Sequence Dependent Exposure of Mammary Carcinoma Cells to Taxotere® and the MEK1/2 Inhibitor U0126 Causes Enhanced Cell Killing In Vitro
Sequence Dependent Exposure of Mammary Carcinoma Cells to Taxotere® and the MEK1/2 Inhibitor U0126 Causes Enhanced Cell Killing In Vitro
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乳腺癌细胞序列依赖性暴露于 Taxotere® 和 MEK1/2 抑制剂 U0126 导致体外细胞杀伤增强
作者：
A. Yacoub;S. Han;R. Carón;D. Gilfor;S. Mooberry;S. Grant;P. Dent
Taxol (paclitaxel) and Taxotere (docetaxel) are considered as two of the most important anti-cancer chemotherapy drugs. The cytotoxic action of these drugs has been linked to their ability to inhibit microtubule depolymerization, causing growth arrest and subsequent cell death. Studies by a number of laboratories have also linked suppression of mitogen activated protein kinase (MAPK) signaling to enhanced Taxol toxicity. The present study examined the interactions of the semi-synthetic taxane Taxotere with MEK1/2 inhibitors in epithelial tumor cells. Concurrent treatment of MDA-MB-231 mammary and DU145 prostate carcinoma cells with Taxotere and MEK1/2 inhibitor resulted in protection from the anti-proliferative effects of Taxotere in MTT assays. In contrast, in MCF-7 mammary cells, concurrent Taxotere and MEK1/2 inhibitor treatment weakly enhanced the anti-proliferative effects of the taxane. Sequential treatment of MDA-MB-231 and MCF-7 cells with Taxotere followed by MEK1/2 inhibitor also enhanced the anti-proliferative effects of the taxane in MTT assays. However, no enhancement was observed in DU145 or PC-3 cells. Colony formation assays, including isobologram analyses, provided a more definitive demonstration that MCF-7 and MDA-MB-231 cells were sensitized to the toxic effects of Taxotere by U0126. Similar data were observed using Laulimalide, which binds to tubulin at a different site to Taxotere. The enhancement in Taxotere anti-proliferative effects by U0126 correlated with increased cell killing, 48-72h after treatment of cells that was blocked by inhibition of caspase 9, but not caspase 8, function. This observation was associated with prolonged suppression of ERK1/2 and AKT activity, without alteration in either p38 or JNK1/2 activity. Collectively these findings demonstrate that sequential administration of Taxotere followed by MEK1/2 inhibition can lead to increased cell death and loss of reproductive capacity in some, but not all, human tumor cells.
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影响因子：
11.2
作者：
S. Mooberry;G. Tien;Anne H. Hernandez;A. Plubrukarn;Bradley S. Davidson
通讯作者：
S. Mooberry;G. Tien;Anne H. Hernandez;A. Plubrukarn;Bradley S. Davidson
影响因子：
11.4
作者：
K. Bhalla;A. M. Ibrado;E. Tourkina;Caroline Tang;M. Mahoney;Yue Huang
通讯作者：
K. Bhalla;A. M. Ibrado;E. Tourkina;Caroline Tang;M. Mahoney;Yue Huang
影响因子：
11.2
作者：
Chunrong Yu;M. Rahmani;Yun Dai;D. Conrad;G. Krystal;P. Dent;S. Grant
通讯作者：
Chunrong Yu;M. Rahmani;Yun Dai;D. Conrad;G. Krystal;P. Dent;S. Grant
苔藓抑素 1 对紫杉醇诱导的人白血病细胞 (U937) 细胞凋亡和细胞毒性的影响。
影响因子：
5.8
作者：
Wang,S;Guo,CY;Castillo,A;Dent,P;Grant,S
通讯作者：
Grant,S
影响因子：
4
作者：
K. Pienta
通讯作者：
K. Pienta