Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway.
Hepatoma cells are known to be highly resistant to chemotherapy. Previously, we have found differential Taxol resistance in human and murine hepatoma cells. The aim of this study was to examine the effect of a multidrug resistance inhibitor, cyclosporin A in combination with Taxol on hepatoma in vitro and in vivo, and to identify the possible mechanism involved in Taxol resistance. Simultaneous treatment of cyclosporin A (0-10 microM) and Taxol (0.1 microM) inhibited cell growth in vitro. Cyclosporin A interfered with Taxol (0.1 microM)-induced AKT activation and BAD phosphorylation. Cyclosporin A combined with Taxol treatment augments caspase-9, -3 activation and loss of mitochondrial membrane potential in HepG2 cells. PI3 kinase inhibitor, wortmannin, or a dominant-negative AKT1 expression vector treatment partially enhanced Taxol-induced apoptosis indicating that PI3 kinase-AKT pathway was involved in Taxol-resistance pathway. Moreover, combination treatment reduced tumour growth in SCID and C57BL/6 mice as compared to either Taxol or cyclosporin A treatment. Our results indicate that the combination of cyclosporin A and Taxol is effective in the reversal of Taxol resistance through the inhibition of PI3 kinase-AKT1 pathway.
Lin
H-L
HL
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
Lui
W-Y
WY
Liu
T-Y
TY
Chi
C-W
CW
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008928:Mitochondria / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D016572:Cyclosporine; D004791:Enzyme Inhibitors; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human