Induction of cell death in pancreatic ductal adenocarcinoma by indirubin 3′-oxime and 5-methoxyindirubin 3′-oxime in vitro and in vivo

Publication date: 1 July 2017
Source:Cancer Letters, Volume 397
Author(s): Makoto Sano, Yoshimi Ichimaru, Masahiro Kurita, Emiko Hayashi, Taku Homma, Hiroaki Saito, Shinobu Masuda, Norimichi Nemoto, Akihiro Hemmi, Takashi Suzuki, Shinichi Miyairi, Hiroyuki Hao
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. To identify potential effective therapeutic drugs for PDAC, we established a screening system based on spheroid formation using 170#3 mouse PDAC cells with or without fibroblasts. We found that indirubin 3′-oxime (Indox) and 5-methoxyindirubin 3′-oxime (5MeOIndox) inhibited PDAC cell proliferation. Furthermore, PDAC xenograft growth was also inhibited in BALB/c nu/nu mice after administration of Indox and 5MeOIndox. Both phosphorylated CDK1 and cyclin B1 levels in 170#3 cells were significantly reduced by treatment with Indox and 5MeOIndox in vitro and in vivo. Cell cycle analysis revealed that 5MeOIndox, but not Indox, induced G2/M arrest. Annexin V–propidium iodide double-staining analysis demonstrated that Indox induced abundant non-apoptotic cell death of 170#3 cells, while 5MeOIndox predominantly induced early apoptosis, indicating that the cytotoxicity of 5MeOIndox is lower than that of Indox. These results suggest that one mechanism of 5MeOIndox is to induce G2/M arrest of PDAC cells via inhibition of CDK1/cyclin B1 levels, thereby leading to apoptosis. Our findings suggest 5MeOIndox as a potential useful anticancer agent in PDAC.



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