Bcl-2 up-regulation and P-p53 down-regulation account for the low sensitivity of murine L929 fibrosarcoma cells to oridonin-induced apoptosis.

Drug resistance has been a major limitation to chemotherapy. There are many mechanisms that contribute to such resistance. In our study, we subcloned oridonin-sensitive and low sensitive L929 cells and both types of cells grew at almost the same growth rate. The acquired low sensitivity to oridonin-induced apoptosis was associated with Bcl-2 up-regulation and down-regulation of p53 phosphorylation. The p38 inhibitor SB203580 decreased Bcl-2 expression in the low sensitive L929 cells and made the cells more sensitive to oridonin. Moreover, a higher dose of oridonin promoted p53 phosphorylation, increased Bax expression and subsequently induced death of low sensitive L929 cells, however, it had no effect on Bcl-2 expression. The increased Bcl-2/Bax ratio in oridonin low sensitive L929 cells did not inhibit caspase-9 or -3 activation, but suppressed the cleavage of poly (ADP-ribose) polymerase (PARP), indicating the existence of caspase-9 or -3 independent PARP activation. These results indicated that in L929 cells, there was a relationship among the low sensitivity to oridonin, down-regulation of p53 phosphorylation and Bcl-2 up-regulation.