Balakrishnan Kumudha, Burger Jan A, Wierda William G, Gandhi Varsha
Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Blood. 2009 Jan 1;113(1):149-53. doi: 10.1182/blood-2008-02-138560. Epub 2008 Oct 3.
Resistance to apoptosis in CLL B cells is associated with overexpression of Bcl-2 family antiapoptotic proteins. Their expression is endogenous, but is also induced by signals from the microenvironment resulting in intrinsic and extrinsic drug resistance. Because AT-101 binds to the BH3 motif of all Bcl-2-family antiapoptotic proteins, we hypothesized that this molecule could overcome resistance. AT-101 treatment (20 microM for 24 hours) resulted in a median 72% apoptosis in CLL cells (patients; n = 32, P < .001). Stromal cells protected CLL B cells from spontaneous and fludarabine-induced apoptosis (P = .003) by increasing the Mcl-1 protein levels. However, AT-101 induced similar extent of down-regulation of Mcl-1 and apoptosis in CLL lymphocytes cultured in suspension or on stroma (P = .999). Stromal cells expressed undetectable levels of antiapoptotic but high levels of activated ERK and AKT proteins and had low or no apoptosis with AT-101. Collectively, these data demonstrate that AT-101 induces apoptosis in CLL B cells and overcomes microenvironment-mediated resistance while sparing normal stromal cells.
慢性淋巴细胞白血病（CLL）B细胞对凋亡的抵抗与Bcl-2家族抗凋亡蛋白的过表达有关。它们的表达是内源性的，但也由微环境中的信号诱导产生，从而导致内在和外在的耐药性。由于AT-101能与所有Bcl-2家族抗凋亡蛋白的BH3基序结合，我们推测该分子可以克服耐药性。AT-101处理（20微摩尔，持续24小时）导致CLL细胞出现中位数为72%的凋亡（患者；n = 32，P < .001）。基质细胞通过提高Mcl-1蛋白水平保护CLL B细胞免受自发和氟达拉滨诱导的凋亡（P = .003）。然而，在悬浮培养或与基质共培养的CLL淋巴细胞中，AT-101诱导的Mcl-1下调程度和凋亡程度相似（P = .999）。基质细胞表达的抗凋亡蛋白水平检测不到，但活化的ERK和AKT蛋白水平较高，并且在使用AT-101时凋亡率较低或无凋亡。总体而言，这些数据表明AT-101可诱导CLL B细胞凋亡并克服微环境介导的耐药性，同时不损伤正常基质细胞。
