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LLL12, a novel small inhibitor targeting STAT3 for hepatocellular carcinoma therapy.

Zuo M, Li C, Lin J, Javle M - Oncotarget (2015)

Bottom Line: Our results show that LLL12 selectively inhibited HCC cell proliferation and induced apoptosis in SNU387, SNU398, SNU449, and Hep3B HCC cells in vitro.Furthermore, LLL12 at 5 mg/kg/day significantly inhibited the growth of SNU398 xenografts in nude mice.Collectively, our results indicate that LLL12 could be used to target STAT3 for the effective prevention or treatment of HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
The constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in clinical incidences of hepatocellular carcinoma (HCC) but not in normal human hepatocytes. STAT3 signaling plays pivotal roles in angiogenesis, survival, metastasis, and growth of HCC. Recent evidence suggests that the blockade of aberrant STAT3 pathways can be exploited as a therapeutic strategy for HCC. We have developed the novel small molecular STAT3 inhibitor LLL12 on the basis of curcumin structure using computer-aided rational design. LLL12 has shown antitumor activity in various solid tumors including breast, brain, pancreatic cancer, and glioblastoma in vitro and in vivo. In this study, we hypothesized LLL12 inhibits STAT3 phosphorylation at tyrosine 705 (Y705) in HCC and show antitumor activity in HCC in vitro and in vivo. Our results show that LLL12 selectively inhibited HCC cell proliferation and induced apoptosis in SNU387, SNU398, SNU449, and Hep3B HCC cells in vitro. Furthermore, LLL12 at 5 mg/kg/day significantly inhibited the growth of SNU398 xenografts in nude mice. Collectively, our results indicate that LLL12 could be used to target STAT3 for the effective prevention or treatment of HCC.

No MeSH data available.


Related in: MedlinePlus

Immunofluorescence staining for p-STAT3 protein in HCC cell linesSNU387 and SNU398 cells were exposed to DMSO or LLL12 (5 μM) for 24 h. Subcellular localization and expression of STAT3 (green) was analyzed by immunofluorescent staining. Nuclei were counterstained using DAPI (blue).
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Figure 6: Immunofluorescence staining for p-STAT3 protein in HCC cell linesSNU387 and SNU398 cells were exposed to DMSO or LLL12 (5 μM) for 24 h. Subcellular localization and expression of STAT3 (green) was analyzed by immunofluorescent staining. Nuclei were counterstained using DAPI (blue).

Mentions: Phosphorylation of STAT3 (Y705) is required for nuclear translocation, which plays central roles in regulating STAT3 downstream target genes. To determine whether LLL12 can suppress nuclear translocation of STAT3, we performed an immunofluorescence assay using monoclonal antibodies against p-STAT3 protein. Images of fluorescence from cells stained with fluorescein isothiocyanate (FITC)-4′,6-diamidino-2-phenylindole (DAPI) show that LLL12 inhibits STAT3 phosphorylation and decreases the amount of p-STAT3 in the nucleus in SNU398 and SNU387 cells stained with a monoclonal anticytokeratin FITC-conjugated secondary antibody (Figure 6). However, no significantly inhibitive effects of LLL12 on nuclear translocation of STAT3 were observed in SNU449 and Hep3B cells (data not shown), possibly because SNU449 and Hep3B cells are more resistant to LLL12 than the other HCC cell lines.


LLL12, a novel small inhibitor targeting STAT3 for hepatocellular carcinoma therapy.

Zuo M, Li C, Lin J, Javle M - Oncotarget (2015)

Immunofluorescence staining for p-STAT3 protein in HCC cell linesSNU387 and SNU398 cells were exposed to DMSO or LLL12 (5 μM) for 24 h. Subcellular localization and expression of STAT3 (green) was analyzed by immunofluorescent staining. Nuclei were counterstained using DAPI (blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4484430&req=5

Figure 6: Immunofluorescence staining for p-STAT3 protein in HCC cell linesSNU387 and SNU398 cells were exposed to DMSO or LLL12 (5 μM) for 24 h. Subcellular localization and expression of STAT3 (green) was analyzed by immunofluorescent staining. Nuclei were counterstained using DAPI (blue).
Mentions: Phosphorylation of STAT3 (Y705) is required for nuclear translocation, which plays central roles in regulating STAT3 downstream target genes. To determine whether LLL12 can suppress nuclear translocation of STAT3, we performed an immunofluorescence assay using monoclonal antibodies against p-STAT3 protein. Images of fluorescence from cells stained with fluorescein isothiocyanate (FITC)-4′,6-diamidino-2-phenylindole (DAPI) show that LLL12 inhibits STAT3 phosphorylation and decreases the amount of p-STAT3 in the nucleus in SNU398 and SNU387 cells stained with a monoclonal anticytokeratin FITC-conjugated secondary antibody (Figure 6). However, no significantly inhibitive effects of LLL12 on nuclear translocation of STAT3 were observed in SNU449 and Hep3B cells (data not shown), possibly because SNU449 and Hep3B cells are more resistant to LLL12 than the other HCC cell lines.

Bottom Line: Our results show that LLL12 selectively inhibited HCC cell proliferation and induced apoptosis in SNU387, SNU398, SNU449, and Hep3B HCC cells in vitro.Furthermore, LLL12 at 5 mg/kg/day significantly inhibited the growth of SNU398 xenografts in nude mice.Collectively, our results indicate that LLL12 could be used to target STAT3 for the effective prevention or treatment of HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
The constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in clinical incidences of hepatocellular carcinoma (HCC) but not in normal human hepatocytes. STAT3 signaling plays pivotal roles in angiogenesis, survival, metastasis, and growth of HCC. Recent evidence suggests that the blockade of aberrant STAT3 pathways can be exploited as a therapeutic strategy for HCC. We have developed the novel small molecular STAT3 inhibitor LLL12 on the basis of curcumin structure using computer-aided rational design. LLL12 has shown antitumor activity in various solid tumors including breast, brain, pancreatic cancer, and glioblastoma in vitro and in vivo. In this study, we hypothesized LLL12 inhibits STAT3 phosphorylation at tyrosine 705 (Y705) in HCC and show antitumor activity in HCC in vitro and in vivo. Our results show that LLL12 selectively inhibited HCC cell proliferation and induced apoptosis in SNU387, SNU398, SNU449, and Hep3B HCC cells in vitro. Furthermore, LLL12 at 5 mg/kg/day significantly inhibited the growth of SNU398 xenografts in nude mice. Collectively, our results indicate that LLL12 could be used to target STAT3 for the effective prevention or treatment of HCC.

No MeSH data available.


Related in: MedlinePlus