S. Isonishi et al., Depletion of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) enhances platinum drug sensitivity in human ovarian carcinoma cells, BR J CANC, 82(1), 2000, pp. 34-38
Down-regulation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-a
cetate (TPA) enhances the sensitivity of human ovarian carcinoma 2008 cells
to various types of platinum compounds such as cisplatin (DDP), carboplati
n and (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)-plati
num(II) monohydrate (DWA) by a factor of two- to threefold. TPA enhanced th
e sensitivity of the DDP-resistant 2008/C13*5.25 subline to each of these t
hree drugs to the same extent as for the 2008 cells. The extent of PKC down
-regulation and drug sensitization depended on the duration of TPA exposure
; maximum effect was achieved with a 48 h pretreatment. Sensitization was T
PA concentration-dependent and was maximal at 0.05 mu M TPA. 2008 cells exp
ressed only the PKC alpha and PKC zeta isoforms. Western blot analysis reve
aled that whereas the expression of PKC alpha was reduced by TPA the level
of PKC zeta was not affected. These results suggest that PKC alpha is the i
sotype responsive to TPA in these cells and that platinum drug sensitivity
can be modulated by this isoform alone. In parallel to its effect on PKC al
pha, TPA decreased cellular glutathione content by 30 +/- 3 (standard devia
tion (s.d) % in 2008 cells and by 41 +/- 3 (s.d.) % in 2008/C13*5.25 cells.
TPA also increased accumulation of DDP and DWA by 70%, although this effec
t was limited to the 2008/C13*5.25 cells. TPA rendered 2008 and 2008/C13*5.
25 cells resistant to cadmium chloride by a factor of 3.7 acid 3.6-fold res
pectively, suggesting a significant increase in cellular metallothionein co
ntent. Although the mechanism of TPA induced sensitization is not yet fully
understood, this study points to a central role for PKC alpha in modulatin
g platinum drug sensitivity. (C) 2000 Cancer Research Campaign.