Transcription factor hypoxia inducible factor-1 (HIF-1) is a master switch under hypoxia that upregulates the expression of multiple angiogenic proteins including stromal derived factor (SDF)-1, placental growth factor (PlGF), endothelin-1, VEGF and its receptor VEGFR-1. HIF-1 consists of a HIF-1α and a HIF-1β subunit. Ciclopirox and its olamine salt are family members of hydroxypyridone, which is a prolyl hydroxylase inhibitor and can stabilize HIF-1α predominantly in fibroblasts induced capillary sprouting in endothelial cells to increase angiogenesis[4]. Moreover, ciclopirox is a potential drug for HBV. In a vitro study, HMSCs were stimulated with ciclopirox at dose of 10 μM for 24 h to perform subsequent gene expression analysis, suggesting that decrease of HIF-1α expression on gene level, whereas VEGF expression was upregulated by ciclopirox[5]. In another vitro assay, a kind of truncated HBV core protein, cp149, was incubated with 0.1 - 10 μM ciclopirox and an anti-HBV core antibody was added for immunoblot analysis. The result showed that IC50 value of ciclopirox was 445 ± 17 nM,, which indicated that ciclopirox potently affected intracellular HBV capsid assembly. In a vivo study, endothelial cells were cultured to observe sprouts of fibroblasts and only a few longer sprouts were observed. However, when ciclopirox at dose of 0.4 mM were introduced, an increase of sprout length ensued with the formation of a basal network and formation of anastomoses, indicating that ciclopirox induced secretion of VEGF[4]. In another study, human liver-chimeric uPA/SCID mice were injected intravenously with HBV virion (5 × 107 copies per mouse), and after 6 weeks the mice were treated daily with ciclopirox at dose of 5 mg/kg daily for 5 weeks. The data indicated that ciclopirox had lowered serum HBV DNA, HBeAg and serum ALT levels significantly. Furthermore, ciclopirox also significantly reduced HBV core protein levels in the liver. These evidences proved that ciclopirox is an effective HBV capsid assembly inhibitor[6].
作用机制
Hydrophobic residues L19, F23, F24, P25, Y118, F122, and W102, with extensive van der Waals interactions between ciclopirox and these residues form a binding pocket[7]. And ciclopirox can mimic the effect of bipyridine, a well-known iron chelator and also an antifungal agent, upregulating the expression of the high-affinity iron permease gene FTR1 and the low-affinity iron permease gene FTR2, which are essential for iron metabolism[8].
Ciclopirox/环吡酮 细胞实验
Cell Line
Concentration
Treated Time
Description
References
NB-1691
5 µM
4 days
Inhibited neuroblastoma cell proliferation and survival
Cancer Res. 2017 Sep 1;77(17):4626-4638.
SK-N-SH
5 µM
4 days
Inhibited neuroblastoma cell proliferation and survival
Cancer Res. 2017 Sep 1;77(17):4626-4638.
IMR-32
5 µM
4 days
Inhibited neuroblastoma cell proliferation and survival
Cancer Res. 2017 Sep 1;77(17):4626-4638.
SK-N-AS
5 µM
4 days
Inhibited neuroblastoma cell proliferation and survival
Cancer Res. 2017 Sep 1;77(17):4626-4638.
HEK293T
5-10 μmol/L
48 hours
To screen small-molecule compounds that promote NP degradation, results showed that Ciclopirox significantly reduced NP expression.
Acta Pharm Sin B. 2024 Jun;14(6):2505-2519.
Huh-7 cells
1μM
36 hours
Evaluating the effect of Ciclopirox on intracellular HBV capsid assembly, finding it inhibits HBV capsid assembly.
Nat Commun. 2019 May 16;10(1):2184.
HepG2.2.15 cells
1μM
3 days
Screening compounds for HBV replication inhibition, finding that Ciclopirox significantly inhibits HBV DNA secretion.
Nat Commun. 2019 May 16;10(1):2184.
HS68
5 µM
4 days
No significant effect on the viability of the normal human fibroblast cell line HS68
Cancer Res. 2017 Sep 1;77(17):4626-4638.
BE(2)-C
5 µM
4 days
Inhibited neuroblastoma cell proliferation and survival, induced cell morphology changes such as neurite outgrowth
Cancer Res. 2017 Sep 1;77(17):4626-4638.
