NSC 74859-mediated inhibition of STAT3 enhances the anti-proliferative activity of cetuximab in hepatocellular carcinoma.

Cetuximab [an epidermal growth factor receptor (EGFR) inhibitor], which was shown to be effective in rectal and non-small cell lung cancers (NSCLCs), was only modestly effective in clinical trials of hepatocellular carcinoma (HCC). STAT3, which is thought to be a determinant of HCC sensitivity to antitumour drugs, may be involved. To evaluate the efficacy of combination therapy using cetuximab and NSC 74859 (a novel STAT3 inhibitor) in EGFR and STAT3 overexpressing hepatoma cells. Hepatoma cell lines were treated with cetuximab, NSC 74859 or a combination of both drugs. Efficacy of treatment was evaluated by determining cell viability using MTT assays and proliferation by cell counting. Expression and activation of STAT3 were determined using Western blot analysis. We evaluated the role of STAT3 in single and combination therapy using siRNA-mediated knock-down of STAT3 or STAT3 overexpression strategies. HepG2 and Huh-7 cells, which had lower levels of pSTAT3 than SK-HEP1 cells, were more sensitive to cetuximab treatment when compared with SK-HEP1 cells. Although none of these cell lines was sensitive to NSC 74859 alone, NSC 74859 potentiated the antiproliferative effect of cetuximab in all three cell lines. siRNA knock-down of STAT3 increased the sensitivity of these cell lines to cetuximab, whereas STAT3 overexpression antagonized these effects. Enhanced growth inhibition in hepatoma cells treated with both NSC 74859 and cetuximab suggests that cetuximab resistance is probably mediated via STAT3. Combination therapy using both inhibitors of EGFR and STAT3 signalling warrants further investigation under in vivo condition.

Chen W ，Shen X ，Xia X ，Xu G ，Ma T ，Bai X ，Liang T ... -  《-》

NSC 74859 enhances doxorubicin cytotoxicity via inhibition of epithelial-mesenchymal transition in hepatocellular carcinoma cells.

Doxorubicin-based therapy is not effective for the treatment of hepatocellular carcinomas (HCCs), which often undergo epithelial-mesenchymal transition (EMT) during tumor progression. Activation of signal transducer and activator of transcription 3 (STAT3) is associated with chemosensitivity and may contribute to EMT during HCC chemotherapy. Low doses of NSC 78459 (a novel STAT3 inhibitor) have little effect on HCC cell proliferation, but efficiently inhibit STAT3. HuH-7, Hep3B, and HepG2 cells, with epithelial phenotypes, show significantly enhanced doxorubicin cytotoxicity following co-treatment with NSC 74859, whereas mesenchymal SNU-449 cells show no such enhancement. NSC 74859 inhibits STAT3 activity and suppressed doxorubicin-induced EMT in epithelial HCC cells. siRNA-mediated STAT3 knockdown resulted in EMT inhibition, which led to attenuation of NSC 74859-mediated chemosensitivity. Our data indicate NSC 74859 co-administration enhances doxorubicin cytotoxicity by inhibiting STAT3 in epithelial HCC cells. STAT3 deactivation and associated EMT attenuation contribute to the synergistic anti-tumor effects of combined NSC 74859/doxorubicin therapy.

Hu QD ，Chen W ，Yan TL ，Ma T ，Chen CL ，Liang C ，Zhang Q ，Xia XF ，Liu H ，Zhi X ，Zheng XX ，Bai XL ，Yu XZ ，Liang TB ... -  《-》

A sorafenib derivative and novel SHP-1 agonist, SC-59, acts synergistically with radiotherapy in hepatocellular carcinoma cells through inhibition of STAT3.

Radiotherapy shows limited benefit as treatment for hepatocellular carcinoma (HCC). In this study, we aimed to overcome the radioresistance of HCC by using a novel sorafenib derivative, SC-59 that targets SHP-1-related signaling. HCC cell lines (SK-Hep1, Hep3B, and Huh7) were treated with sorafenib, SC-59, radiation, sorafenib plus radiation, or SC-59 plus radiation, and then apoptosis, colony formation, signal transduction and the phosphatase activity were analyzed. The synergistic effect of radiotherapy and SC-59 was analyzed using a combination index (CI) approach. In vivo efficacy was determined in a Huh7-bearing subcutaneous model. Mice were treated with radiation (5 Gy, one fraction per day) for 4 days, SC-59 (10mg/kg/day) for 24 days, or a combination. Tumor samples were further analyzed for p-STAT3 and SHP-1 activity. SC-59 displayed a better synergistic effect when used in combination with radiotherapy than sorafenib in HCC cell lines. SC-59 downregulated p-STAT3 and its downstream targets and increased SHP-1 phosphatase activity. Both ectopic STAT3 and inhibition of SHP-1 abolished SC-59-induced radiosensitization. Moreover, SC-59 significantly synergized radiotherapy in a Huh7 xenograft model by targeting SHP-1/STAT3 signaling. The novel sorafenib derivative, SC-59, acting as a SHP-1 agonist, displays a better synergistic effect when used in combination with radiotherapy than sorafenib for the treatment of HCC. Further clinical investigation is warranted.

Huang CY ，Tai WT ，Hsieh CY ，Hsu WM ，Lai YJ ，Chen LJ ，Shiau CW ，Chen KF ... -  《-》

The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling.

Lin L ，Amin R ，Gallicano GI ，Glasgow E ，Jogunoori W ，Jessup JM ，Zasloff M ，Marshall JL ，Shetty K ，Johnson L ，Mishra L ，He AR ... -  《-》

In-vitro growth inhibition of chemotherapy and molecular targeted agents in hepatocellular carcinoma.

Chang AY ，Wang M 《-》