DAT-230, a Novel Microtubule Inhibitor, Induced Aberrant Mitosis and Apoptosis in SGC-7901 Cells.
2-Methoxy-5-(2-(3,4,5-trimethoxyphenyl)thiophen-3-yl) aniline (DAT-230) is a novel synthesized compound of combretastatin-A-4 derivative with more stability. The present study is to investigate its anti-tumor activity and molecular mechanisms in human gastric adenocarcinoma SGC-7901 cells. DAT-230 inhibited SGC-7901 cells growth. The treatment of DAT-230 resulted in microtubule de-polymerization and G2/M phase arrest. Besides the accumulation and translocation of Cyclin B1, reduction of p-14/15-cdc2 and mitosis delay denoted the Cyclin B1-cdc2 complex active and M phase arrest in SGC-7901 cells treated with DAT-230. Mitochondria pathway participated in apoptosis after G2/M arrest in SGC-7901 cells treated with DAT-230, which was characterized by DNA fragmentation, cleavage of poly(ADP-ribose) polymerase (PARP), activation of caspase-3 and caspase-9, changes of Bcl-2 and Bax expression, decrease of mitochondrial membrane potential and release of cytochrome c from mitochondria. In vivo, DAT-230 delayed tumor growth in BALB/c nude mice with human gastric adenocarcinoma xenografts. Besides apoptosis was detected with terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay in tumor tissue. In conclusion, DAT-230 is a promising microtubule inhibitor with great anti-tumor activity to SGC-7901, in vitro and in vivo. Its potential to be a candidate of anti-cancer agent is worth of being further investigated.
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
Foxiao
F
Qiao
Daiying
D
Zuo
Haifeng
H
Wang
Zengqiang
Z
Li
Huan
H
Qi
Weige
W
Zhang
Yingliang
Y
Wu
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C575717:2-methoxy-5-(2-(3,4,5-trimethoxyphenyl)thiophen-3-yl)aniline; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D013876:Thiophenes; D050257:Tubulin Modulators; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053453:Caspase 9