Gene Expression Profiling of Exposure to TZT-1027, a Novel Microtubule-Interfering Agent, in Non-Small Cell Lung Cancer PC-14 Cells and Astrocytes

Clinical use of TZT-1027, amicrotubule-interfering agent that inhibitsthe polymerization of tubulin, is expectedbecause of its potent effects on solidtumors. TZT-1027 is thought to act directlyon cellular microtubules, and arrest cellmitosis, however, the molecular mechanismsof the microtubule damage by TZT-1027 havenot been fully identified. To investigatethe possible novel mechanisms of action ofTZT-1027, we used the cDNA macroarraytechnique to examine its effect on theexpression of hundreds of tightlytranscriptionally controlled genes. We usedtwo cell lines, one was human non-smallcell lung carcinoma PC-14 cells as a modelfor cancer cells, and the other was humanastrocytes as a model for normal neuronalcells, because the dose-limiting-factor ofmicrotubule-interfering agents is mainlyperipheral neurotoxicity. mRNAs preparedfrom the PC-14 and astrocyte cell linestreated with TZT-1027 were compared with588 genes spotted onto the filter, andwhich gene groups TZT-1027 modulatedbetween the two cell lines wasinvestigated. TZT-1027 exposure modulatedexpression of a variety of genes includingthe genes encoding cell-cycle and growthregulators, receptors, angiogenesis andinvasion regulators, rho family smallGTPases and their regulators and growthfactors and cytokines. However, the way ofgene regulation by TZT-1027 exposure wasdifferent between PC-14 cells andastrocytes. Genes up-regulated in bothPC-14 cells and astrocytes were those forRAR-ε, TNFR 1 and 2 and so on.Specifically altered genes in PC-14 cells,such as the genes coding for cytokeratin 8,XPG, fau and the genes regulated only inPC-14 cells may be involved in theantitumor activity of TZT-1027. On theother hand, growth factor receptorprecursors was upregulated specifically inastrocytes by TZT-1027 and this generegulation only in astrocytes may becandidates related with neurotoxicity.