Purpose: In this study, the cytotoxic effects of patupilone (epothilone B; EPO906) were assessed in a panel of hepatocellular carcinoma (HCC) cell lines, and were compared with doxorubicin and the microtubule-stabilizing taxanes. Methods: The following HCC cell lines were used: PLC/PRF/5, HepG2, Hep3B, SNU-387, SNU-398, SNU-423, SNU-449, and SNU-475. Cells were treated with various concentrations of patupilone, paclitaxel, docetaxel, or doxorubicin for 72 h; 50% inhibitory concentrations (IC50) were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. P-glycoprotein expression was assessed using standard Western blotting techniques. Results: Patupilone was found to be the most potent drug in all 8 HCC cell lines. All cell lines except SNU-449 were 4- to19-fold more sensitive to patupilone than to paclitaxel and docetaxel, and 59- to 208-fold more sensitive than to doxorubicin. SNU-449, the most resistant cell line and the only one overexpressing P-glycoprotein, was 3- to 39-fold more resistant to paclitaxel, docetaxel, and doxorubicin than were other cell lines. The IC50 of patupilone in SNU-449 was 1.14 nmol, which was 108- to 529-fold lower than those of the other agents. Conclusion: Patupilone was more potent than taxanes and doxorubicin in HCC cell lines and may result in reduced clinical resistance by overcoming P-glycoprotein overexpression. A clinical study in HCC is warranted.
Gefitinib, a specific inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK), has shown promising activity in lung cancer. However, tumor cells eventually acquire the resistance limiting duration of efficacy. To characterize lung cancer cells with the acquired resistance to gefitinib, a resistant subline HCC827/GR was established by repeated exposure to the drug for more than 6 months. Compared with parent HCC827 cells having delE746-A750 mutation, HCC827/ GR cells were 5676.8-fold more resistant to gefitinib and showed the cross-resistance against erlotinib and cetuximab. However, the resistance to other chemotherapeutic drugs such as CL-387,785, ZD6474, cisplatin, etoposide, gemcitabine and paclitaxel, developed to a lesser degree suggesting that they would have more favorable response. Several factors related with the sensitivity to gefitinib were evaluated. The secondary mutation of T790M was not detected by sequencing and EGFR gene copy number by FISH was not changed. In addition, the epithelial-to-mesenchymal transition was not found. However, the expression of p-Akt was markedly increased and not reduced by treatment with gefitinib. The redundant pathways to activate Akt other than EGFR might develop and exert an important role in the acquired resistance to gefitinib.
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