Paclitaxel induces primary and postmitotic G1 arrest in human arterial smooth muscle cells.
Paclitaxel (PTX), a microtubule-active drug, causes mitotic arrest leading to apoptosis in certain tumor cell lines. Here we investigated the effects of PTX on human arterial smooth muscle cell (SMC) cells. In SMC, PTX caused both (a) primary arrest in G(1) and (b) post-mitotic arrest in G(1). Post-mitotic cells were multinucleated (MN) with either 2C (near-diploid) or 4C (tetraploid) DNA content. At PTX concentrations above 12 ng/ml, MN cells had 4C DNA content consistent with the lack of cytokinesis during abortive mitosis. Treatment with 6-12 ng/ml PTX yielded MN cells with 2C DNA content. Finally, 1-6 ng/ml of PTX, the lowest concentrations that affected cell proliferation, caused G(1) arrest without multinucleation. It is important that PTX did not cause apoptosis in SMC. The absence of apoptosis could be explained by mitotic exit and G(1) arrest as well as by low constitutive levels of caspase expression and by p53 and p21 induction. Thus, following transient mitotic arrest, SMC exit mitosis to form MN cells. These post-mitotic cells were subsequently arrested in G(1) but maintained normal elongated morphology and were viable for at least 21 days. We conclude that in SMC PTX causes post-mitotic cell cycle arrest rather than cell death.
Blagosklonny
Mikhail V
MV
Brander Cancer Research Institute, New York Medical College, Hawthorne, New York, USA.
Darzynkiewicz
Zbigniew
Z
Halicka
H Dorota
HD
Pozarowski
Piotr
P
Demidenko
Zoya N
ZN
Barry
James J
JJ
Kamath
Kalpana R
KR
Herrmann
Robert A
RA
D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000166:cytology; D016193:G1 Phase / Q000187:drug effects*; D018922:HL-60 Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008938:Mitosis / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology*; D011003:Ploidies; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism
C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D017239:Paclitaxel