![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
R Danesi, WD Figg, E Reed and CE Myers
Division of Hematology/Oncology, University of Virginia, Charlottesville 22908, USA.
Paclitaxel was examined for its effects on cell survival, internucleosomal DNA fragmentation, and protein isoprenylation in the human prostate cancer cell line PC-3. Treatment of cells with paclitaxel at 5-60 nM for 24 hr resulted in a dose-dependent inhibition of cell viability (IC50, 31.2 nM), which was partially prevented by supplementing the cell culture medium with two nonsterol polyisoprenyl compounds, farnesyl-pyrophosphate (-PP) and geranylgeranyl-PP (3 microM each). Furthermore, agarose gel electrophoresis of DNA extracted from cells treated with paclitaxel (15-60 nM) for 24 hr showed DNA laddering with production of fragments of 180-base pair multiples, indicating the occurrence of apoptotic cell death. Internucleosomal DNA fragmentation by paclitaxel was also detected by a photometric enzyme immunoassay using antihistone antibodies; if culture medium was supplemented with farnesyl-PP and geranylgeranyl-PP (3 microM each), a reduction in mono- and oligonucleosome production was observed. The post-translational incorporation of metabolites of (RS)-[5-3H]mevalonolactone (100 microCi/ml) into prenylated proteins of PC-3 cells was inhibited by paclitaxel at 30 and 60 nM. In addition, the immunoprecipitation of p21ras and p21rap-1 proteins from PC-3 cells exposed to paclitaxel (30 and 60 nM) and labeled with (RS)-[5-3H]mevalonolactone showed a substantial inhibition of the incorporation of farnesyl and geranylgeranyl prenoid groups, respectively, into the aforementioned proteins. These results indicate that the inhibition of protein isoprenylation is a novel component of the complex biochemical effects of the drug and plays an important role in the mechanism of paclitaxel cytotoxicity in PC-3 cells.
This article has been cited by other articles:
|
|
 |
|
  J. Michalakis, S. D. Georgatos, E. de Bree, H. Polioudaki, J. Romanos, V. Georgoulias, D. D. Tsiftsis, and P. A. Theodoropoulos Short-Term Exposure of Cancer Cells to Micromolar Doses of Paclitaxel, with or without Hyperthermia, Induces Long-Term Inhibition of Cell Proliferation and Cell Death In Vitro Ann. Surg. Oncol., March 1, 2007; 14(3): 1220 - 1228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ferlini, G. Raspaglio, S. Mozzetti, M. Distefano, F. Filippetti, E. Martinelli, G. Ferrandina, D. Gallo, F. O. Ranelletti, and G. Scambia Bcl-2 Down-Regulation Is a Novel Mechanism of Paclitaxel Resistance Mol. Pharmacol., July 1, 2003; 64(1): 51 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Hu, J. Hofmann, C. Zaloudek, N. Ferrara, T. Hamilton, and R. B. Jaffe Vascular Endothelial Growth Factor Immunoneutralization Plus Paclitaxel Markedly Reduces Tumor Burden and Ascites in Athymic Mouse Model of Ovarian Cancer Am. J. Pathol., November 1, 2002; 161(5): 1917 - 1924. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Holstein and R. J. Hohl Synergistic Interaction of Lovastatin and Paclitaxel in Human Cancer Cells Mol. Cancer Ther., December 1, 2001; 1(2): 141 - 149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Theodoropoulos, H. Polioudaki, O. Kostaki, S. P. Derdas, V. Georgoulias, C. Dargemont, and S. D. Georgatos Taxol Affects Nuclear Lamina and Pore Complex Organization and Inhibits Import of Karyophilic Proteins into the Cell Nucleus Cancer Res., September 1, 1999; 59(18): 4625 - 4633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Moasser, L. Sepp-Lorenzino, N. E. Kohl, A. Oliff, A. Balog, D.-S. Su, S. J. Danishefsky, and N. Rosen Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones PNAS, February 17, 1998; 95(4): 1369 - 1374. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
