Cytostatic activity of paclitaxel in coronary artery smooth muscle cells is mediated through transient mitotic arrest followed by permanent post-mitotic arrest: comparison with cancer cells.
The anti-cancer agent paclitaxel (PTX) is an effective anti-restenosis agent on drug eluting stents, primarily due to growth inhibition of coronary artery smooth muscle cells (CASMC) across a wide dose range. In this study, we compared the effects of PTX on CASMC to apoptotic-prone HL60 leukemia cells and apoptotic-reluctant A549 lung cancer cells to assess cell survival mechanisms. In comparison to HL60 and A549 cells, CASMC had a shorter mitotic arrest and a lower mitotic index. While CASMC and A549 cells did not become apoptotic and displayed a multi-nucleated phenotype, HL60 cells showed prolonged mitotic arrest followed by apoptosis. CASMC exiting mitosis were arrested in G1 as MN tetraploid cells, with decreased levels of cyclin B1 and PCNA. CASMC remained metabolically active, becoming permanently arrested as evidenced by increased levels of beta-galactosidase activity. These cells did not demonstrate elevated levels of inflammatory markers. Our findings suggest that a weak mitotic checkpoint or inhibited apoptotic cascade, or a combination of both, determine cell survival following PTX treatment. These in vitro findings suggest a mechanism for the cytostatic activity of PTX in CASMC for the inhibition of restenosis.
Blagosklonny
Mikhail V
MV
Brander Cancer Research Institute, New York Medical College, Valhalla, New York, USA. mblagosklonny@ordwayresearch.org
Demidenko
Zoya N
ZN
Giovino
Maria
M
Szynal
Carmin
C
Donskoy
Elina
E
Herrmann
Robert A
RA
Barry
James J
JJ
Whalen
Anne M
AM
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000188:drug therapy; D003331:Coronary Vessels / Q000166:cytology*; D016193:G1 Phase; D018922:HL-60 Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*
D017239:Paclitaxel