Laboratoire d'Hémato-Cancérologie Expérimentale, CRP-Santé, Val Fleuri, Luxembourg.
Br J Haematol. 2009 Dec;147(5):662-71. doi: 10.1111/j.1365-2141.2009.07902.x. Epub 2009 Sep 29.
The main challenge in using chemotherapy to treat multiple myeloma (MM) is drug resistance. In order to evaluate the anti-neoplastic properties of a new drug combination in MM, two clinically available drugs, valproic acid (VPA) a histone deacetylase (HDAC) inhibitor and pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, were tested in vitro on MM cell lines and MM patient cells. The sensitivity towards VPA alone was observed on several MM cell lines tested and also on primary myeloma cells and peripheral blood mononuclear cells from healthy donors. Importantly, the addition of a PPARgamma agonist to the VPA treatment increased the cytotoxic effect of VPA in a synergistic/additive manner on the different MM cell lines and MM patient cells. This effect was observed at the physiological range of VPA used to treat epileptic patients. The mechanisms underlying this increase induced a cell cycle arrest and caspase-dependent apoptosis. The potentiation of the effect of VPA by pioglitazone was mediated by higher acetylation levels of histones H3 and H4 compared to levels induced by HDAC inhibitors alone. This association reveals a new promising chemotherapeutic combination to be tested in MM.
用化疗治疗多发性骨髓瘤（MM）的主要挑战是耐药性。为了评估新药物组合在 MM 中的抗肿瘤特性，两种临床可用的药物——丙戊酸（VPA），一种组蛋白去乙酰化酶（HDAC）抑制剂和吡格列酮，一种过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，在体外对 MM 细胞系和 MM 患者细胞进行了测试。在测试的几种 MM 细胞系以及来自健康供体的原代骨髓瘤细胞和外周血单核细胞中，观察到了 VPA 单独的敏感性。重要的是，在不同的 MM 细胞系和 MM 患者细胞中，将 PPARγ 激动剂添加到 VPA 治疗中以协同/累加的方式增加了 VPA 的细胞毒性作用。这种作用在用于治疗癫痫患者的 VPA 的生理范围内观察到。这种增加所诱导的机制导致细胞周期停滞和 caspase 依赖性细胞凋亡。与单独使用 HDAC 抑制剂相比，吡格列酮通过增加组蛋白 H3 和 H4 的乙酰化水平来增强 VPA 的作用。这种关联揭示了一种新的有前途的化疗组合，有待在 MM 中进行测试。
