Yan H, Zhao R-M, Wang Z-J, Zhao F-R, Wang S-L
Department of Medical Imaging, People's Hospital of Rizhao, Rizhao, China.
Eur Rev Med Pharmacol Sci. 2015 Dec;19(24):4827-34.
Leukemia is resistant to currently available chemotherapy, and new strategies have been proposed to improve its efficacy. Such an approach requires know of the mechanisms involved in the resistance and survival of leukemia cells. Previous studied has found that Preferentially Expressed Antigen of Melanoma (PRAME) is overexpressed in the leukemia cells, and knockdown of PRAME promoted apoptosis in leukemia K562 cells. In the present study, we investigated whether inhibition of PRAME could sensitize K562 cells to chemotherapy.
K562 cells were treated with PRAME siRNA, and/or adriamycin (ADR), and cell viability and apoptosis, mRNA and protein expression levels were, then, evaluated. Furthermore, the efficacy of PRAME siRNA combined with ADR was further examined in established xenograft models.
PRAME suppression was sufficient to induce spontaneous apoptosis of K562 cells. PRAME knockdown showed antiproliferative effects and induced tumor regression in established K562 xenograft models. ADR showed antitumor activity against K562 cells, co-treatment with PRAME siRNA induced an increased apoptosis rate than the sum of the single-treatment rates and promoted tumor regression without enhanced body weight loss in the K562 xenograft models.
PRAME is responsible for the inherent low levels of spontaneous apoptosis in K562 cells. The combination of PRAME siRNA with ADR induced more intense apoptosis compared with each single treatment. PRAME siRNA in combination with ADR is well tolerated and shows greater efficacy than either agent alone in mouse xenograft models.
白血病对目前可用的化疗具有抗性，因此人们提出了新的策略来提高其疗效。这种方法需要了解白血病细胞抗性和存活所涉及的机制。先前的研究发现，黑色素瘤优先表达抗原（PRAME）在白血病细胞中过表达，敲低PRAME可促进白血病K562细胞凋亡。在本研究中，我们调查了抑制PRAME是否能使K562细胞对化疗敏感。
用PRAME siRNA和/或阿霉素（ADR）处理K562细胞，然后评估细胞活力、凋亡情况、mRNA和蛋白质表达水平。此外，在已建立的异种移植模型中进一步检测PRAME siRNA与ADR联合使用的疗效。
抑制PRAME足以诱导K562细胞自发凋亡。在已建立的K562异种移植模型中，敲低PRAME显示出抗增殖作用并诱导肿瘤消退。ADR对K562细胞显示出抗肿瘤活性，与PRAME siRNA联合处理诱导的凋亡率高于单药处理率之和，并促进肿瘤消退，且在K562异种移植模型中未增加体重减轻。
PRAME是K562细胞固有低水平自发凋亡的原因。与每种单一处理相比，PRAME siRNA与ADR联合诱导更强烈的凋亡。在小鼠异种移植模型中，PRAME siRNA与ADR联合使用耐受性良好，且比单独使用任何一种药物都显示出更大的疗效。
