Krämer O H, Knauer S K, Zimmermann D, Stauber R H, Heinzel T
Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Jena, Germany.
Oncogene. 2008 Jan 31;27(6):732-40. doi: 10.1038/sj.onc.1210677. Epub 2007 Jul 23.
Therapy resistance represents a major problem for disease management in oncology. Histone deacetylase inhibitors (HDACi) have been shown to modulate the cell cycle, to induce apoptosis and to sensitize cancer cells for other chemotherapeutics. Our study shows that the HDACi valproic acid (VPA) and the ribonucleotide reductase inhibitor hydroxyurea (HU) potentiate the pro-apoptotic effects of each other towards several cancer cell lines. This correlates with the HU-induced degradation of the cyclin-dependent kinase inhibitors (CDKI) p21 and p27, mediated by the proteasome or caspase-3. Moreover, we found that caspase-3 activation is required for VPA-induced apoptosis. Remarkably, p21 and p27 can confer resistance against VPA and HU. Both CDKI interact with caspase-3 and compete with other caspase-3 substrates. Hence, p21 and p27 may contribute to chemotherapy resistance as apoptosis inhibitors. Since the biological effects of VPA and HU could be achieved at concentrations used in current treatment protocols, the combined application of these compounds might be considered as a potential strategy for cancer treatment.
治疗耐药性是肿瘤疾病管理中的一个主要问题。组蛋白脱乙酰酶抑制剂（HDACi）已被证明可调节细胞周期、诱导细胞凋亡并使癌细胞对其他化疗药物敏感。我们的研究表明，HDACi丙戊酸（VPA）和核糖核苷酸还原酶抑制剂羟基脲（HU）对几种癌细胞系具有相互增强的促凋亡作用。这与HU诱导的细胞周期蛋白依赖性激酶抑制剂（CDKI）p21和p27的降解相关，该降解由蛋白酶体或半胱天冬酶-3介导。此外，我们发现半胱天冬酶-3激活是VPA诱导细胞凋亡所必需的。值得注意的是，p21和p27可赋予对VPA和HU的抗性。两种CDKI都与半胱天冬酶-3相互作用并与其他半胱天冬酶-3底物竞争。因此，p21和p27可能作为凋亡抑制剂导致化疗耐药。由于VPA和HU的生物学效应可在当前治疗方案所用的浓度下实现，这些化合物的联合应用可能被视为一种潜在的癌症治疗策略。
