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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.

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.