Drullion Claire, Lagarde Valérie, Gioia Romain, Legembre Patrick, Priault Muriel, Cardinaud Bruno, Lippert Eric, Mahon François-Xavier, Pasquet Jean-Max
Laboratoire Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université Bordeaux Ségalen, 146 Rue Léo Saignat Bat TP 4e étage, 33076 Bordeaux, France.
Leuk Res Treatment. 2012;2012:861301. doi: 10.1155/2012/861301. Epub 2012 Feb 23.
We used K562 cells sensitive or generated resistant to imatinib or nilotinib to investigate their response to mycophenolic acid (MPA). MPA induced DNA damage leading to cell death with a minor contribution of apoptosis, as revealed by annexin V labeling (up to 25%). In contrast, cell cycle arrest and positive staining for senescence-associated β-galactosidase activity were detected for a large cell population (80%). MPA-induced cell death was potentialized by the inhibition of autophagy and this is associated to the upregulation of apoptosis. In contrast, senescence was neither decreased nor abrogated in autophagy deficient K562 cells. Primary CD34 cells from CML patients sensitive or resistant to imatinib or nilotinib respond to MPA although apoptosis is mainly detected. These results show that MPA is an interesting tool to overcome resistance in vitro and in vivo mainly in the evolved phase of the disease.
我们使用对伊马替尼或尼洛替尼敏感或产生抗性的K562细胞来研究它们对霉酚酸（MPA）的反应。如膜联蛋白V标记所示（高达25%），MPA诱导DNA损伤导致细胞死亡，其中凋亡的作用较小。相比之下，在大量细胞群体（80%）中检测到细胞周期停滞以及衰老相关β-半乳糖苷酶活性的阳性染色。抑制自噬可增强MPA诱导的细胞死亡，这与凋亡的上调有关。相反，在自噬缺陷的K562细胞中，衰老既未减少也未消除。来自对伊马替尼或尼洛替尼敏感或耐药的慢性粒细胞白血病患者的原代CD34细胞对MPA有反应，尽管主要检测到凋亡。这些结果表明，MPA是一种在体外和体内克服耐药性的有趣工具，主要适用于疾病的进展期。
