The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. Proteasome Subunit β5 is a component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. Proteasome Subunit β5 displays a chymotrypsin-like activity.
Carfilzomib is a proteasome inhibitor, specifically inhibiting the chymotrypsin-like (ChT-L) activity at the β5 subunits of the core 20S proteasome[3]. According to a report, extracts from multiple myeloma ANBL-6 cells were exposed to increasing concentrations of carfilzomib and assayed for 20S catalytic activities. Carfilzomib displayed preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, with over 80% inhibition at the dose of 10 nM and little or no effect on the PGPH and T-L activities at doses up to 100 nM. In an ELISA assay utilizing cell extracts from ANBL-6 cells, designed to identify subunit binding, short exposure to Carfilzomib at the concentration as low as 0.1 μM exhibited preferential binding specificity for the β5 constitutive 20S proteasome. Based on a WST-1 assay, the inhibitory IC50s of Carfilzomib against multiple myeloma ANBL-6 and RPMI8226 cells were both less than 5 nM, with the drug incubation time of 24h. In a caspase activity assay, ANBL-6 cells were exposed to a 1-hour pulse of 100 nM Carfilzomib and allowed to recover for 8 hours. The results indicated that Carfilzomib increased caspase-3 activity approximately 6-fold, and caspase-8, caspase-9 activity approximately 4-fold[4].
In a mouse model of bone marrow disseminated multiple myeloma established by intravenous injection of 5TGM1-GFP cells into KaLwRij mice, Carfilzomib was intravenously administrated at the dose of 3 mg/kg daily for 2 days. The treatment of Carfilzomib significantly decreased tumor burden as measured by serum levels of the clonotypic antibody IgG2b and by percentage of bone marrow or spleen GFP-expressing tumor cells. Protection from tumor-induced bone loss was also observed by microCT[5].
To evaluate the protective effect of Eplerenone on Carfilzomib-induced cytotoxicity, it was found that Eplerenone significantly inhibited Carfilzomib-induced cytotoxicity and suppressed SGK-1 upregulation.
Hemasphere. 2022 Oct 18;6(11):e791.
HMC-1.1 and HMC-1.2 cells
5 nM
24 h
Carfilzomib restored SETD2 expression and activity (as shown by rescue of H3K36Me3) and induced significant apoptosis.
Biomark Res. 2023 Mar 10;11(1):29.
ROSAKIT D816V cells
5 nM
24 h
Carfilzomib significantly reduced clonogenic potential and induced a higher percentage of apoptosis in SETD2 RNAi-depleted cells.
Biomark Res. 2023 Mar 10;11(1):29.
NK-92 cells
10 nM
24 h
Carfilzomib activates autophagy via induction of the unfolded protein response and ATF4, restoring the cytotoxic ability of NK-92 cells
Nat Commun. 2024 Nov 28;15(1):10343.
VACO432
5.9nM±2.3
24 h
To evaluate the effect of Carfilzomib and ACY-1215 on the survival of BRAF MT CRC cells, the results showed that combined treatment significantly increased apoptosis
Mol Cancer Ther. 2018 Jun;17(6):1280-1290.
Carfilzomib/卡非佐米 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Myeloma xenograft model
Oral
30 mg/kg and 100 mg/kg
Once daily for 3 weeks
Inhibited tumor growth and was well tolerated by mice
Cell Death Dis. 2015 Jul 9;6(7):e1815.
BALB/c nude mice
VACO432 xenograft model
Intraperitoneal injection
6mg/kg
3 times per week for 15 days
To evaluate the therapeutic efficacy of combined Carfilzomib and ACY-1215 in BRAF MT CRC xenograft models, the results showed that combined treatment significantly inhibited tumor growth and induced apoptosis
Mol Cancer Ther. 2018 Jun;17(6):1280-1290.
BALB/c nude mice
VACO432 xenograft model
Intraperitoneal injection
6mg/kg
3 times per week for 15 days
To evaluate the effect of combined Carfilzomib and ACY-1215 treatment on tumor growth in the BRAF MT VACO432 xenograft model, the results showed that combined treatment significantly inhibited tumor growth and induced apoptosis.
Mol Cancer Ther. 2018 Jun;17(6):1280-1290.
BALB/c nude mice
ARP1 xenograft model
Intravenous injection
4 mg/kg
Twice a week for 7 weeks
Evaluate the anti-tumor effect of Carfilzomib, results showed Carfilzomib significantly inhibited tumor growth
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