Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/50187
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Título : Farnesyl transferase inhibitors reverse taxane-resistence
Autor : Marcus, Adam I., O'Brate, Aurora M., Martínez Buey, Rubén, Zhou, Jun, Thomas, Shala, Khuri, Fadlo R., Andreu Morales, José Manuel, Díaz, José Fernando, Giannakakou, Paraskevi
Palabras clave : Farnesyltransferase Inhibitors
xane-resistance
βTa-tubulin mutation
HDAC6
Fecha de publicación : 1-Sep-2006
Editor: American Association for Cancer Research
Citación : Cancer Research 66:8838-8846(2006)
Resumen: The combination of farnesyltransferase inhibitors (FTIs) and taxanes has been shown to result in potent antiproliferative and antimitotic synergy. Recent phase I and II clinical trials have shown that this combination shows clinical activity in taxane-refractory or taxane-resistant cancer patients. To understand the mechanism behind these clinical observations, we used a cancer cell model of paclitaxel resistance and showed that the FTI/taxane combination retains potent antiproliferative, antimitotic, and proapoptotic activity against the paclitaxel-resistant cells, at doses where each drug alone has little or no activity. To probe the mechanistic basis of these observations, paclitaxel activity was monitored in living cells using the fluorescently conjugated paclitaxel, Flutax-2. We observed that all FTIs tested increase the amount of microtubule-bound Flutax-2 and the number of microtubules labeled with Flutax-2 in both paclitaxel-resistant and paclitaxel-sensitive cells. Importantly, we observed a consequential increase in microtubule stability and tubulin acetylation with the combination of the two drugs, even in paclitaxel-resistant cells, confirming that the enhanced taxane binding in the presence of FTI affects microtubule function. Furthermore, this mechanism is dependent on the function of the tubulin deacetylase, HDAC6, because in cells overexpressing a catalytically inactive HDAC6, FTIs are incapable of enhancing Flutax-2–microtubule binding. Similar results were obtained by using an FTI devoid of farnesyltransferase inhibitory activity, indicating that functional inhibition of farnesyltransferase is also required. Overall, these studies provide a new insight into the functional relationship between HDAC6, farnesyltransferase, and microtubules, and support clinical data showing that the FTI/taxane combination is effective in taxane-refractory patients. (Cancer Res 2006; 66(17): 8838-46)
Descripción : 9 páginas, 5 figuras -- PAGS nros. 8838-8846
Versión del editor: http://dx.doi.org/ 10.1158/0008-5472.CAN-06-0699
URI : http://hdl.handle.net/10261/50187
ISSN: 0008-5472
DOI: 10.1158/0008-5472.CAN-06-0699
Citación : Cancer Research 66:8838-8846(2006)
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