Hinokitiol, a tropolone-related natural compound, is known to induce apoptosis and cell cycle arrest and has anti-inflammatory and anti-tumor activities. Hinokitiol may exert DNA demethylation by inhibiting the expression of DNMT1 (DNA methyltransferase 1) and UHRF1 (RING finger domain 1) in colon cancer cells[3]. In U87MG and T98G glioma cell lines, hinokitiol demonstrates a dose-dependent decrease in viability, with IC50 values of 316.5 ± 35.5 and 152.5 ± 25.3 µM, respectively. Hinokitiol represses ALDH activity and self-renewal ability in glioma stem cells, and inhibits in vitro oncogenicity. Hinokitiol also reduces Nrf2 expression in glioma stem cells in a dose-dependent manner[4]. Hinokitiol attenuates liver injury following HS/R (Haemorrhagic shock and resuscitation), partly through the inhibition of NF-κB activation[5]. Moreover, hinokitiol inhibited the migration of lung cancer A549 cells through several mechanisms, including the activation of caspases-9 and -3, induction of p53/Bax and antioxidant CAT (antioxidant enzymes catalase) and SOD (superoxide dismutase), and reduction of MMP-2 and -9 (matrix metalloproteinases) activities. It also induces cytochrome c expression[6].
Hinokitiol/桧木醇 细胞实验
Cell Line
Concentration
Treated Time
Description
References
FPN1-deficient J774 macrophages
1 μM
Restored iron release in FPN1-deficient cells
Science. 2017 May 12;356(6338):608-616
PANC-1 human pancreatic cancer cells
80 μg/mL
10 h
To evaluate the effect of Hinokitiol on iron content and mitochondrial function in mammalian cells. Results showed that Hinokitiol had minor effects on iron content and mitochondrial function in mammalian cells, indicating selectivity towards fungal cells.
J Adv Res. 2021 Jun 17;34:65-77
BEAS-2B human bronchial epithelial cells
80 μg/mL
10 h
To evaluate the effect of Hinokitiol on iron content and mitochondrial function in mammalian cells. Results showed that Hinokitiol had minor effects on iron content and mitochondrial function in mammalian cells, indicating selectivity towards fungal cells.
J Adv Res. 2021 Jun 17;34:65-77
Candida albicans SC5314
2-8 μg/mL
30 min to 10 h
To evaluate the effect of Hinokitiol on fungal intracellular iron content and its inhibition of mitochondrial respiration. Results showed that Hinokitiol significantly reduced intracellular Fe2+ levels, inhibited the activities of mitochondrial respiratory chain complexes I and II, leading to decreased mitochondrial membrane potential and ATP production.
J Adv Res. 2021 Jun 17;34:65-77
Mfrn1-deficient MEL cells
1 μM
Restored iron uptake and hemoglobinization in Mfrn1-deficient cells
Science. 2017 May 12;356(6338):608-616
DS19 murine erythroleukemia (MEL) cells
1 μM
3 days
Restored iron uptake, iron-heme incorporation, and hemoglobinization in DMT1-deficient cells
Science. 2017 May 12;356(6338):608-616
Caco-2 gut epithelial cells
500 nM
Restored iron uptake and transepithelial iron transport in DMT1-deficient monolayers
Science. 2017 May 12;356(6338):608-616
Kupffer cells
5 μM
60 minutes
restore iron transport and reduce intracellular iron accumulation
Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2121400119
RAW264.7 macrophages
5 μM
assess iron release and intracellular labile iron levels
Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2121400119
HL-7702 cells
25, 50, 100, 200, 400 nM
24, 48, 72 hours
To evaluate the cytotoxicity of β-Thujaplicin on normal liver cells, results showed that β-Thujaplicin had minimal effect on the growth of HL-7702 cells
Cell Death Dis. 2019 Mar 15;10(4):255
HCCLM3 cells
25, 50, 100, 200, 400 nM
24, 48, 72 hours
To evaluate the cytotoxicity of β-Thujaplicin on HCC cells, results showed that β-Thujaplicin significantly inhibited the growth of HCCLM3 cells in a dose-dependent manner
Cell Death Dis. 2019 Mar 15;10(4):255
SMMC-7721 cells
25, 50, 100, 200, 400 nM
24, 48, 72 hours
To evaluate the cytotoxicity of β-Thujaplicin on HCC cells, results showed that β-Thujaplicin significantly inhibited the growth of SMMC-7721 cells in a dose-dependent manner
Cell Death Dis. 2019 Mar 15;10(4):255
HepG2 cells
25, 50, 100, 200, 400 nM
24, 48, 72 hours
To evaluate the cytotoxicity of β-Thujaplicin on HCC cells, results showed that β-Thujaplicin significantly inhibited the growth of HepG2 cells in a dose-dependent manner
Cell Death Dis. 2019 Mar 15;10(4):255
CRL-8024 cells
10–100μM
To evaluate the effect of hinokitiol on HCC cell proliferation, results showed that hinokitiol significantly attenuated the proliferation of HCC cell lines in a dose-dependent manner while downregulating the protein levels of UHRF1, GLI1, CD44, and CD133.
