Research ReportNon-taxoid site microtubule-stabilizing drugs work independently of tau overexpression in mouse N2a neuroblastoma cells

Microtubule-stabilizing drugs are useful in cancer therapy and show promise for treatment of neurodegenerative diseases. An overlapping binding site between tau and taxoid site drugs has led to a number of research papers investigating the competitive interaction between these drugs and the microtubule. This has implications for cancer treatment since increased tau could confer resistance to paclitaxel. Variations in the tau isoform ratio have also been reported in tauopathies, especially the rise in the levels of the four-repeat tau isoform. Therefore, in conditions of increased or altered expression of tau and its isoforms, a therapy that is not directly affected by changes in tau is desirable. Peloruside A and laulimalide are of particular interest in this respect because of their distinct binding site on the microtubule in relation to the clinically used drugs paclitaxel and ixabepilone. In the present study, we show that peloruside A and laulimalide stabilize microtubules independently of tau overexpression; whereas, the effects of paclitaxel and ixabepilone are masked by the presence of extra tau in the cell.

► N2a cells overexpressing tau are resistant to paclitaxel- and ixabepilone-induced microtubule polymerization. ► The IC50 of paclitaxel is 2-fold greater in N2a cells overexpressing tau. ► The non-taxoid binding site drugs peloruside and laulimalide work independently of tau overexpression in N2a cells.