The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

Abstract

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.There are three standard therapies for cancer treatment including surgery, radiotherapy and chemotherapy. Chemotherapy has a role either as strategic treatment for locally advanced disease or as a palliative treatment for metastatic tumors. 1,2 However, clinical use of chemotherapy is still unsatisfactory due to limited response rate, small survival benefit and poor prognosis. Therefore, the development of novel anticancer drug, which is more effective and shows less side effect for cancer patients, is urgently needed.Several studies have indicated that compounds containing indole structure are highly cytotoxic against many tumoral cell lines, and the indole ring seems to be the core nucleus of several potent tubulin polymerization inhibitors. 3 The most wildly used clinical antimicrotubule drugs containing indole structure is Vinca alkaloids. They are also known as microtubule-destabilizing agents, which includes natural compound vinblastine, vincristine and two semisynthetic derivatives, vindesine and vinorelbine. 4 Several new compounds containing indole structure isolated from natural sources or synthesized were shown to have high potential for cancer treatment. For example, indole-3-carbinol (I3C) was isolated from cruciferous vegetables with high potential for cancer therapy. I3C and its metabolites inhibited ...

Tackling the Cytotoxic Effect of a Marine Polycyclic Quinone-Type Metabolite: Halenaquinone Induces Molt 4 Cells Apoptosis via Oxidative Stress Combined with the Inhibition of HDAC and Topoisomerase Activities

“…Increasing evidence suggested that mitochondria are the critical source of ROS and could be considered as a potential target in cancer therapy. Many naturally-derived compounds were found to effect mitochondrial activity, such as curcumin, colchicine, paclitaxel and vinca alkaloid-derivative SK228 [ 33 , 34 , 35 , 36 ]. Alternations in the mitochondrial functions via the increase of ROS generation and disruption of mitochondrial membrane potential can lead to cell death [ 35 ].…”

Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression

“…For example, inhibition of paxillin phosphorylation by the sialytransferase inhibitor Lith-O-Asp or other small molecules suppress lung tumor progression and metastasis (Chen et al, 2011;Huang et al, 2012), as well as breast cancer progression (Golubovskaya et al, 2008), in vivo. Interestingly, these molecules affect phosphorylation activity in the N-terminal region of paxillin, and we have shown here and in a previous study that the expression of the N-terminal alone substantially increases migration when transfected into paxillin knockdown cells, where N-terminus and C-terminus of paxillin have been shown to have complementary but opposite effects on cell migration and invasion (Sero et al, 2011).…”

The Tetraindole SK228 Reverses the Epithelial-to-Mesenchymal Transition of Breast Cancer Cells by Up-Regulating Members of the miR-200 Family

“…In an earlier investigation, we showed that tetraindole (1,4-bis{di[1 H -indol-3-yl]methyl}benzene) and its 5-hydroxy tetraindole derivative, SK228, which contains a benzene core structure with four appended hydroxyindole groups, induce G2 arrest and apoptosis in human breast adenocarcinoma (MCF 7 and MDA-MB-231) cells through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3 [19]. In addition, it also has been shown that SK228 treatment causes a marked inhibition of the growth of an A549 tumor cell xenograft without producing adverse effects on liver and kidney function of treated mice [20].…”