SW480
20 μM
24 hours
To evaluate the effect of CPX on CRC cell proliferation and apoptosis, results showed that CPX significantly inhibited CRC cell proliferation and induced apoptosis.
Theranostics. 2019 Jul 28;9(19):5577-5594.
HCT116
20 μM
24 hours
To evaluate the effect of CPX on CRC cell proliferation and apoptosis, results showed that CPX significantly inhibited CRC cell proliferation and induced apoptosis.
Theranostics. 2019 Jul 28;9(19):5577-5594.
PANC1 cells
5 μM
72 hours
Inhibited cell proliferation and eIF5A1 hypusination
Cancer Res. 2014 Nov 15;74(22):6671-81.
FG cells
5 μM
72 hours
Inhibited cell proliferation and eIF5A1 hypusination
Cancer Res. 2014 Nov 15;74(22):6671-81.
SiHa cells
20 μM
24 hours
To evaluate the inhibitory effect of CPX on the proliferation of cervical cancer cells. Results showed that CPX treatment significantly inhibited the proliferation of SiHa cells.
Redox Biol. 2022 Jul;53:102339.
HeLa cells
20 μM
24 hours
To evaluate the inhibitory effect of CPX on the proliferation of cervical cancer cells. Results showed that CPX treatment significantly inhibited the proliferation of HeLa cells.
Redox Biol. 2022 Jul;53:102339.
Calu-3
2.8 μmol/L
24 hours
To evaluate the inhibitory effect of Ciclopirox on SARS-CoV-2 replication, results showed that Ciclopirox significantly inhibited viral RNA levels.
Acta Pharm Sin B. 2024 Jun;14(6):2505-2519.
HeLa-ACE2
1.7 μmol/L
24 hours
To evaluate the inhibitory effect of Ciclopirox on SARS-CoV-2 replication, results showed that Ciclopirox significantly inhibited viral RNA levels.
Acta Pharm Sin B. 2024 Jun;14(6):2505-2519.
Vero-E6
1.3 μmol/L
24 hours
To evaluate the inhibitory effect of Ciclopirox on SARS-CoV-2 replication, results showed that Ciclopirox significantly inhibited viral RNA levels.
Acta Pharm Sin B. 2024 Jun;14(6):2505-2519.
Ciclopirox/环吡酮 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
SD rats
Middle cerebral artery occlusion (MCAO) model
Intravenous injection
3 mg/kg
Single or multiple doses, lasting for 7 days
Evaluate the alleviating effect of CPX on brain infarction, neurological deficits and brain edema
Acta Pharm Sin B. 2020 Mar;10(3):434-446
SCID mice
Neuroblastoma disseminated disease model
Subcutaneous pump continuous release
12 mg/ml
Continuous for 4 weeks
CPX significantly reduced tumor burden and inhibited or prevented disease dissemination
Cancer Res. 2017 Sep 1;77(17):4626-4638.
Nude mice
HCT116 xenograft model
Oral gavage
25 mg/kg
Once daily for three weeks
To evaluate the antitumor effect of CPX in vivo, results showed that CPX significantly inhibited tumor growth.
Theranostics. 2019 Jul 28;9(19):5577-5594.
C57BL/6 mice
MOC2-E6/E7 subcutaneous xenograft model
Intraperitoneal injection
10 mg/kg and 15 mg/kg
Once or twice daily for 21 days
To evaluate the inhibitory effect of Ciclopirox on tumor growth in vivo. The results showed that SC144 significantly delayed tumor growth, while the effect of CPX was not significant.
Theranostics. 2020 May 25;10(15):6959-6976
BALB/C mice
SARS-CoV-2 infection model
Intraperitoneal injection
20 mg/kg/day
Once daily for 5 days
To evaluate the inhibitory effect of Ciclopirox on SARS-CoV-2 replication in vivo, results showed that Ciclopirox significantly reduced viral titers and lung pathology.
Acta Pharm Sin B. 2024 Jun;14(6):2505-2519.
PXB mice (humanized liver mouse model)
HBV infection model
Oral
5 mg/kg
Once daily for 5 weeks
Evaluating the inhibitory effect of Ciclopirox on HBV replication in vivo, finding it significantly reduces serum HBV DNA levels.
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