Cellular and Molecular Biology, Gembloux Agro-Bio Tech, Gembloux, Belgium.
Eur J Cancer. 2010 Jun;46(9):1724-34. doi: 10.1016/j.ejca.2010.03.021. Epub 2010 May 5.
Prognosis of small cell lung carcinoma (SCLC) is particularly poor, less than 5% of patients with extensive stage being alive after two years. We hypothesized that SCLC chemotherapy could be improved by using histone deacetylase (HDAC) inhibitors based on their ability to interfere with lysine acetylation and to alter gene expression. The goal of this study was to evaluate the anticancer efficacy of a HDAC inhibitor (valproate: VPA) on SCLC cells in combination with the standard chemotherapeutic first-line regimen (cisplatin+etoposide). We show that VPA induces apoptosis of small cell lung cancer cell lines and improves efficacy of cisplatin combined with etoposide. Both mitochondrial and death receptor pathways are involved in VPA-induced apoptosis. As expected for an HDAC inhibitor, VPA hyperacetylates histone H3. The mechanism of VPA pro-apoptotic activity involves induction of p21, inhibition of Bcl-xL, cleavage of Bid and phosphorylation of Erk and H2AX. In the presence of VPA, Bax is translocated from the cytoplasm to the mitochondria and cleaved in an 18kDa isoform. Cytochrome c is released from the mitochondria into the cytosol. Transcriptomic analyses by microarray show that VPA modulates transcription of genes (Na(+)/K(+) ATPase, Bcl-xL) involved in chemoresistance to cisplatin and etoposide. Finally, the efficacy of VPA combined with cisplatin and etoposide is supported by preclinical models of SCLC cells engrafted into SCID mice. Together, these data demonstrate that VPA augments anticancer activity of cisplatin and etoposide, two components of the standard first-line chemotherapy of small cell lung cancer.
小细胞肺癌（SCLC）的预后尤其差，广泛期患者两年后生存率不足 5%。我们假设基于组蛋白去乙酰化酶（HDAC）抑制剂干扰赖氨酸乙酰化和改变基因表达的能力，SCLC 化疗可以得到改善。本研究的目的是评估 HDAC 抑制剂（丙戊酸：VPA）联合标准一线化疗方案（顺铂+依托泊苷）对 SCLC 细胞的抗癌疗效。我们表明 VPA 诱导小细胞肺癌细胞系凋亡，并提高顺铂联合依托泊苷的疗效。线粒体和死亡受体途径都参与了 VPA 诱导的细胞凋亡。与 HDAC 抑制剂一致，VPA 使组蛋白 H3 乙酰化。VPA 促凋亡活性的机制涉及诱导 p21、抑制 Bcl-xL、切割 Bid 和磷酸化 Erk 和 H2AX。在 VPA 的存在下，Bax 从细胞质易位到线粒体并被切割成 18kDa 同工型。细胞色素 c 从线粒体释放到细胞质中。通过微阵列进行的转录组分析表明，VPA 调节参与顺铂和依托泊苷耐药的基因（Na(+)/K(+)ATP 酶、Bcl-xL）的转录。最后，VPA 联合顺铂和依托泊苷的疗效得到了 SCID 小鼠植入 SCLC 细胞的临床前模型的支持。总之，这些数据表明 VPA 增强了顺铂和依托泊苷的抗癌活性，这两种药物都是小细胞肺癌标准一线化疗的组成部分。
