Author of

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  MO04 - Lung Cancer Biology I (ID 86)

  • Event: WCLC 2013
  • Type: Mini Oral Abstract Session
  • Track: Biology
  • Presentations: 1
  • Moderators:G. Sozzi, D.C. Lam
  • Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 103, Level 1

  • 11262

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    MO04.02 - Paclitaxel resistance is associated with drug accumulation in intracellular compartments and paclitaxel-binding proteins in human lung cancer cell lines (ID 75)

    16:20 - 16:25  |  Author(s): S. Fushiki
    • Abstract
    • Presentation
    • Slides

    Background
    Several mechanisms have been suggested for paclitaxel resistance in cancer cells, including overexpression of the multidrug transporter gene, ATP-binding cassette, sub-family B, member 1 (ABCB1), and the presence of a point mutation in the β-tubulin gene at the paclitaxel-binding site. However, the mechanisms underlying resistance to this agent have not yet been completely elucidated.

    Methods
    Three human lung cancer cell lines, II18, A549, and RERF-LC-KJ, were analyzed; their 50% inhibitory concentrations of paclitaxel were -8.33, -7.69, and -4.51 logM, respectively. The cell lines did not have any β-tubulin mutation. We evaluated the expression levels of ABCB1, intracellular accumulation of paclitaxel, paclitaxel-induced stabilization of microtubules, and intracellular localization of Oregon Green[®] 488-conjugated paclitaxel in these cell lines. Moreover, we prepared paclitaxel conjugated ferriteglycidyl metacrylate (FG) beads to purify paclitaxel-binding proteins from whole cell lysates of these cells.

    Results
    The ABCB1 expression level was strongly correlated to intracellular [[3]H]-paclitaxel accumulation (r[2] = -0.804) but was not related with paclitaxel resistance. The changes in the quantities of polymerized tubulin and acetylated tubulin after paclitaxel exposure were not related to paclitaxel resistance. Differences were observed between the intracellular localization of paclitaxel in RERF-LC-KJ, the most resistant cell line, and in the other 2 cell lines. The use of Oregon Green[®] 488-conjugated paclitaxel enabled visualization of not only the normal microtubule formation in the partial cells but also the aggregated vesicle formation in RERF-LC-KJ cells; aggregated vesicle formation was not remarkable in the other cell lines. Affinity purification by paclitaxel immobilized beads revealed several specific bands in RERF-LC-KJ; these bands were not revealed in the other cell lines.

    Conclusion
    We propose that paclitaxel resistance is associated with intracellular compartments in which paclitaxel accumulates and paclitaxel-binding proteins expressed specifically in resistant cell line.

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