Curcumol induces cell cycle arrest in colon cancer cells via reactive oxygen species and Akt/ GSK3β/cyclin D1 pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Curcuma kwangsiensis S. G. Lee & C. F. Liang (Guangxi ezhu, in Chinese) belongs to the Zingiberaceae family, has been used as a traditionally Chinese medicine nearly 2000 year. Curcumol is one of the guaiane-type sesquiterpenoid hemiketal isolated from medicine plant Curcuma kwangsiensis S. G. Lee & C. F. Liang, which has been reported possesses anti-cancer effects. Our previous study found that the most contribution to inhibit nasopharyngeal carcinoma cell growth was curcumol.

AIM OF THE STUDY:

To assess the effect of curcumol on cell cycle arrest against human colon cancer cells (CRC) cells (LoVo and SW480) and explore its mechanism in vitro and in vivo.

MATERIALS AND METHODS:

Curcumol was dissolved in absolute ethyl alcohol. The concentration of absolute ethyl alcohol in the control group or in experimental samples was always 1/500 (v/v) of the final medium volume. LoVo and SW480 cells were treated with different concentrations of curcumol (0, 53, 106, 212 and 424μM). And then the cell cycle of each group was examined by flow cytometry. The protein levels of PI3K, p-Akt, cyclin D1, cyclin E, CDK2, CDK4 and GSK3β were determined by Western blot. The mRNA expression of PI3K, Akt, cyclin D1, CDK4, P27, p21, and P16 in the treated cells were analyzed by real-time RT-PCR. In addition, the antitumor activity of curcumol was evaluated in nude mice bearing orthotopic tumor implants.

RESULTS:

Curcumol induced cell cycle arrest in G1/S phase. RT-qPCR and Western blot data showed that curcumol enhanced the expression of GSK3β, P27, p21 and P16, and decreased the levels of PI3K, phosphorylated Akt (p-Akt), cyclin D1, CDK4, cyclin E and CDK2. Furthermore, curcumol induced reactive oxygen species (ROS) generation in LoVo cells, and ROS scavenger N-acetylcysteine (NAC) significantly reversed curcumol-induced cell growth inhibition. Besides, curcumol also prevented the growth of human colon cancer cells xenografts in nude mouse, accompanied by the reduction of PI3K, Akt, cyclin D1, CDK4, cycln E and significant increase of GSK3β.

CONCLUSIONS:

Curcumol caused cell cycle arrest at the G0/G1 phase by ROS production and Akt/ GSK3β/cyclin D1 pathways inactivation, indicating the potential of curcumol in the prevention of colon cancer carcinogenesis.

• Authors: Juan Wang, Xu-Mei Li, Zhun Bai, Bi-Xia Chi, Yan Wei, Xu Chen
• Journal: Journal of ethnopharmacology (J Ethnopharmacol) Vol. 210 Pg. 1-9 (Jan 10 2018) ISSN: 1872-7573 [Electronic] Ireland
• PMID: 28684297 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• Antineoplastic Agents, Phytogenic
• Reactive Oxygen Species
• Sesquiterpenes
• Cyclin D1
• curcumol
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, isolation & purification, pharmacology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, pathology)
• Curcuma (chemistry)
• Cyclin D1 (metabolism)
• Dose-Response Relationship, Drug
• Flow Cytometry
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Sesquiterpenes (administration & dosage, isolation & purification, pharmacology)
• Xenograft Model Antitumor Assays