Quercetin abrogates taxol-mediated signaling by inhibiting multiple kinases

Cell cycle block in G(2)/M initiates apoptosis, but the mechanism of this s ignaling cascade are largely unknown. The microtubule-perturbing agent Taxo l has multiple effects on this signaling pathway and is a potent inducer of apoptosis. The specific pathways activated by low, clinically relevant con centrations of the drug are still largely unknown and are dependent on cell type and drug concentration. In this work, we have investigated why HeLa c ells respond to Taxol by undergoing complete apoptosis, whereas MCF-7 cells remain in an intermediate phase with reduced death. Three phases were dist inguished in these apoptotic pathways. The initial phase characterized by c ellular detachment is followed by a second phase which includes the onset o f apoptotic morphology, and p38 and Bcl-2 phosphorylation. These two phases are common to both cell lines. HeLa cells then proceed to the third and fi nal execution phase, which culminates in death, whereas MCF-7 cells do not progress. Interestingly, the isoflavonoid Quercetin, a known general kinase inhibitor and an antioxidant, was able to prevent the onset of Taxol-induc ed cellular detachment and to protect from cell death. Moreover, it blocked Taxol-induced phosphorylation of p38 and Bcl-2, and prevented a Taxol-indu ced change in relative mobility of the apoptosis signal-regulating kinase 1 (Ask1). Our data elucidate the signaling pathways activated by Taxol at lo w clinically relevant concentrations. (C) 2001 Academic Press.