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

Abstract

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.

• Authors: Qi-Da Hu, Wei Chen, Tian-Lian Yan, Tao Ma, Cong-Lin Chen, Chao Liang, Qi Zhang, Xue-Feng Xia, Hao Liu, Xiao Zhi, Xiao-Xiao Zheng, Xue-Li Bai, Xia-Zhen Yu, Ting-Bo Liang
• Journal: Cancer letters (Cancer Lett) Vol. 325 Issue 2 Pg. 207-13 (Dec 28 2012) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 22781398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Aminosalicylic Acids
• Antibiotics, Antineoplastic
• Antineoplastic Agents
• Benzenesulfonates
• Cadherins
• NSC 74859
• Nuclear Proteins
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• TWIST1 protein, human
• Twist-Related Protein 1
• Vimentin
• Doxorubicin

Topics

• Aminosalicylic Acids (pharmacology)
• Antibiotics, Antineoplastic (pharmacology)
• Antineoplastic Agents (pharmacology)
• Benzenesulfonates (pharmacology)
• Cadherins (biosynthesis, genetics)
• Carcinoma, Hepatocellular (pathology)
• Cell Line, Tumor (drug effects)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Drug Synergism
• Epithelial-Mesenchymal Transition (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inhibitory Concentration 50
• Liver Neoplasms (pathology)
• Nuclear Proteins (biosynthesis, genetics)
• RNA Interference
• RNA, Small Interfering (pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Twist-Related Protein 1 (biosynthesis, genetics)
• Vimentin (biosynthesis, genetics)