Enhancing and priming of macrophages for superoxide anion production by taxol.
Taxol, an anticancer drug, has been known not only to block cell division by stabilizing microtubules but also to activate murine macrophages to express TNF-alpha, interleukin-1, and to produce nitric oxide (NO). We therefore reasoned that taxol could activate murine macrophages to generate reactive oxygen intermediates, such as superoxide anion (O2-), which are responsible for intracellular killing of pathogenic microbes. Treatment of RAW264.7 cells, murine macrophage cell line, with taxol increased phorbol ester-induced O2- production in a dose dependent manner (approximately 2 fold). In addition, taxol rapidly (< 1 hr) primed RAW264.7 cells to enhance O2- release stimulated with PMA. Taxol also enhanced stimulation of O2- production by FMLP, but not by Con A. This effect was abolished by prior treatment with both superoxide dismutase (SOD) and N-acetyl-L-cystein, a free radical scavenger. To investigate the mechanism of taxol-induced macrophage stimulation, we evaluated the ability of colchicine, a drug that inhibit tubulin polymerization, and cAMP analogues, which is known to depolymerize microtubule. Taxol-induced O2- production was inhibited by the treatment with both colchicine and DB-cAMP. Taken together, these results demonstrated that taxol provides two signals, "priming" and "enhancing", to generate superoxide anion via the stabilization of microtubules in murine RAW264.7 cells
Pae
H O
HO
Department of Microbiology and Immunology, Wonkwang University School of Medicine, Chonbuk, Korea.
Jun
C D
CD
Yoo
J C
JC
Kwak
H J
HJ
Lee
S J
SJ
Kook
Y A
YA
Park
R K
RK
Chung
H T
HT
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D013481:Superoxides; D003994:Bucladesine; D013755:Tetradecanoylphorbol Acetate; D017239:Paclitaxel; D003078:Colchicine