DAT-230, a Novel Microtubule Inhibitor, Induced Aberrant Mitosis and Apoptosis in SGC-7901 Cells.

Abstract

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.

• Authors: Foxiao Qiao, Daiying Zuo, Haifeng Wang, Zengqiang Li, Huan Qi, Weige Zhang, Yingliang Wu
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 36 Issue 2 Pg. 193-201 ( 2013) ISSN: 1347-5215 [Electronic] Japan
• PMID: 23370351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-methoxy-5-(2-(3,4,5-trimethoxyphenyl)thiophen-3-yl)aniline
• Aniline Compounds
• Antineoplastic Agents
• BAX protein, human
• Proto-Oncogene Proteins c-bcl-2
• Thiophenes
• Tubulin Modulators
• bcl-2-Associated X Protein
• Poly(ADP-ribose) Polymerases
• Caspase 3
• Caspase 9

Topics

• Aniline Compounds (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Inbred BALB C
• Mitosis (drug effects)
• Neoplasms (drug therapy, pathology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Thiophenes (pharmacology)
• Tubulin Modulators (pharmacology, therapeutic use)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (metabolism)