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, a microtubule-interfering agent that inhibits the polymerization of tubulin, is expected because of its potent effects on solid tumors. TZT-1027 is thought to act directly on cellular microtubules, and arrest cell mitosis, however, the molecular mechanisms of the microtubule damage by TZT-1027 have not been fully identified. To investigate the possible novel mechanisms of action of TZT-1027, we used the cDNA macroarray technique to examine its effect on the expression of hundreds of tightly transcriptionally controlled genes. We used two cell lines, one was human non-small cell lung carcinoma PC-14 cells as a model for cancer cells, and the other was human astrocytes as a model for normal neuronal cells, because the dose-limiting-factor of microtubule-interfering agents is mainly peripheral neurotoxicity. mRNAs prepared from the PC-14 and astrocyte cell lines treated with TZT-1027 were compared with 588 genes spotted onto the filter, and which gene groups TZT-1027 modulated between the two cell lines was investigated. TZT-1027 exposure modulated expression of a variety of genes including the genes encoding cell-cycle and growth regulators, receptors, angiogenesis and invasion regulators, rho family small GTPases and their regulators and growth factors and cytokines. However, the way of gene regulation by TZT-1027 exposure was different between PC-14 cells and astrocytes. Genes up-regulated in both PC-14 cells and astrocytes were those for RAR-epsilon, 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 in PC-14 cells may be involved in the antitumor activity of TZT-1027. On the other hand, growth factor receptor precursors was upregulated specifically in astrocytes by TZT-1027 and this gene regulation only in astrocytes may be candidates related with neurotoxicity.
Natsume
T
T
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Nakamura
T
T
Koh
Y
Y
Kobayashi
M
M
Saijo
N
N
Nishio
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009842:Oligopeptides / Q000494:pharmacology*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009842:Oligopeptides; C105791:soblidotin