Effects of Taxol on the Synthesis of Nitric Oxide in Murine Microglial Cells

Chung, Hun Taeg; Park, Rae Kil; Jun, Chang Duk; Kwak, Hyun Jeong; Yoo, Ji Chang; Pae, Hyun Ock; Song, Jung Ho

Abstract

Taxol, an anticancer drug, 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 microglial cells. Here, we report that taxol, like LPS, provides a ""second"" signal for murine microglial cell activation to induce tumoricidal activity. Tumoricidal activity determined by MTT assay appeared that taxol or LPS alone weakly activated microglial cells to kill P815 mastocytoma cells, whereas combinations of taxol or LPS with IFN-r synergized to activate macrophages to lyse tumor cells in a dose dependent manner. Secretion of nitric oxide (NO) correlated with tumor cell killing, and the activated microglial cells failed to kill tumor cell targets in the presence of N'-monomethyl-L-arginine (N'MMA), a competitive inhibitor of NO synthase (NOS). Treatment of the cells with anti-TNF-a neutralizing antibodies clearly blocked taxol plus IFN-r induced tumoricidal activity as well as NO production. Collectively, the data illustrate the potential for taxol to activate microglial cell mediated-antitumor mechanisms in addition to its better characterized role as an anti-mitotic agent.