1 research outputs found
<i>N</i>‑Hydroxycinnamide Derivatives of Osthole Presenting Genotoxicity and Cytotoxicity against Human Colon Adenocarcinoma Cells in Vitro and in Vivo
Osthole
is extracted from the Chinese herbs <i>Cnidium monnieri</i> and <i>Angelica pubescens</i>, and it was found to have
antitumor activity in vitro and in vivo. A series of osthole derivatives
have been synthesized, and the <i>N</i>-hydroxycinnamide
derivatives of osthole, WJ1376-1 and WJ1398-1 were found to have the
greatest potential against human colon adenocarcinoma cells. In contrast
to the parental osthole, both WJ1376-1 and WJ1398-1 were found to
induce multinucleation and polyploidy by microscopic observation and
flow cytometry. WJ1376-1 and WJ1398-1 significantly activated ataxia
telangiectasia and rad3 related (ATR) kinase, which triggered activation
of the checkpoint kinase 2 (Chk2) signaling pathway and then down
regulated Cdc25 phosphatase and Cdc2/cyclin B kinase activities. WJ1376-1
and WJ1398-1 also inhibited the phosphorylation of Aurora A kinase,
which is associated with important processes during mitosis. The presence
of a “comet” DNA fragment and phosphorylation of p53
at Ser 15 clearly indicated that DNA damage occurred with WJ1376-1
and WJ1398-1 treatment. WJ1376-1 and WJ1398-1 ultimately induced apoptosis
as evidenced by the upregulation of Bad and activation of caspases-3,
-7, and -9. Furthermore, WJ1376-1 and WJ1398-1 also showed a great
effect in attenuating tumor growth without affecting the body weight
of xenograft nude mice. Taken together, these results suggest that
the toxic activities of WJ1376-1 and WJ1398-1 were dissimilar to that
of the parental osthole, which can induce cell polyploidy and G<sub>2</sub>/M cell cycle arrest in colon adenocarcinoma cells and may
provide a potential therapeutic target for colon cancer treatment
in the future