Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor that mediates the transport of proteins and mRNAs. KPT-330 is a selective inhibitor of CRM1 which shows cytotoxic activity with a median IC50 value of 123 nM in a characterized cell penal with 23 cell lines[1]. In both STO and MesoII cells, the treatment of 1 μM KPT-330 markedly increased the accumulation of G1phase at 48 hours after the exposure, and reached a maximum at 72 hours. STO cells demonstrated a high sensitivity to KPT-330 with an IC50 of 0.7 μM, whereas MesoII cells with IC50 of 0.35 μM[2]. KPT-330 at the concentration between 0.1 μM–1 μM induced growth inhibition dose-dependently in eleven NSCLC cell lines. KPT-330 at 1 μM also stimulated the activation of caspase-3 and caspase-9, as well as the protein levels of several pro-apoptotic mediators, including Bax, Bim, and Puma in NSCLC cells. When evaluating the tumor volume of H1975 NSCLC cells engrafted in NOD/SCID mice, KPT-330 treatment (10 mg/kg, twice weekly for 4 weeks) markedly inhibited tumor growth compared with vehicle-treated controls[3].
作用机制
KPT-330 inactivates CRM1 by modifying the critical CRM1-binding residue, thereby irreversibly inhibiting CRM1-mediated nuclear export of proteins and mRNAs[4].
Selinexor 细胞实验
Cell Line
Concentration
Treated Time
Description
References
WiT49
100 nM
48 hours
Evaluate the effect of selinexor on cell cycle and apoptosis, showing decreased nuclear XPO1 levels and a marginal increase in p21
Med. 2022 Nov 11;3(11):774-791.e7.
KPMRT-NS
30 nM
6 and 24 hours
Evaluate the effect of selinexor on XPO1 activity, showing a significant decrease in XPO1 activity at 6 and 24 hours
Med. 2022 Nov 11;3(11):774-791.e7.
G401
30 nM
6 and 24 hours
Evaluate the effect of selinexor on XPO1 activity, showing a significant decrease in XPO1 activity at 24 hours
Med. 2022 Nov 11;3(11):774-791.e7.
OCI-AML2
200 nM
48 h
To validate the activation of AKT signaling by Selinexor, results showed that Selinexor treatment significantly increased AKT phosphorylation.
Nat Cancer. 2022 Jul;3(7):837-851.
MOLM-13
75 nM
36 h
To validate the transcriptional upregulation of P2RY2 by Selinexor, results showed that Selinexor treatment significantly increased P2RY2 expression.
Nat Cancer. 2022 Jul;3(7):837-851.
AML cells
100 nM
16 h
To assess the drug-induced increase in mitochondrial apoptotic priming using Dynamic BH3 profiling to predict tumor cell response to therapy.
Leukemia. 2016 Jan;30(1):190-9.
WSU-FSCCL
100 nM
72 h
Selinexor combined with DEX or EVER significantly enhanced cytotoxicity in WSU-FSCCL cells
Cancer Lett. 2016 Dec 28;383(2):309-317.
WSU-DLCL2
100 nM
72 h
Selinexor combined with DEX or EVER significantly enhanced cytotoxicity in WSU-DLCL2 cells
Cancer Lett. 2016 Dec 28;383(2):309-317.
Neuroblastoma cells
23.4–365.8 nM
72 h
To evaluate the cytotoxic effects of Selinexor on neuroblastoma cells, results showed that Selinexor induced cell death, and TP53 wild-type cells were more sensitive than mutant cells.
Neoplasia. 2022 Apr;26:100776.
P493-6 B cells
1μM
6 h
To evaluate the effect of XPO1 inhibition on MYC-induced replication stress, results showed that XPO1 inhibition increased DNA damage and caused G2-M phase cell cycle arrest.
Cancer Res. 2024 Jan 2;84(1):101-117.
OCI-Ly1 cells
1μM
24 h
To evaluate the effect of XPO1 inhibition on the expression of DNA damage repair proteins, results showed that XPO1 inhibition reduced the expression of CHEK1, RAD51, and WEE1.
