Induction of proinflammatory and chemokine genes by lipopolysaccharide andpaclitaxel (Taxol (TM)) in murine and human breast cancer cell lines

In murine macrophages, the anti-tumor agent, paclitaxel, induces expression of a wide variety of inflammatory and anti-inflammatory genes, and causes cytokine secretion via signaling pathways that overlap with those engaged b y lipopolysaccharide (LPS), the endotoxic component of Gram-negative bacter ia. Using semi-quantitative RT-PCR for detection of gene expression, couple d with ELISA for the detection of secreted gene products, we analyzed the r esponsiveness of an extensive panel of cytokine and non-cytokine genes to i nduction by paclitaxel and LPS in the murine DA-3 breast cancer line. A sub set of the genes examined (e.g., G-CSF, MIP-2, iNOS, and EL-1 beta, and GM- CSF) was upregulated >3-20-fold by both LPS and paclitaxel in the DA-3 cell line, while IP-10 mRNA was induced by paclitaxel, but not by LPS. In the h uman MDA-MB-231 breast cancer cell line, LPS also increased mRNA levels for both GM-CSF and IP-10 significantly, while, paclitaxel increased IP-10 mRN A levels with delayed kinetics and failed to induce GM-CSF mRNA. Co-culture s of murine breast cancer cells and macrophages, stimulated with IFN-gamma plus either paclitaxel or LPS, resulted in augmented release of nitric oxid e. As both GM-CSF and IP-10 have been implicated in tumor rejection in vivo through either indirect actions on the host immune system or by inhibiting tumor angiogenesis, our data strengthen the hypothesis that tumor cell-der ived inflammatory mediators may, in part, underlie the anti-tumor efficacy of paclitaxel in breast cancer. (C) 2001 Academic Press.