Abstract
Oxypeucedanin (OPD), a furocoumarin compound from Angelica dahurica (Umbelliferae), exhibits potential antiproliferative activities in human cancer cells. However, the underlying molecular mechanisms of OPD as an anticancer agent in human hepatocellular cancer cells have not been fully elucidated. Therefore, the present study investigated the antiproliferative effect of OPD in SK-Hep-1 human hepatoma cells. OPD effectively inhibited the growth of SK-Hep-1 cells. Flow cytometric analysis revealed that OPD was able to induce G2/M phase cell cycle arrest in cells. The G2/M phase cell cycle arrest by OPD was associated with the downregulation of the checkpoint proteins cyclin B1, cyclin E, cdc2, and cdc25c, and the up-regulation of p-chk1 (Ser345) expression. The growth-inhibitory activity of OPD against hepatoma cells was found to be p53-dependent. The p53-expressing cells (SK-Hep-1 and HepG2) were sensitive, but p53-null cells (Hep3B) were insensitive to the antiproliferative activity of OPD. OPD also activated the expression of p53, and thus leading to the induction of MDM2 and p21, which indicates that the antiproliferative activity of OPD is in part correlated with the modulation of p53 in cancer cells. In addition, the combination of OPD with gemcitabine showed synergistic growth-inhibitory activity in SK-Hep-1 cells. These findings suggest that the anti-proliferative activity of OPD may be highly associated with the induction of G2/M phase cell cycle arrest and upregulation of the p53/MDM2/p21 axis in SK-HEP-1 hepatoma cells.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer and the second most common cause of death from cancer [1]
Since OPD was shown to have the anti-proliferative activity against SK-Hep-1 cells, the isolated OPD analogs from the roots of Angelica dahurica were evaluated for their antiproliferative activity in SK-Hep-1 cells
The present study revealed that the induction of G2 /M phase cell cycle arrest by OPD was correlated with the regulation of Chk1-mediated G2 /M checkpoint proteins, including cdc25c/cdc2 and cdc2/cyclin B1 complex pathways, in hepatoma cells
Summary
Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer and the second most common cause of death from cancer [1]. 30 to 40% of patients with HCC diagnosed at early stages are potentially effectively treated by surgical therapies such as hepatectomy or liver transplantation [2]. The disease diagnosed at an advanced stage or re-progression stage after treatment has poor prognosis due to the fundamental liver disease and lack of other treatment options [2,3,4]. Any systemic therapy has not effectively contributed to survival for patients with advanced HCC [5]. Angelica dahurica (Umbelliferae) is an indigenous plant mainly distributed in Korea, China, and Russia. The root of Angelica dahurica has been used for the control of hysteria, bleeding, menstrual disorder, neuralgia and pain as a traditional medicine in Korea. Previous phytochemical studies revealed that the plant is a rich source of furanocoumarins, including oxypeucedanin [6].
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