Quercetin abrogates taxol-mediated signaling by inhibiting multiple kinases.
Cell cycle block in G(2)/M initiates apoptosis, but the mechanism of this signaling cascade are largely unknown. The microtubule-perturbing agent Taxol has multiple effects on this signaling pathway and is a potent inducer of apoptosis. The specific pathways activated by low, clinically relevant concentrations of the drug are still largely unknown and are dependent on cell type and drug concentration. In this work, we have investigated why HeLa cells respond to Taxol by undergoing complete apoptosis, whereas MCF-7 cells remain in an intermediate phase with reduced death. Three phases were distinguished in these apoptotic pathways. The initial phase characterized by cellular detachment is followed by a second phase which includes the onset of 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 final 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-induced cellular detachment and to protect from cell death. Moreover, it blocked Taxol-induced phosphorylation of p38 and Bcl-2, and prevented a Taxol-induced change in relative mobility of the apoptosis signal-regulating kinase 1 (Ask1). Our data elucidate the signaling pathways activated by Taxol at low clinically relevant concentrations.
Marone
M
M
Laboratory of Anti-neoplastic Pharmacology, Catholic University, Rome, Italy.
D'Andrilli
G
G
Das
N
N
Ferlini
C
C
Chatterjee
S
S
Scambia
G
G
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006131:Growth Inhibitors; D007093:Imidazoles; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011794:Quercetin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; D017239:Paclitaxel; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one