Taxol provides a second signal for murine macrophage tumoricidal activity.
The anticancer drug, taxol, blocks cell division by stabilizing microtubules. However, taxol has distinct cell-cycle-independent effects. For example, taxol and bacterial LPS induce strikingly similar responses in murine macrophages. Here we report that taxol, like LPS, provides a "second" signal for murine macrophage activation to tumoricidal activity. Tumoricidal activity was determined by the release of 51Cr from prelabeled P815 mastocytoma target cells. Taxol or LPS alone weakly induced C3H/OuJ (Lpsn) murine macrophages to kill P815 mastocytoma cells, and tumoricidal activity was not induced by the classic "priming" signal, IFN-gamma. However, combinations of taxol or LPS with IFN-gamma synergized to activate macrophages to lyse tumor cells. Taxol activation of macrophages required an intact LPS signaling pathway, as taxol did not induce IFN-gamma-treated C3H/HeJ (Lpsd) macrophages to lyse target cells. In normal (Lpsn) murine macrophages, IFN-gamma, LPS, or taxol alone induced low or moderate levels of nitric oxide synthase gene expression and nitric oxide secretion. However, this gene and cytostatic metabolite were induced synergistically by combinations of taxol or LPS with IFN-gamma. Secretion of nitric oxide correlated with tumor cell killing, and taxol-activated macrophages failed to kill tumor targets in the presence of NG-monomethyl-L-arginine, a competitive inhibitor of nitric oxide synthase. The data illustrate the potential for taxol to activate macrophage mediated-antitumor mechanisms in addition to its better characterized role as an anti-mitotic agent.
Manthey
C L
CL
Department of Microbiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Perera
P Y
PY
Salkowski
C A
CA
Vogel
S N
SN
D000594:Amino Acid Oxidoreductases / Q000235:genetics; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D015870:Gene Expression; D007111:Immunity, Cellular / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000276:immunology*; D012515:Mast-Cell Sarcoma / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000276:immunology
D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D017239:Paclitaxel