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.
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.
Department of Life Sciences, National Taiwan Normal University, Taipei, Taiwan.
Sin-Ming
SM
Huang
Pei-Chun
PC
Hsu
Mei-Yu
MY
Chen
Wen-Shan
WS
Li
Shivaji V
SV
More
Kwok-Tung
KT
Lu
Yi-Ching
YC
Wang
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D004938:Esophageal Neoplasms; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051419:Paxillin / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D014992:Xylenes / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis
C572350:1,4-bis(di(5-hydroxy-1H-indol-3-yl)methyl)benzene; D000970:Antineoplastic Agents; D007211:Indoles; D051419:Paxillin; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D014992:Xylenes; D045304:Cytochromes c; D051416:Focal Adhesion Protein-Tyrosine Kinases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020742:rhoA GTP-Binding Protein