| The primary goal of this study is to investigate the underlying mechanisms of paclitaxel induced lethality in human leukemia cells as a model of p53 null human cancer cells. Based on our understanding of these proposed mechanisms, efforts were taken to modulate paclitaxel induced lethality by controlling signal transudation pathways either by using a specific pharmacological inhibitors to inhibit JNK pathway and PI3K or ectopic enforced expression of proteins using inducible systems (e.g. p21cip1/WAF1, MEK. AKT). Our results indicate that the CDKI p21Cip1/WAF1 plays a significant role in the cell death response of p53-null human leukemia cells to paclitaxel-mediated lethality. Ectopic expression of p21cp1/WAF1 blocked the inactivation of ERK accompanying paclitaxel exposure. In addition, it attenuated, albeit modestly, paclitaxel-induced JNK activation which was accompanied by diminished phosphorylation of Bcl-2.; Enforced expression of MEK pathway protects Jurkat human leukemia cells from paclitaxel-induced apoptosis. In addition, paclitaxel inhibits ERK phosphorylation in human leukemia cell lines. On the other hand, Inhibition of JNK pathway significantly reduced paclitaxel induced lethality. Interestingly, JNK inhibition significantly decreased paclitaxel-induced Bcl-2 phophorylation. Finally, inhibition of PI3K potentiates paclitaxel-induced lethality. Enforced expression of AKT failed to protect the Jurkat cells from paclitaxel-induced lethality. |
