Drugs in clinical use with
indole structure exhibit side effects. Therefore, to search for
indole compounds with more efficacy and less side effect for
cancer therapy, we developed a novel
indole compound
SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and
tumor xenografts in nude mice models.
SK228 significantly inhibited growth of different lung and
esophageal cancer cell lines at sub-micromolar range, but not normal lung cells.
SK228 induced
DNA damages mainly by producing
reactive oxygen species (ROS) resulting in apoptosis.
SK228 treatment increased the release of
cytochrome c into the cytosol along with the increased activity of
caspase-3 and -9 without affecting
caspase-8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL-2 family regulators were also affected. Moreover, low-dose
SK228 significantly reduced the invasion of
cancer cells. The active phosphorylated form of FAK/
Paxillin signaling pathway
proteins and active form of RhoA were decreased. Moreover, the
F-actin cytoskeleton was disrupted after low-dose
SK228 treatment. Growth of an A549
tumor cell xenograft was markedly inhibited without significant side effects. SK228-induced apoptosis was confirmed by
terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved
caspase-3 in
tumors from treated mice. Our study provides the first evidence that
SK228 exhibits
cancer cell-specific cytotoxicity by inducing mitochondria-mediated apoptosis. In addition,
SK228 inhibits
cancer cell invasion via FAK/
Paxillin disruption at noncytotoxic doses.
SK228 can be further tested as a
pharmaceutical compound for
cancer treatment.