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Cell Cycle, Cell Death, and Senescence

Parthenolide Cooperates with NS398 to Inhibit Growth of Human Hepatocellular Carcinoma Cells through Effects on Apoptosis and G₀-G₁ Cell Cycle Arrest

Departments of ¹ Surgery and ² Biochemistry/Molecular Biology and ³ Walther Oncology Center, Indiana University School of Medicine; ⁴ Indiana University Cancer Center; ⁵ Richard L. Roudebush VA Medical Center, Indianapolis, Indiana

Requests for reprints: C. Max Schmidt, Departments of Surgery and Biochemistry/Molecular Biology, Indiana University School of Medicine, 1044 West Walnut Street, Building R4, Room 039, Indianapolis, IN 46202. Phone: 317-274-4122; Fax: 317-278-4325; E-mail: maxschmi{at}iupui.edu

Chemotherapy to date has not been effective in the treatment of human hepatocellular carcinoma. More effective treatment strategies may involve combinations of agents with activity against hepatocellular carcinoma. Parthenolide, a nuclear factor-B (NF-B) inhibitor, and NS398, a cyclooxygenase (COX)-2 inhibitor, have been shown to individually suppress the growth of hepatocellular carcinoma cells in vitro. To investigate their effects in combination, three human hepatocellular carcinoma lines (Hep3B, HepG2, and PLC) were treated with parthenolide and/or NS398. Parthenolide (0.1-10 µmol/L) and NS398 (1-100 µmol/L) each caused concentration-dependent growth inhibition in all cell lines. The addition of parthenolide to NS398 reduced the concentration of NS398 required to inhibit hepatocellular carcinoma growth. Because parthenolide and COX-2 inhibitors have been reported to influence NF-B activity, the effects on this pathway were investigated. The combination of parthenolide/NS398 inhibited phosphorylation of the NF-B-inhibitory protein IB and increased total IB levels. NF-B DNA-binding and transcriptional activities were inhibited more by the combination than the single agents in Hep3B and HepG2 cells but not in PLC cells. The response of PLC cells to NS398 was augmented by p65 small interfering RNA to inhibit NF-B p65 protein expression. The combination of parthenolide/NS398 increased apoptosis only in PLC cells, suggesting that the combination may decrease the apoptotic threshold in these cells. In Hep3B and HepG2 cells, combination treatment with NS398/parthenolide altered the cell cycle distribution resulting in more G₀-G₁ accumulation. Cyclin D1 levels were further decreased by combination treatment in all cell lines, correlating with the cell cycle alterations. Our results suggest that parthenolide may be effective in combination with COX-2 inhibitors for the treatment of hepatocellular carcinoma. (Mol Cancer Res 2006;4(6):387–400)

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