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. 2003 Mar 24;88(6):973-80.
doi: 10.1038/sj.bjc.6600788.

Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway

H-L Lin  1 , W-Y Lui, T-Y Liu, C-W Chi
Affiliations

Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway

H-L Lin et al. Br J Cancer. .

Abstract

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.

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Figures

Figure 1
Figure 1
Effect of Taxol (0.1 μM) and cyclosporin A (1–10 μM) (A), or Taxol (0.1 μM) and FK506 (0.01–10 μM) (B) on cell viability of hepatoma cells. Data are expressed as mean±s.e. of mean from duplicate samples of three to five separate experiments. *indicates P<0.05 as compared with respective control group.
Figure 2
Figure 2
Effect of combined cyclosporin A (1–10 μM) and Taxol (0.1 μM) treatment on caspase-1, -3 and -8 activities in hepatoma cells at 24 h (A). The time-course response on caspase-1, -3, -8 and -9 activities after treatment of hepatoma cells with cyclosporin A (10 μM) and Taxol (0.1 μM) (B). Data are expressed as mean±s.e. of mean from duplicate samples of two to three separate experiments.
Figure 3
Figure 3
Percent changes in mitochondrial membrane potential after cyclosporin A (CA, 10 μM) and Taxol (Tx, 0.1 μM) treatment for 2–24 h in HepG2 cells.
Figure 4
Figure 4
Western blot analysis of phospho-AKT1, AKT1, PTEN, phospho-BAD, BAD and procaspase-3 expression in HepG2 cells treated with cyclosporin A (CA, 10 μM) and/or Taxol (Tx, 0.1 μM).
Figure 5
Figure 5
(A) Caspase-3 activity in HepG2 cells after wortmannin (10 μM) and/or Taxol (0.1 μM) treatment for 24 h. *P<0.001 as compared with wortmannin alone treatment; #P<0.01 as compared with Taxol alone treatment, (B) Effect of a dominant-negative AKT1 expression vector (dn AKT) and control vector (vector) in combination with 0.1 μM Taxol on caspase-3 activation. Caspase-3 activation is shown as fold of respective transient transfection control groups.
Figure 6
Figure 6
Growth inhibition of Hepa 1-6 tumours in SCID (A) and C57BL/6 (B) mice after treatment with cyclosporin A (CA) and/or Taxol (Tx). Cyclosporin A was given at two doses (CA (H): 6.67 mg kg−1; CA (L): 5 mg kg−1). The dose of Taxol was Tx (H): 2.68 mg kg−1 and Tx (L): 2 mg kg−1, respectively. Each point represents average from five to seven mice. The detailed procedures of animal studies were described in Materials and Methods. #P<0.05; *P<0.01 compared with DMSO control.
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