The farnesyltransferase inhibitor lonafarnib induces growth arrest or apoptosis of human lung cancer cells without Downregulation of at
The farnesyltransferase inhibitor lonafarnib induces growth arrest or apoptosis of human lung cancer cells without Downregulation of at
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DOI：
10.4161/cbt.3.11.1176
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发表时间：
2004-11-01
影响因子：
3.6
通讯作者：
Khuri, FR
中科院分区：
文献类型：
--
作者：
Sun, SY;Zhou, ZM;Khuri, FR
法尼基转移酶抑制剂(FTI)已被证明不依赖于RAS突变而诱导生长停滞或细胞凋亡。或者，Akt已被提议作为快速道行动的潜在目标。本研究探讨Lonafarnib是否能有效抑制人非小细胞肺癌(NSCLC)细胞的生长，并阐明Akt在抑制NSCLC细胞生长中的作用。在临床可达到的浓度范围内，洛那法尼有效地抑制了10个非小细胞肺癌细胞系的生长，特别是在延长治疗时间后，无论RAS突变状态如何。在大多数受试细胞系中，Lonafarnib使细胞生长停滞于G(1)或G(2)/M期。但在低血清(0.1%)培养条件下，可诱导细胞发生凋亡。大多数NSCLC细胞株表达未检测到的磷酸化Akt(P-Akt)。即使在处理48h后，高达10 mU M的Lonafarnib也没有降低任何受试细胞株的总Akt水平或P-Akt水平。出乎意料的是，Lonafarnib甚至增加了一个细胞株的p-Akt水平，尽管它与其他细胞株一样对Lonafarnib治疗敏感，并经历了G(2)/M期阻滞。牛血清白蛋白在低血清介质中完全挽救了Lonafarnib诱导的细胞凋亡，这表明血清中的蛋白质而不是细胞因子或生长因子掩盖了Lonafarnib的前视效应。因此，我们得出结论，Lonafarnib通过抑制NSCLC细胞的生长或诱导细胞凋亡而不下调Akt，从而有效地抑制NSCLC细胞的生长。
Farnesyltransferase inhibitors (FTIs) have been demonstrated to induce growth arrest or apoptosis independent of Ras mutation. Alternatively, Akt has been proposed as a potential target for the FTI's actions. This study investigated whether Lonafarnib was effective in inhibiting the growth of human non-small cell lung cancer (NSCLC) cells and elucidated the role of Akt in mediating such growth inhibitory effects. Lonafarnib, at clinical achievable concentration ranges, was effective in inhibiting the growth of 10 NSCLC cell lines, particularly after a prolonged treatment, regardless of Ras mutational status. Lonafarnib arrested cells growth at G(1) or G(2)/M phase in the majority tested cell lines. However it induced apoptosis when cells were cultured in a low serum (0.1%) medium. The majority of NSCLC cell lines expressed undetectable level of phosphorylated Akt (P-Akt). Lonafarnib at up to 10 mu M did not decrease either total Akt level or P-Akt level in any of the tested cell lines, even after a 48 h treatment. Unexpectedly, Lonafarnib even increased p-Akt level in one cell line, although it was as sensitive as others to Lonafarnib treatment and underwent G(2)/M arrest. Bovine serum albumin completely rescued cells from Lonafarnib-induced apoptosis in low serum medium, indicating that proteins rather than cytokines or growth factors in serum masks Lonafarnib's pro-opoptotic effect. Therefore, we conclude that Lonafarnib is effective in inhibiting the growth of NSCLC cells either via growth arrest or induction of opoptosis without downregulation of Akt.