Hinokitiol Inhibits Cell Growth through Induction of S-Phase Arrest and Apoptosis in Human Colon Cancer Cells and Suppresses Tumor Growth in a Mouse Xenograft Experiment

Abstract

Hinokitiol (1), a tropolone-related natural compound, induces apoptosis and has anti-inflammatory, antioxidant, and antitumor activities. In this study, the inhibitory effects of 1 were investigated on human colon cancer cell growth and tumor formation of xenograft mice. HCT-116 and SW-620 cells derived from human colon cancers were found to be similarly susceptible to 1, with IC50 values of 4.5 and 4.4 μM, respectively. Compound 1 induced S-phase arrest in the cell cycle progression and decreased the expression levels of cyclin A, cyclin E, and Cdk2. Conversely, 1 increased the expression of p21, a Cdk inhibitor. Compound 1 decreased Bcl-2 expression and increased the expression of Bax, and cleaved caspase-9 and -3. The effect of 1 on tumor formation when administered orally was evaluated in male BALB/c-nude mice implanted intradermally separately with HCT-116 and SW-620 cells. Tumor volumes and tumor weights in the mice treated with 1 (100 mg/kg) were decreased in both cases. These results suggest that the suppression of tumor formation by compound 1 in human colon cancer may occur through cell cycle arrest and apoptosis.

3-Hydroxyterphenyllin, a natural fungal metabolite, induces apoptosis and S phase arrest in human ovarian carcinoma cells

“…3-HT significantly inhibited the expression of cyclin E1, cyclin A2 and CDK2; thus, preventing the formation of cyclin E-CDK2 and cyclin A2-CDK2 complexes, which play pivotal role in the initiation and progression of the S phase (33), ultimately leading to S phase arrest. The results were in accordance with previous studies that natural compounds induced S phase arrest by inhibiting the expression of cyclin E, cyclin A2 and CDK in different types of human cancer cells (27,28). A previous study reported that h-PNAS-4 induced S phase arrest in ovarian cancer cells via activation of the Cdc25A-Cdk2-cyclin E/cyclin A pathway, the expression of cyclin E and cyclin A were upregulated while Cdc25A was inhibited (34).…”

Natural product β-thujaplicin inhibits homologous recombination repair and sensitizes cancer cells to radiation therapy

“…Additionally, It has also been reported to regulate tumor growth and metastasis, β-thujaplicin’s antitumor effects have been investigated in a variety of cancer models, including models of melanoma,breast cancer,lung cancer,colon cancer,prostate cancer, and oral cancer [33–35,38,46,47]. Some studies have shown that β-thujaplicin can inhibit cancer cell proliferation by inducing the p53-independent DNA damage response, S or G1 cell cycle arrest [33,34,48]. However,we found β-thujaplicin can inhibit HR repair through regulating the recruitment of RAD51 rather than inducing cell cycle arrest.…”

Hinokitiol Induces DNA Damage and Autophagy followed by Cell Cycle Arrest and Senescence in Gefitinib-Resistant Lung Adenocarcinoma Cells

“…Hinokitiol has been reported to have applications in regulating several biological activities including anti-inflammation [23], anti-bacterial [24], anti-fungal [25], and anti-viral activities [26]. It has also been shown to have anti-proliferative effects in various cancer cell lines including melanoma [27], prostate carcinoma [28], oral cancer [22] and colon cancer cells [29]. However, the effects of hinokitiol on lung adenocarcinoma cells and the mechanisms underlying its effects have not been fully elucidated.…”