Cancer Res. 2024 Jan 2;84(1):101-117.
OCI-AML2
200 nM
24 h
To validate selinexor’s ability to activate PI3K/AKT signaling, the results showed a significant increase in AKT phosphorylation after selinexor treatment.
Nat Cancer. 2022 Jul;3(7):837-851.
MOLM-13
75 nM
24 h
To validate selinexor’s ability to activate PI3K/AKT signaling, the results showed a significant increase in AKT phosphorylation after selinexor treatment.
Nat Cancer. 2022 Jul;3(7):837-851.
MV4;11
50 nM
24 h
To validate selinexor’s ability to activate PI3K/AKT signaling, the results showed a significant increase in AKT phosphorylation after selinexor treatment.
Nat Cancer. 2022 Jul;3(7):837-851.
HL-60
300 nM
24 h
To validate selinexor’s ability to activate PI3K/AKT signaling, the results showed a significant increase in AKT phosphorylation after selinexor treatment.
Nat Cancer. 2022 Jul;3(7):837-851.
OCI-AML3
250 nM
24 h
To validate selinexor’s ability to activate PI3K/AKT signaling, the results showed a significant increase in AKT phosphorylation after selinexor treatment.
Nat Cancer. 2022 Jul;3(7):837-851.
Selinexor 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
SCID mice
MDA-MB-468 xenograft model
Oral
5-25 mg/kg
Twice weekly or once weekly for 42 days
To evaluate the effect of KPT-330 on MDA-MB-468 xenograft model tumor growth, results showed that KPT-330 significantly inhibited tumor growth
Mol Cancer Ther. 2014 Mar;13(3):675-86.
Mice
MLL-AF9-driven AML model
Oral
15 mg/kg
Every other day for five cycles
To evaluate the efficacy of Selinexor combined with AKT inhibitor in AML mouse models, results showed that the combination therapy significantly prolonged survival.
Nat Cancer. 2022 Jul;3(7):837-851.
NSG mice
Patient-derived AML xenograft model
Oral
20 mg/kg
Three times a week for 4 weeks
To evaluate the antileukemic activity of Selinexor against AML cells, results showed that Selinexor significantly reduced the AML burden and was highly cytotoxic to leukemia-initiating cells (LICs).
Leukemia. 2016 Jan;30(1):190-9.
Mice
WSU-DLCL2 subcutaneous tumor model
Oral
10 mg/kg
Every other day for three weeks
Selinexor combined with DEX or EVER significantly inhibited tumor growth in the WSU-DLCL2 subcutaneous tumor model
Cancer Lett. 2016 Dec 28;383(2):309-317.
Mice
A2780-res1 orthotopic ovarian cancer model
Orally
20 mg/kg
Twice weekly, until mice became moribund
ERBB3 depletion restored the anti-tumor effect of selinexor
Mol Cancer Ther. 2020 Aug;19(8):1727-1735.
Mice
Neuroblastoma xenograft models
Oral
15 mg/kg
Twice weekly for 3 weeks
To evaluate the anti-tumor effects of Selinexor combined with Alisertib in neuroblastoma xenograft models, results showed that the combination therapy significantly inhibited tumor growth and induced tumor regression.
Neoplasia. 2022 Apr;26:100776.
NSG mice
Patient-derived tumor xenograft (PDTX) model
Oral
7.5 mg/kg
According to the dosing schedule shown in Fig. 3B
To evaluate the effect of XPO1 inhibition combined with CHOP on tumor growth, results showed that the combination significantly suppressed tumor growth and increased apoptosis.
Cancer Res. 2024 Jan 2;84(1):101-117.
Mice
MLL-AF9-driven AML model
Oral
15 mg/kg
Every other day for five weeks
To evaluate the efficacy of Selinexor combined with Ipatasertib in AML mouse models, the results showed that the combination significantly prolonged the survival of the mice.
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