Cell lines

SKOV-3, OVCAR-3, KGN and A2780 ovarian cancer (OC) cell line

Preparation Method

The OC cells were seeded in 96-well microplates (1×104 cells/well) and incubated at 37°C overnight. Following incubation with chaetocin (0.05, 0.1, 0.25, 0.5, 0.75, 1 and 2 µM) at 37°C for 24 h,

Reaction Conditions

0.05, 0.1, 0.25, 0.5, 0.75, 1 and 2 µM for 24 hours

Applications

Chaetocin significantly inhibited the viability of SKOV-3, OVCAR-3, KGN and A2780 cells in a dose-dependent manner, with half-maximal inhibitory concentrations of 0.30, 60.66, 81.86 and 100.60 nM, respectively.

Animal models

Female BALB/C nude mice

Preparation Method

Paired mice with equal tumor volume were divided into the chaetocin-treated group and the vehicle-treated group (n = 6 for each group), and then injected intraperitoneally (i.p.) daily with chaetocin (0.5 mg/kg) and the vehicle (DMSO), respectively. After 10 days of drug treatment, mice were sacrificed and the tumor were weighed.

Dosage form

Intraperitoneal injection, 0.5 mg/kg/day for 10 days

Applications

Significantly lower average tumor weight for chaetocin treatment group compared to control group

Chaetocin was reported to be a nonspecific inhibitor of histone methyl transferase (HMT) such as SUV39H1, thereby affecting gene expression^[1]. Chaetocin inhibited HMT SU(VAR)3-9 with an IC50 of 0.6 µM^[2].

Chaetocin significantly reduces the proliferation, cloning potential, and migration ability of the glioblastoma cell line T98G^[3]. Chaetocin abrogated the maintenance of stem cell characteristics and tumor growth of bladder cancer stem cells (BCSCs) by suppressing the KMT1A-GATA3-STAT3 circuit (inhibition ratio: 80.1%)^[4]. Chaetocin inhibited ovarian cancer (OC) cell proliferation, induced G2/M phase cell cycle arrest, and induced apoptosis at the concentration of 2µM (24 hours)^[5]. Chaetocin inhibited cell proliferation and reduced PI3K/AKT pathway and p-AKT in gastric cancer HGC-27 cell, at the concentration of 200µM (24 hours)^[6].

Chaetocin inhibited tumor growth in HGC-27 cell injected Gastric cancer mice model, by 0.5 mg/kg/day every alternate day for 24 days^[6]. Chaetocin inhibited tumor progression and reduced PCNA in U87MG cell injected glioma mice model, by 0.5 mg/kg/day every alternate day for 25 days^[7].

References:
[1]. Cherblanc F L, Chapman K L, Brown R, et al. Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases[J]. Nature chemical biology, 2013, 9(3): 136-137.
[2]. Greiner D, Bonaldi T, Eskeland R, et al. Identification of a specific inhibitor of the histone methyltransferase SU (VAR) 3-9[J]. Nature chemical biology, 2005, 1(3): 143-145.
[3]. Sepsa A, Levidou G, Gargalionis A, et al. Emerging role of linker histone variant H1x as a biomarker with prognostic value in astrocytic gliomas. A multivariate analysis including trimethylation of H3K9 and H4K20[J]. PLoS One, 2015, 10(1): e0115101.
[4]. Yang Z, Wang H, Zhang N, et al. Chaetocin Abrogates the Self-Renewal of Bladder Cancer Stem Cells via the Suppression of the KMT1A-GATA3-STAT3 Circuit[J]. Frontiers in cell and developmental biology, 2020, 8: 424.
[5]. Li Z, Huang L, Wei L, et al. Chaetocin induces caspase?dependent apoptosis in ovarian cancer cells via the generation of reactive oxygen species[J]. Oncology Letters, 2019, 18(2): 1915-1921.
[6]. Wen C, Wang H, Wu X, et al. ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin[J]. Cell death & disease, 2019, 10(11): 1-16.
[7]. Dixit D, Ghildiyal R, Anto N P, et al. Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism[J]. Cell death & disease, 2014, 5(5): e1212-e1212.