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[6]. 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[7]. 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[6]. 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[8].
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[9]. Ciclopirox Olamine is an olamine form of ciclopiro. 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[10].
Ciclopirox olamine/环吡酮胺 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HeLa-NP-GFP
1, 5, 10 μM
48 h
To screen small-molecule compounds that promote NP degradation, results showed that ciclopirox significantly decreased GFP signal.
Acta Pharm Sin B. 2024 Jun;14(6):2505-2519.
U118 cells
5, 10, 20, 40, 80, 160, 320 μM
48 h
To evaluate the cytotoxicity of CPX on GBM cells, results showed that CPX significantly inhibited GBM cell growth.
Cell Death Dis. 2021 Mar 5;12(3):251.
A172 cells
5, 10, 20, 40, 80, 160, 320 μM
48 h
To evaluate the cytotoxicity of CPX on GBM cells, results showed that CPX significantly inhibited GBM cell growth.
Cell Death Dis. 2021 Mar 5;12(3):251.
SF126 cells
5, 10, 20, 40, 80, 160, 320 μM
48 h
To evaluate the cytotoxicity of CPX on GBM cells, results showed that CPX significantly inhibited GBM cell growth.
Cell Death Dis. 2021 Mar 5;12(3):251.
U251 cells
5, 10, 20, 40, 80, 160, 320 μM
48 h
To evaluate the cytotoxicity of CPX on GBM cells, results showed that CPX significantly inhibited GBM cell growth.
Cell Death Dis. 2021 Mar 5;12(3):251.
SGC cells
0, 20, 40, 80 μM
24 h
To evaluate the antitumor activity of CPX in vitro, CPX markedly inhibited the proliferation of all tested cell lines and reduced their viability in a dose-dependent manner.
Cell Death Dis. 2022 Nov 28;13(11):1007.
AGS cells
0, 5, 10, 20 μM
24 h
To evaluate the antitumor activity of CPX in vitro, CPX markedly inhibited the proliferation of all tested cell lines and reduced their viability in a dose-dependent manner.
Cell Death Dis. 2022 Nov 28;13(11):1007.
MGC cells
0, 5, 10, 20 μM
24 h
To evaluate the antitumor activity of CPX in vitro, CPX markedly inhibited the proliferation of all tested cell lines and reduced their viability in a dose-dependent manner.
Cell Death Dis. 2022 Nov 28;13(11):1007.
Huh-7 cells
1μM
36 h
Evaluating the effect of ciclopirox on intracellular HBV capsid assembly, it inhibited HBV capsid assembly
Nat Commun. 2019 May 16;10(1):2184.
HepG2.2.15 cells
1μM
3 days
Screening compounds for HBV replication inhibition, ciclopirox strongly inhibited HBV DNA secretion
Nat Commun. 2019 May 16;10(1):2184.
DLD-1
5, 10, 20 μM
48 h
To evaluate the anticancer activity of CPX in CRC cells, the results showed that CPX markedly suppressed CRC viability and proliferation in vitro.
Cell Death Dis. 2020 Jul 27;11(7):582.
HCT-8/5-FU
10, 20, 40 μM
7 days
To evaluate the antiproliferative activity of CPX, the results showed that CPX significantly reduced the colony-forming ability of CRC cells in a dose-dependent manner.
Cell Death Dis. 2020 Jul 27;11(7):582.
HCT-8
5, 10, 20, 40, 80 μM
48 h
To evaluate the anticancer activity of CPX in CRC cells, the results showed that CPX markedly suppressed CRC viability and proliferation in vitro.
Cell Death Dis. 2020 Jul 27;11(7):582.
Murine lymphatic endothelial cells (LECs)
5 μM
0-24 h
CPX inhibited LEC tube formation in a time-dependent manner, significantly blocking tube formation by ~20% after 4 h and ~90% after 24 h.
Oncogene. 2011 May 5;30(18):2098-107.
Murine lymphatic endothelial cells (LECs)
0-5 μM
24 h
CPX inhibited LEC tube formation in a concentration-dependent manner, with approximately 70% and 90% inhibition at 2.5 and 5 μM, respectively.
Oncogene. 2011 May 5;30(18):2098-107.
adenocarcinoma SK-HEP-1 cells
10 μM
12 h
CPX completely blocked H2O2-stimulated release of lactate dehydrogenase (a marker of cell death) and decrease in MTT reduction (a marker of mitochondrial function).
Br J Pharmacol. 2005 Jun;145(4):469-76.
Ciclopirox olamine/环吡酮胺 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/C mice
SARS-CoV-2 infection model
Intraperitoneal injection
20 mg/kg
5 consecutive 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.
SD rats
Middle cerebral artery occlusion (MCAO) model
Intravenous injection
3 mg/kg
Single dose or continuous administration every 24 hours for 7 days
To evaluate the alleviative effect of CPX on brain infarction, neurological deficits, and brain edema in MCAO rats, results showed CPX significantly reduced brain infarction, neurological deficits, and brain edema, and improved long-term motor function recovery.
Acta Pharm Sin B. 2020 Mar;10(3):434-446
BALB/c nude mice
GBM xenograft model
Intraperitoneal injection
20 mg/kg, 15 mg/kg
Once daily for 12 days
To evaluate the inhibitory effect of CPX on GBM tumor growth, results showed that CPX significantly suppressed tumor growth.
Cell Death Dis. 2021 Mar 5;12(3):251.
BALB/c nude mice
GC xenograft model
Intraperitoneal injection
20 mg/kg
Once daily for 12 days
To evaluate the antitumor tumor growth potential of CPX in vivo, CPX significantly suppressed GC tumor growth when compared to the control group.
Cell Death Dis. 2022 Nov 28;13(11):1007.
BALB/c male mice
Humanized liver mouse model
Oral
5 mg/kg
Daily for 4 weeks
Assessing the antiviral effect of ciclopirox on HBV replication in vivo, it significantly reduced serum HBV DNA levels
Nat Commun. 2019 May 16;10(1):2184.
Balb/c nude mice
CRC xenograft model
Intraperitoneal injection
20 mg/kg
Once a day for 12 days
To evaluate the antitumor activity of CPX in vivo, the results showed that CPX significantly inhibited CRC xenograft growth.
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