Novel agents targeting the IGF-1R/PI3K pathway impair cell proliferation and survival in subsets of medulloblastoma and neuroblastoma.
Novel agents targeting the IGF-1R/PI3K pathway impair cell proliferation and survival in subsets of medulloblastoma and neuroblastoma.
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DOI：
10.1371/journal.pone.0047109
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Arcaro A
中科院分区：
文献类型：
--
作者：
Wojtalla A;Salm F;Christiansen DG;Cremona T;Cwiek P;Shalaby T;Gross N;Grotzer MA;Arcaro A
受体酪氨酸激酶（RTK）/磷酸肌醇3-激酶（PI 3 K）途径是癌细胞增殖的基础，并且已知在瘤形成（包括胚胎性肿瘤）中经常改变和激活。基于高频率的改变，靶向PI 3 K信号通路的组分被认为是用于癌症治疗的有前景的治疗方法。在这里，我们研究了靶向胰岛素样生长因子-1受体（IGF-1 R）和PI 3 K信号传导在两种常见的儿童癌症中的潜力：神经母细胞瘤，儿童最常见的颅外肿瘤和髓母细胞瘤，最常见的恶性儿童脑肿瘤。通过用针对IGF-1 R的特异性人源化单克隆抗体R1507治疗神经母细胞瘤和髓母细胞瘤细胞，我们可以观察到细胞系特异性反应，并且在某些情况下细胞增殖强烈下降。相反，用特异性抑制剂PIK 75靶向PI 3 K p110α，在一组神经元和髓母细胞瘤细胞系中产生了广泛的抗增殖作用。此外，在用R1507或PIK 75处理后，在神经母细胞瘤细胞中发生对常用化疗剂的敏化。此外，通过研究IGF-1 R/PI 3 K下游信号转导靶点的表达和磷酸化状态，我们发现IGF-1 R/PI 3 K下游信号转导通路的激活被下调。此外，在用PIK 75或R1507处理后，在胚胎肿瘤细胞中发生凋亡。总之，我们的研究证明了在胚胎肿瘤中靶向IGF-1 R/PI 3 K信号传导轴的潜力。希望这些知识将有助于开发迫切需要的新的胚胎肿瘤靶向治疗。
The receptor tyrosine kinase (RTK)/phosphoinositide 3-kinase (PI3K) pathway is fundamental for cancer cell proliferation and is known to be frequently altered and activated in neoplasia, including embryonal tumors. Based on the high frequency of alterations, targeting components of the PI3K signaling pathway is considered to be a promising therapeutic approach for cancer treatment. Here, we have investigated the potential of targeting the axis of the insulin-like growth factor-1 receptor (IGF-1R) and PI3K signaling in two common cancers of childhood: neuroblastoma, the most common extracranial tumor in children and medulloblastoma, the most frequent malignant childhood brain tumor. By treating neuroblastoma and medulloblastoma cells with R1507, a specific humanized monoclonal antibody against the IGF-1R, we could observe cell line-specific responses and in some cases a strong decrease in cell proliferation. In contrast, targeting the PI3K p110α with the specific inhibitor PIK75 resulted in broad anti-proliferative effects in a panel of neuro- and medulloblastoma cell lines. Additionally, sensitization to commonly used chemotherapeutic agents occurred in neuroblastoma cells upon treatment with R1507 or PIK75. Furthermore, by studying the expression and phosphorylation state of IGF-1R/PI3K downstream signaling targets we found down-regulated signaling pathway activation. In addition, apoptosis occurred in embryonal tumor cells after treatment with PIK75 or R1507. Together, our studies demonstrate the potential of targeting the IGF-1R/PI3K signaling axis in embryonal tumors. Hopefully, this knowledge will contribute to the development of urgently required new targeted therapies for embryonal tumors.
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人类癌症中的磷酸肌醇3-激酶途径：遗传改变和治疗意义。
影响因子：
2.6
作者：
Arcaro A;Guerreiro AS
通讯作者：
Guerreiro AS
DOI：
10.1097/00005072-199205000-00005
发表时间：
1992-05-01
影响因子：
3.2
作者：
FULTS, D;PEDONE, CA;MCKAY, RDG
通讯作者：
MCKAY, RDG
影响因子：
3.6
作者：
Cianfarani, S;Rossi, P
通讯作者：
Rossi, P
影响因子：
7.5
作者：
Brachmann, Saskia;Fritsch, Christine;Garcia-Echeverria, Carlos
通讯作者：
Garcia-Echeverria, Carlos
影响因子：
11.5
作者：
Guerreiro, Ana S.;Fattet, Sarah;Arcaro, Alexandre
通讯作者：
Arcaro, Alexandre