The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase
The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase
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DOI：
10.1158/0008-5472.can-04-3757
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Giannakakou, P
中科院分区：
文献类型：
--
作者：
Marcus, AI;Zhou, J;Giannakakou, P
法尼基转移酶（FT）抑制剂（FTI）是通过抑制Ras法尼基化而开发的靶向致癌Ras蛋白的抗癌剂。FTIs与紫杉醇和其他微管稳定药物有效协同;然而，这种协同相互作用的机制基础仍然难以捉摸。在这里，我们表明FTI洛那法尼影响微管细胞骨架，导致微管束形成，增加微管稳定性和乙酰化，并抑制微管动力学。值得注意的是，与单独的任一种药物相比，用低剂量的洛那法尼与紫杉醇的组合治疗显著增强了微管蛋白乙酰化（微管稳定性的标志物）。这种协同效应与FT抑制相关，并伴随有丝分裂阻滞和细胞死亡的协同增加。从机制上讲，我们表明洛那法尼和紫杉醇的组合抑制了唯一已知的微管蛋白脱乙酰酶，历史上的脱乙酰酶6（HDAC 6）的体外脱乙酰化活性。此外，洛那法尼/紫杉烷组合仅在表达野生型HDAC 6的细胞系中是协同的，而在表达催化突变型HDAC 6的细胞系中不是，这揭示了洛那法尼与紫杉烷的协同作用需要功能性HDAC 6。此外，与洛那法尼和紫杉醇的组合类似，特异性HDAC 6抑制剂微管蛋白协同增强微管蛋白乙酰化。总之，这些数据表明FT抑制、HDAC 6功能和细胞死亡之间的关系，提供了对洛那法尼/紫杉烷协同抗增殖组合的推定分子基础的深入了解。
Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetylation, and suppression of microtubule dynamics. Notably, treatment with the combination of low doses of lonafarnib with paclitaxel markedly enhanced tubulin acetylation (a marker of microtubule stability) as compared with either drug alone. This synergistic effect correlated with FT inhibition and was accompanied by a synergistic increase in mitotic arrest and cell death. Mechanistically, we show that the combination of lonafarnib and paclitaxel inhibits the in vitro deacetylating activity of the only known tubulin deacetylase, historic deacetylase 6 (HDAC6). In addition, the lonafarnib/taxane combination is synergistic only in cells lines expressing the wild-type HDAC6, but not a catalytic-mutant HDAC6, revealing that functional HDAC6 is required for the synergy of lonafarnib with taxanes. Furthermore, tubacin, a specific HDAC6 inhibitor, synergistically enhanced tubulin acetylation in combination with paclitaxel, similar to the combination of lonafarnib and paclitaxel. Taken together, these data suggest a relationship between FT inhibition, HDAC6 function, and cell death, providing insight into the putative molecular basis of the lonafarnib/taxane synergistic antiproliferative combination.