Taxanes such as paclitaxel and docetaxel are widely used in cancer chemotherapy regimens due to their ability to stabilize microtubules and to arrest cell division in mitosis (Chazard, 1994). While the events leading to mitotic arrest are well understood, the mechanism by which the drug induces cytotoxicity is unclear. Paclitaxel has previously been shown to promote secretion of TNFα in macrophages; however this has not been observed in other cell lines (Bogdan, 1992). TNFα induces cell death in many cell lines through interaction with its receptor TNFR1 (Hsu, 1996). TNFα also binds to a second receptor, TNFR2, which does not possess a death domain. TNFR2 does however retain the ability to induce expression of NFκB-dependent survival genes.

Our laboratory group recently selected MCF-7 cells for survival in increasing concentrations (doses) of paclitaxel or docetaxel (MCF-7TAX and MCF-7TXT, respectively). Resistance was only achieved at or above selection dose 9 (3.33nM docetaxel) (Hembruff et al., 2008). MCF-7 cells were also “selected” in the absence of these drugs to control for changes simply associated with extended cell propagation. The ABC transporter inhibitor cyclosporin A either had no effect on docetaxel sensitivity at selection dose 9, or partially restored sensitivity at selection dose 12 (Hembruff, 2008). These observations suggest there are likely additional mechanisms of docetaxel resistance at selection doses 9 through 12.

Interestingly, we observed that docetaxel concentrations between 1.11nM and 3.33nM induced a >100-fold increase in TNFα secretion from MCF-7 cells, which likely contributes to cytotoxicity. Consistent with this view, a neutralizing TNFR1 antibody decreased cytotoxicity of docetaxel in MCF-7 cells. We also discovered that MCF-7TXT and MCF-7TAX cells at or above selection dose 9 were resistant to TNFα-induced cell death. Moreover, MCF-7TXT cells displayed downregulation of TNFR1 upon the acquisition of resistance to taxanes. Increased levels of TNFα were observed within the media of MCF-7TXT cells selected to dose levels 9 and 10, but not dose levels 11 or 12. We further provide evidence that the increased levels of TNFα in the medium of MCF-7TXT cells contributes to increased cell survivability through a TNFR2-dependent activation of NFκB and its resulting increase in the expression of cell survival genes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3550.