-2548.
HCT-15R
1-5 µM
48 hours
B-AP15 significantly reduced the viability of HCT-15R cells, with an IC50 value of 0.858 μM.
Acta Pharmacol Sin. 2023 Dec;44(12):2537-2548.
HCT116 colon carcinoma cells
1 µM
6 hours
To study the effect of b-AP15 on gene expression in HCT116 cells, it was found that b-AP15 induced the expression of genes related to oxidative stress, ER stress, and heat shock.
Antioxid Redox Signal. 2014 Dec 10;21(17):2271-85.
KMBC cells
13 nM
72 hours
Evaluate the sensitivity of b-AP15 in low BAP1 expressing cells, results showed increased sensitivity in KMBC cells with low BAP1 expression
Mol Cancer. 2017 Jan 25;16(1):22.
HuCCT1 cells
1.9 µM
72 hours
Evaluate the sensitivity of b-AP15 in high BAP1 expressing cells, results showed lower sensitivity in HuCCT1 cells with high BAP1 expression
Mol Cancer. 2017 Jan 25;16(1):22.
HAP1 BAP1 KO cells
9 nM
72 hours
Evaluate the sensitivity of b-AP15 in BAP1 knockout cells, results showed increased sensitivity in HAP1 BAP1 KO cells
Mol Cancer. 2017 Jan 25;16(1):22.
HAP1 WT cells
38 nM
72 hours
Evaluate the sensitivity of b-AP15 in wild-type cells, results showed lower sensitivity in HAP1 WT cells
Mol Cancer. 2017 Jan 25;16(1):22.
HeLa cells
20 mM
B-AP15 increased the levels of ubiquitinated proteins in cells and led to a 2- to 2.5-fold stimulation of proteasomal peptidase activity.
Proc Natl Acad Sci U S A. 2022 Jun 21;119(25):e2122482119.
HCT116 colon cancer cells
1 µM
Assess the cytotoxicity of b-AP15 on colon cancer cells
J Med Chem. 2020 Dec 24;63(24):15075-15093.
b-AP15 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Colon cancer xenograft model
Intraperitoneal injection
100 mg/kg
Daily
Evaluate the antitumor activity of EF24 in colon cancer xenograft model
J Med Chem. 2020 Dec 24;63(24):15075-15093.
Nude mice
HNSCC tumor xenograft model
Subcutaneous injection
5 mg/kg
Multiple times per week for 2 weeks
B-AP15 as a monotherapy or in combination with radiation significantly delayed tumor growth and enhanced survival.
Cell Death Differ. 2023 May;30(5):1382-1396.
Nude mice
NGP and SH-SY5Y xenograft models
Intraperitoneal injection
5 mg/kg
Once daily for two weeks
Inhibits tumor growth and induces tumor cell apoptosis
Mol Cancer Ther. 2019 Jun;18(6):1045-1056.
Nude mice
SU-DHL-4 and SU-DHL-2 cell xenograft models
Intraperitoneal injection
5 mg/kg/day
Once daily for 11 days
B-AP15 significantly inhibited the growth of GCB- and ABC-DLBCL xenograft models.
J Exp Clin Cancer Res. 2019 Nov 6;38(1):453.
Nude mice
CML xenograft model
Intraperitoneal injection
5 mg/kg/day
Once daily until the tumor volume reached 1500 mm³
B-AP15 significantly inhibited tumor growth in the CML xenograft model and reduced tumor volume and weight.
Clin Transl Med. 2022 Sep;12(9):e1038
Mice
Subcutaneous xenograft model
Intraperitoneal injection
7.5 mg/kg
Thrice a week for 4 weeks
The combination of b-AP15 and cisplatin is superior to cisplatin monotherapy against UC in vivo
Mol Ther Oncolytics. 2022 Aug 5;26:387-398.
Mice
PRV infection model
Intraperitoneal injection
8 mg/kg
Every two days for 10 days
To evaluate the protective effect of b-AP15 on PRV infection in vivo, results showed that b-AP15 significantly reduced the mortality of PRV-infected mice and inhibited PRV replication.
Autophagy. 2022 Aug;18(8):1801-1821.
Nude mice
RKO and RKO-R xenograft models
Intraperitoneal injection
8 mg/kg/d
Once daily, continuous treatment
B-AP15 significantly suppressed the growth of RKO and RKO-R xenograft tumors without significantly affecting mouse body weight.
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