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.
Huang
Jian
J
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, P.R.China.
Wu
Lijun
L
Tashiro
Shin-ichi
S
Onodera
Satoshi
S
Ikejima
Takashi
T
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006690:Bisbenzimidazole; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002999:Clone Cells; D053938:DNA Fragmentation / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D045786:Diterpenes, Kaurane; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D019254:Genes, bcl-2 / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics*; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D045786:Diterpenes, Kaurane; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C011959:oridonin; D020169:Caspases; D006690:Bisbenzimidazole; C093642:SB 203580