title: Drug resistance to paclitaxel is not only associated with ABCB1 mRNA             expression but also with drug accumulation in intracellular compartments in human             lung cancer cell lines.
abstract: In order to clarify the mechanisms of resistance to paclitaxel in lung cancer, three human lung cancer cell lines which exhibit different sensitivity to paclitaxel were investigated from the following viewpoints: overexpression of ATP-binding cassette, sub-family B, member 1 (ABCB1), mutations on paclitaxel binding site of β-tubulin genes, quantity of polymerized tubulin and the intracellular localization of paclitaxel. ABCB1 expression was evaluated by real-time RT-PCR. No correlations were noted between the ABCB1 expression in the sensitive and resistant cell lines at the mRNA level. No mutations on the paclitaxel binding site of the β-tubulin genes were detected in either the resistant or sensitive cells. Live cell images obtained by confocal laser microscopy revealed that the resistant cell line, RERF-LC-KJ, had more accumulation of Oregon Green® 488 conjugated paclitaxel in the lysosomal and extra-lysosomal compartments of cytoplasm than other cell lines. The results obtained in this study indicated that the changes in the subcellular localization could contribute to the production of paclitaxel resistance in lung cancer cell lines. Further studies should be conducted to elucidate the molecular mechanisms that differentiate the intracellular localization of paclitaxel.
authors.affiliation: Department of General Thoracic Surgery, Kyoto Prefectural University                     of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566,                     Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Shimomura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yaoi
authors.forename: Kyoko
authors.initials: K
authors.lastname: Itoh
authors.forename: Daishiro
authors.initials: D
authors.lastname: Kato
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Terauchi
authors.forename: Junichi
authors.initials: J
authors.lastname: Shimada
authors.forename: Shinji
authors.initials: S
authors.lastname: Fushiki
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D000107:Acetylation; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology*; D017354:Point Mutation; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D014404:Tubulin; D017239:Paclitaxel