destruxin-b and Colorectal-Neoplasms

In continuation to our studies toward the identification of direct anti-cancer targets, here we showed that destruxin B (DB) from Metarhizium anisopliae suppressed the proliferation and induced cell cycle arrest in human colorectal cancer (CRC) HT29, SW480 and HCT116 cells. Additionally, DB induced apoptosis in HT29 cells by decreased expression level of anti-apoptotic proteins Bcl-2 and Bcl-xL while increased pro-apoptotic Bax. On the other hand, DB attenuated Wnt-signaling by downregulation of β-catenin, Tcf4 and β-catenin/Tcf4 transcriptional activity, concomitantly with decreased expression of β-catenin target genes cyclin D1, c-myc and survivin. Furthermore, DB affected the migratory and invasive ability of HT29 cells through suppressed MMPs-2 and -9 enzymatic activities. We also found that DB targeted the MAPK and/or PI3K/Akt pathway by reduced expression of Akt, IKK-α, JNK, NF-κB, c-Jun and c-Fos while increased that of IκBα. Finally, we demonstrated that DB inhibited tumorigenesis in HT29 xenograft mice using non-invasive bioluminescence technique. Consistently, tumor samples from DB-treated mice demonstrated suppressed expression of β-catenin, cyclin D1, survivin, and endothelial marker CD31 while increased caspase-3 expression. Collectively, our data supports DB as an inhibitor of Wnt/β-catenin/Tcf signaling pathway that may be beneficial in the CRC management.

Topics: Animals; Antineoplastic Agents; Apoptosis; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; beta Catenin; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Depsipeptides; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Luminescent Measurements; Metarhizium; Mice; Mice, Inbred NOD; Mice, SCID; Transcription Factor 4; Transcription Factors; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

The study of the anticancer effects of destruxin B (DB) is rare and its anticancer mechanism remains unknown. The aim of this study was to test the in vitro and in vivo anticancer effects of DB, on human HT-29 colorectal cancer (CRC).. DB was isolated and characterized by high pressure liquid chromatography, electrospray ionization mass spectrometry and (1)H-nuclear magnetic resonance spectroscopy. (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess the effects of DB on HT-29 cells in vitro. The anticancer effects of DB were investigated in a murine xenograft model of human colon cancer.. A significant inhibition of cell viability was observed with DB treatment in time- and dose-dependent manners. DB administered subcutaneously daily at 0.6-15 mg/kg was proven to be safe and effective in inhibiting the growth of CRC cells. Expression of Bax, cleaved poly (ADP-ribose) polymerase and active caspase-3 were observed with DB treatment and the increase in tumor volumes of treated groups were significantly (p<0.05) lower than those of the mock-treated group.. DB has potential as a new therapeutic agent against human CRC.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; bcl-2-Associated X Protein; Body Weight; Caspase 3; Cell Survival; Colorectal Neoplasms; Depsipeptides; Female; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Organ Size; Poly(ADP-ribose) Polymerases; Spleen; Xenograft Model Antitumor Assays