Effects of chemical manipulation of mitotic arrest and slippage on cancer cell survival and proliferation.
Microtubule-targeting cancer therapies interfere with mitotic spindle dynamics and block cells in mitosis by activating the mitotic checkpoint. Cells arrested in mitosis may remain arrested for extended periods of time or undergo mitotic slippage and enter interphase without having separated their chromosomes. How extended mitotic arrest and mitotic slippage contribute to subsequent cell death or survival is incompletely understood. To address this question, automated fluorescence microscopy assays were designed and used to screen chemical libraries for modulators of mitotic slippage. Chlorpromazine and triflupromazine were identified as drugs that inhibit mitotic slippage and SU6656 and geraldol as chemicals that stimulate mitotic slippage. Using the drugs to extend mitotic arrest imposed by low concentrations of paclitaxel led to increased cell survival and proliferation after drug removal. Cells arrested at mitosis with paclitaxel or vinblastine and chemically induced to undergo mitotic slippage underwent several rounds of DNA replication without cell division and exhibited signs of senescence but eventually all died. By contrast, cells arrested at mitosis with the KSP/Eg5 inhibitor S-trityl-L-cysteine and induced to undergo mitotic slippage were able to successfully divide and continued to proliferate after drug removal. These results show that reinforcing mitotic arrest with drugs that inhibit mitotic slippage can lead to increased cell survival and proliferation, while inducing mitotic slippage in cells treated with microtubule-targeting drugs seems to lead to protracted cell death.
Riffell
Jenna L
JL
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
Zimmerman
Carla
C
Khong
Anthony
A
McHardy
Lianne M
LM
Roberge
Michel
M
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002746:Chlorpromazine / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014273:Triflupromazine / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
C560847:3,4',7-trihydroxy-3'-methoxyflavone; D047309:Flavones; D007211:Indoles; C416927:SU 6656; D013449:Sulfonamides; C003724:3-tritylthio-L-alanine; D014747:Vinblastine; D003545:Cysteine; D017239:Paclitaxel; D014273:Triflupromazine; D002746:Chlorpromazine