Farnesyltransferase inhibitors reverse taxane resistance.
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.
Marcus
Adam I
AI
Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
O'Brate
Aurora M
AM
Buey
Ruben M
RM
Zhou
Jun
J
Thomas
Shala
S
Khuri
Fadlo R
FR
Andreu
Jose Manuel
JM
Díaz
Fernando
F
Giannakakou
Paraskevi
P
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D010051:Ovarian Neoplasms; D043823:Taxoids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; C413450:Flutax 2; D043823:Taxoids; D014404:Tubulin; C080625:taxane; D051231:Farnesyltranstransferase