Tarnowski Maciej, Tkacz Marta, Zgutka Katarzyna, Bujak Joanna, Kopytko Patrycja, Pawlik Andrzej
Department of Physiology, Pomeranian Medical University, al. Powstańców Wielkopolskich 72, 70-111, Szczecin, Poland.
BMC Cancer. 2017 Aug 9;17(1):532. doi: 10.1186/s12885-017-3495-y.
Insulin-like growth factors and insulin are important factors promoting cancer growth and metastasis. The molecules act through IGF1 (IGF1R) and insulin (InsR) receptors. Rhambodmyosarcomas (RMS) overproduce IGF2 - a potent ligand for IGF1R and, at the same time, highly express IGF1 receptor. The purpose of the study was to evaluate possible application of picropodophyllin (PPP) - a potent IGF1R inhibitor.
In our study we used a number of in vitro assays showing influence of IGF1R blockage on RMS cell lines (both ARMS and ERMS) proliferation, migration, adhesion, cell cycling and signal transduction pathways. Additionally, we tested possible concomitant application of PPP with commonly used chemotherapeutics (vincristine, actinomycin-D and cisplatin). Moreover, we performed an in vivo study where PPP was injected intraperitoneally into RMS tumor bearing SCID mice.
We observed that PPP strongly inhibits RMS proliferation, chemotaxis and adhesion. What is more, application of the IGF1R inhibitor attenuates MAPK phosphorylation and cause cell cycle arrest in G2/M phase. PPP increases sensitivity of RMS cell lines to chemotherapy, specifically to vincristine and cisplatin. In our in vivo studies we noted that mice treated with PPP grew smaller tumors and displayed significantly decreased seeding into bone marrow.
The cyclolignan PPP effectively inhibits RMS tumor proliferation and metastasis in vitro and in an animal model.
胰岛素样生长因子和胰岛素是促进癌症生长和转移的重要因素。这些分子通过IGF1（IGF1R）和胰岛素（InsR）受体发挥作用。横纹肌肉瘤（RMS）过度产生IGF2——一种IGF1R的强效配体，同时高度表达IGF1受体。本研究的目的是评估强效IGF1R抑制剂鬼臼苦素（PPP）的可能应用。
在我们的研究中，我们使用了多种体外试验来显示IGF1R阻断对RMS细胞系（ARMS和ERMS）增殖、迁移、黏附、细胞周期和信号转导途径的影响。此外，我们测试了PPP与常用化疗药物（长春新碱、放线菌素-D和顺铂）联合应用的可能性。此外，我们进行了一项体内研究，将PPP腹腔注射到携带RMS肿瘤的SCID小鼠体内。
我们观察到PPP强烈抑制RMS的增殖、趋化性和黏附。此外，IGF1R抑制剂的应用减弱了MAPK磷酸化并导致细胞周期停滞在G2/M期。PPP增加了RMS细胞系对化疗的敏感性，特别是对长春新碱和顺铂。在我们的体内研究中，我们注意到用PPP治疗的小鼠肿瘤生长较小，并且骨髓中的播种明显减少。
环木脂素PPP在体外和动物模型中均能有效抑制RMS肿瘤的增殖和转移。
