| Summary: | 碩士 === 中山醫學大學 === 毒理學研究所 === 91 === Microtubules (MTs) of the eukaryotic cytoskeleton are hollow cylinders that form by the polymerization of tubulin, a heterodimer of α-and β-tubulin. MTs perform a wide variety of cellular functions, such as structural organization, maintaining of cell shape, and used as highway for intracellular protein, organelle and other macromolecule transport action. The most important function of MTs is rearranging to form mitotic spindle during mitosis which assist to segregate chromosome. For this reason, MTs is a major target for chemotherapeutic drugs such as Tubulin-binding agents (TBAs).
Taxotere (Docetaxel) is a new semisynthetic taxane of TBAs. Taxotere selectively bind to the β-tubulin subunit of MTs and promotes the polymerization of tubulin, thereby causing cancer cell death by disrupting the normal MTs dynamics that required for cell division. Although Taxotere are used extensively in the treatment of cancer, there are some patients who losing growth-inhibitory effects of cancer cell due to the acquisition of drug resistance. Therefore, resistant to Taxotere treatment remains a serious clinical problem. Although, there are many mechanisms of resistance to TBAs have been reported. However, the precise mechanisms of TBAs resistance remain controversial. Therefore, we study the response of tubulins in Taxotere-treated cell lines in order to find out the correlation between Taxotere treatment and cellular MTs expression. Firstly, we studied the genomic sequence of ClassⅠβ-tubulin from lung cancer patients and cancer cells isolated from lung cancer, and rule out the possibility that β-tubulin gene innate mutations in the mechanism of resistance to Taxotere. Then we treated A549 and H1299 cell lines with long term treatment of Taxotere (8 days), and short term treatment of A549, H1299 and HeLa cell lines with Taxotere or Vincristine (18 hours) to observe tubulin response. We observed that TBAs-treated cells varied in tubulin isotype distribution within different cell lines, and that alterations in tubulin isotype distribution and induction may represent as two important mechanisms of resistance to TBAs. In conclusion from our data, correlation between Taxotere treatment and MTs expression clearly through two different pathway: a p53-dependent pathway and a p53-independent pathway. Both pathways need other factors to modulate and the regulators of TBAs response in cancer cells required farther investigation.
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