MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer.
MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer.
复制标题
DOI：
10.1186/1471-2407-9-142
复制
发表时间：
2009-05-11
期刊：
影响因子：
3.8
通讯作者：
Mahadevan D
中科院分区：
文献类型：
--
作者：
Qi W;Cooke LS;Stejskal A;Riley C;Croce KD;Saldanha JW;Bearss D;Mahadevan D
前列腺癌是男性的常见疾病，目前没有有效的治疗方法，因为尽管雄激素剥夺治疗，但其复发。表皮生长因子受体家族（EGFR/HER 1、HER 2/neu和HER 3）/PI 3 K/Akt信号传导轴与前列腺癌的发生和进展有关。然而，EGFR酪氨酸激酶抑制剂厄洛替尼对前列腺癌细胞系的增殖和凋亡的影响较小。在这项研究中，我们评估是否MP470，一种新的受体酪氨酸激酶抑制剂单独或与厄洛替尼在体外和体内对前列腺癌的抑制作用。使用三种前列腺癌细胞系通过MTS和凋亡测定在体外评估MP470或MP470加厄洛替尼的功效。采用磷酸化抗体芯片、免疫印迹和免疫组织化学等方法对该作用的分子机制进行了研究。还使用LNCaP小鼠异种移植物模型来确定MP470、厄洛替尼或组合治疗的肿瘤生长抑制。MP470在前列腺癌细胞系中表现出低μM IC 50。当用MP470与厄洛替尼组合处理LNCaP时，观察到对细胞毒性和细胞凋亡诱导的累加效应。这种组合治疗完全抑制HER家族成员（HER 1、2、3）的磷酸化、PI 3 K调节单元p85与HER 3的结合和下游Akt活性，即使在雄激素耗竭后。此外，在LNCaP小鼠异种移植模型中，MP470-厄洛替尼组合产生30-65%剂量依赖性肿瘤生长抑制（TGI）。我们认为MP470-Erlotinib靶向HER家族/PI 3 K/Akt通路，可能代表前列腺癌的一种新的治疗策略。
Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The epidermal growth factor receptor family (EGFR/HER1, HER2/neu and HER3)/PI3K/Akt signaling axis has been implicated in prostate cancer development and progression. However, Erlotinib, an EGFR tyrosine kinase inhibitor, has less effect on proliferation and apoptosis in prostate cancer cell lines. In this study, we evaluate whether MP470, a novel receptor tyrosine kinase inhibitor alone or in combination with Erlotinib has inhibitory effect on prostate cancer in vitro and in vivo. The efficacy of MP470 or MP470 plus Erlotinib was evaluated in vitro using three prostate cancer cell lines by MTS and apoptosis assays. The molecular mechanism study was carried out by phosphorylation antibody array, immunoblotting and immunohistochemistry. A LNCaP mouse xenograft model was also used to determine the tumor growth inhibition by MP470, Erlotinib or the combination treatments. MP470 exhibits low μM IC50 in prostate cancer cell lines. Additive effects on both cytotoxicity and induction of apoptosis were observed when LNCaP were treated with MP470 in combination with Erlotinib. This combination treatment completely inhibited phosphorylation of the HER family members (HER1, 2, 3), binding of PI3K regulatory unit p85 to HER3 and downstream Akt activity even after androgen depletion. Furthermore, in a LNCaP mouse xenograft model, the MP470-Erlotinib combination produced 30–65% dose-dependent tumor growth inhibition (TGI). We propose that MP470-Erlotinib targets the HER family/PI3K/Akt pathway and may represent a novel therapeutic strategy for prostate cancer.
登录
查看更多内容
影响因子：
8
作者：
Grasso, AW;Wen, DZ;Kung, HJ
通讯作者：
Kung, HJ
影响因子：
8
作者：
Mahadevan, D.;Cooke, L.;Bearss, D.
通讯作者：
Bearss, D.
影响因子：
4.8
作者：
El Sheikh, SS;Domin, J;Lalani, EN
通讯作者：
Lalani, EN
影响因子：
4.8
作者：
Graff, JR;Konicek, BW;Neubauer, BL
通讯作者：
Neubauer, BL
影响因子：
8.8
作者：
Le Page C;Koumakpayi IH;Alam-Fahmy M;Mes-Masson AM;Saad F
通讯作者：
Saad F