Li X, Luwor R, Lu Y, Liang K, Fan Z
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
Oncogene. 2006 Jan 26;25(4):525-35. doi: 10.1038/sj.onc.1209075.
Mutational inactivation or deletion of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/MMAC1/TEP gene in human cancer cells leads to a constitutively active status of the phosphatidylinositol 3-kinase/Akt pathway in the cells and has been linked to the lack of responses of the cells to the epidermal growth factor (EGF) receptor-targeted therapeutics. Akt is strongly inhibited by perifosine, an orally active alkyl-lysophospholipid currently being evaluated as an anti-cancer agent in phase 1 and 2 clinical trials. To determine whether perifosine may enhance the antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 in PTEN-deficient cancer cells, we exposed MDA468 breast cancer cells (which contain mutated PTEN gene) and PC3 prostate cancer cells (in which the PTEN gene is deleted) to perifosine and cetuximab, alone and in combination. Treatment of the cells with perifosine reduced baseline levels of phosphorylated Akt, phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and p38MAPK, and increased baseline levels of phosphorylated stress-activated protein kinase (SAPK)/c-jun NH(2)-terminal kinase (JNK). A 72-h exposure of the MDA468 and PC3 cells to perifosine alone resulted in cell death in a dose-dependent manner, which was enhanced by cetuximab. Addition of subtoxic doses of perifosine to cetuximab treatment also enhanced the cetuximab-induced growth inhibition. The combination treatment enhanced the inhibition of phosphorylation of Akt, p44/42MAPK and p38MAPK, but offset the phosphorylation of SAPK/JNK that was activated by perifosine treatment alone. Taken together, the data showed that perifosine enhances the antitumor activity of cetuximab in PTEN-deficient cancer cells. Further evaluation of the combination treatment in preclinical and clinical studies is warranted.
人类癌细胞中10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）/MMAC1/TEP基因的突变失活或缺失会导致细胞中磷脂酰肌醇3激酶/Akt信号通路持续激活，并与细胞对表皮生长因子（EGF）受体靶向治疗缺乏反应有关。Akt受到哌立福新的强烈抑制，哌立福新是一种口服活性烷基溶血磷脂，目前正在1期和2期临床试验中作为抗癌药物进行评估。为了确定哌立福新是否能增强抗EGF受体单克隆抗体西妥昔单抗/C225在PTEN缺陷癌细胞中的抗肿瘤活性，我们将MDA468乳腺癌细胞（含有突变的PTEN基因）和PC3前列腺癌细胞（PTEN基因缺失）单独或联合暴露于哌立福新和西妥昔单抗中。用哌立福新处理细胞可降低磷酸化Akt、磷酸化p44/42丝裂原活化蛋白激酶（MAPK）和p38MAPK的基线水平，并增加磷酸化应激激活蛋白激酶（SAPK）/c-jun氨基末端激酶（JNK）的基线水平。MDA468和PC3细胞单独暴露于哌立福新72小时会导致细胞死亡，且呈剂量依赖性，西妥昔单抗可增强这种作用。在西妥昔单抗治疗中添加亚毒性剂量的哌立福新也增强了西妥昔单抗诱导的生长抑制。联合治疗增强了对Akt、p44/42MAPK和p38MAPK磷酸化的抑制，但抵消了单独哌立福新治疗激活的SAPK/JNK的磷酸化。综上所述，数据表明哌立福新可增强西妥昔单抗在PTEN缺陷癌细胞中的抗肿瘤活性。有必要在临床前和临床研究中对联合治疗进行进一步评估。
