Antiproliferating activity of the mitotic inhibitor pironetin against vindesine- and paclitaxel-resistant human small cell lung cancer H69 cells.
Pironetin, isolated from Streptomyces sp., is a potent inhibitor of microtubule assembly and the first compound identified that covalently binds to alpha-tubulin at Lys352. We examined whether pironetin is an effective agent against human small cell lung cancer H69 cells, including two cell lines resistant to the microtubule-targeted drugs vindesine (H69/VDS) and paclitaxel (H69/Txl) that interact with beta-tubulin. Pironetin was found to be effective against these resistant cells as well as their parental cells. In addition, pironetin inhibited the growth of human leukemic K562 multidrug-resistant cells (K562/ADM), which have mdr1 gene expression, as well as the parental K562 cells. In these cell lines, including the parental and resistant cells, pironetin caused complete mitotic arrest; in addition, apoptosis inductions by 30 and 100 nM pironetin were observed. In this study, the new mitotic inhibitor, pironetin, was found to be effective not only against human tumor cell lines resistant to microtubule-targeted drugs, but also multidrug-resistant cells with mdr1 gene expression. These results suggest that pironetin is a useful agent for overcoming drug resistance in cancer chemotherapy.
Yoshida
Mitsuzi
M
Pharmacology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji Chuo-ku, Tokyo 104-0045, Japan. myoshida@gan2.res.ncc.go.jp
Matsui
Yuki
Y
Ikarashi
Yoshinori
Y
Usui
Takeo
T
Osada
Hiroyuki
H
Wakasugi
Hiro
H
D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D014751:Vindesine / Q000494:pharmacology*
D011753:Pyrones; C088446:pironetin; D004317:Doxorubicin; D017239:Paclitaxel; D014751:Vindesine