Cell Death Dis. 2023 Jun 28;14(6):381
MEL cells
1 μM
probe hemoglobinization and iron uptake
Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2121400119
MDA-MB-231 cells
6.25 to 100 µg/mL
48 hours
To evaluate anticancer efficacy, results showed that Hinokitiol-loaded phytosomal formulation had higher cytotoxicity than pure Hinokitiol, with an IC50 value of 5.7 µg/mL
Int J Nanomedicine. 2024 Oct 12;19:10321-10339
MCF-7 cells
6.25 to 100 µg/mL
48 hours
To evaluate anticancer efficacy, results showed that Hinokitiol-loaded phytosomal formulation had higher cytotoxicity than pure Hinokitiol, with an IC50 value of 18.6 µg/mL
Int J Nanomedicine. 2024 Oct 12;19:10321-10339
normal liver cell line HL-7702
25, 50, 100, 200, 400 nM
24, 48, 72 h
To evaluate the effect of β-Thujaplicin on normal liver cells, results showed that β-Thujaplicin had only a slight effect on the viability of HL-7702 cells at 400 nM
Cell Death Dis. 2019 Mar 15;10(4):255.
human hepatoma cell lines HCCLM3
25, 50, 100, 200, 400 nM
24, 48, 72 h
To evaluate the inhibitory effect of β-Thujaplicin on HCC cell growth, results showed that β-Thujaplicin significantly inhibited the viability of HCCLM3 cells in a dose-dependent manner
Cell Death Dis. 2019 Mar 15;10(4):255.
human hepatoma cell lines SMMC-7721
25, 50, 100, 200, 400 nM
24, 48, 72 h
To evaluate the inhibitory effect of β-Thujaplicin on HCC cell growth, results showed that β-Thujaplicin significantly inhibited the viability of SMMC-7721 cells in a dose-dependent manner
Cell Death Dis. 2019 Mar 15;10(4):255.
human hepatoma cell lines HepG2
25, 50, 100, 200, 400 nM
24, 48, 72 h
To evaluate the inhibitory effect of β-Thujaplicin on HCC cell growth, results showed that β-Thujaplicin significantly inhibited the viability of HepG2, SMMC-7721, and HCCLM3 cells in a dose-dependent manner
Cell Death Dis. 2019 Mar 15;10(4):255.
Hinokitiol/桧木醇 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Galleria mellonella
Candida albicans-infected larvae
Injection
2 μg/larva
Single dose, observed for 7 days
To evaluate the therapeutic effect of Hinokitiol on Candida albicans infection in vivo. Results showed that Hinokitiol significantly improved the survival rate of infected larvae and reduced fungal burden.
J Adv Res. 2021 Jun 17;34:65-77
Belgrade rats
DMT1-deficient rat model
Oral gavage
1.5 mg/kg
Single dose
Promoted gut iron absorption in DMT1-deficient rats
Science. 2017 May 12;356(6338):608-616
Nude mice
HepG2 tumor xenograft model
Intraperitoneal injection
5 mg/kg body weight
Once daily for 15 days
To evaluate the inhibitory effect of β-Thujaplicin on HepG2 tumor growth in vivo, results showed that β-Thujaplicin significantly reduced tumor volume and weight
Cell Death Dis. 2019 Mar 15;10(4):255
Mice
Myc-driven HCC model
Intraperitoneal injection
25 mg/kg
Twice a week from 4 to 9 weeks of birth
To evaluate the effect of hinokitiol on Myc-driven HCC mouse model, results showed that hinokitiol significantly reduced tumor growth and CSC phenotypes, and downregulated the expression of UHRF1, GLI1, CD44, and CD133.
Cell Death Dis. 2023 Jun 28;14(6):381
Mice
FPN1-deficient mice
Intraperitoneal injection
10 mg/kg
Daily for 1 week
Restore hemoglobinization and iron distribution
Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2121400119
Nude mice
HepG2 tumor xenograft model
Intraperitoneal injection
5 mg/kg body weight
Once daily for 15 days
To verify the antitumor effect of β-Thujaplicin in vivo, results showed that β-Thujaplicin significantly inhibited the growth of HepG2 tumor xenografts
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