Morotti Alessandro, Cilloni Daniela, Messa Francesca, Arruga Francesca, Defilippi Ilaria, Carturan Sonia, Catalano Renata, Rosso Valentina, Chiarenza Annalisa, Pilatrino Chiara, Guerrasio Angelo, Taulli Riccardo, Bracco Enrico, Pautasso Marisa, Baraban Daniela, Gottardi Enrico, Saglio Giuseppe
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Cancer. 2006 Mar 1;106(5):1188-96. doi: 10.1002/cncr.21725.
The objective of this study was to evaluate the ability of the clinically available histone deacetylase (HDAC) inhibitor valproate to enhance the cytotoxicity of the Bcr-Abl inhibitor imatinib in imatinib-resistant cell lines.
Interactions between imatinib, and valproate have been examined in imatinib-sensitive and -resistant chronic myeloid leukemia (CML)cell lines (K562, KCL-22, CML-T1) and in bone marrow mononuclear cells (MNCs) derived from imatinib-resistant CML patients.
In imatinib-sensitive cell lines, cotreatment with imatinib 0.5 muM and valproate 5 microM for 48 hours potently enhanced imatinib-induced growth arrest and apoptosis. In resistant cell lines and in primary MNCs derived from imatinib-rsistant patients, valproate restored sensitivity to the cytotoxic effects of imatinib. Coexposure of cells to valproate and imatinib was associated with repression of several genes involved in Bcr-Abl transformation. In particular, the combination valproate-imatinib downregulated the expression of Bcr-Abl and the antiapoptotic protein Bcl-2, which is particularly overexpressed in imatinib-resistant clones.
Data from this study suggested that administration of the clinically available HDAC inhibitor valproate may be a powerful strategy to enhance cytotoxic effects of imatinib in those patient resistant to imatinib or in which complete cytogenetic remission has been not reached.
本研究的目的是评估临床可用的组蛋白去乙酰化酶（HDAC）抑制剂丙戊酸盐增强Bcr-Abl抑制剂伊马替尼对伊马替尼耐药细胞系细胞毒性的能力。
在伊马替尼敏感和耐药的慢性粒细胞白血病（CML）细胞系（K562、KCL-22、CML-T1）以及源自伊马替尼耐药CML患者的骨髓单个核细胞（MNC）中检测了伊马替尼与丙戊酸盐之间的相互作用。
在伊马替尼敏感细胞系中，0.5μM伊马替尼与5μM丙戊酸盐共同处理48小时可有效增强伊马替尼诱导的生长停滞和凋亡。在耐药细胞系以及源自伊马替尼耐药患者的原代MNC中，丙戊酸盐恢复了对伊马替尼细胞毒性作用的敏感性。细胞同时暴露于丙戊酸盐和伊马替尼与几种参与Bcr-Abl转化的基因的抑制有关。特别是，丙戊酸盐-伊马替尼联合用药下调了Bcr-Abl和抗凋亡蛋白Bcl-2的表达，Bcl-2在伊马替尼耐药克隆中尤其过表达。
本研究数据表明，给予临床可用的HDAC抑制剂丙戊酸盐可能是增强伊马替尼对那些对伊马替尼耐药或未达到完全细胞遗传学缓解的患者细胞毒性作用的有效策略。
