Selective disruption of rb-raf-1 kinase interaction inhibits pancreatic adenocarcinoma growth irrespective of gemcitabine sensitivity.
Selective disruption of rb-raf-1 kinase interaction inhibits pancreatic adenocarcinoma growth irrespective of gemcitabine sensitivity.
复制标题
无论吉西他滨敏感性如何，选择性破坏 rb-raf-1 激酶相互作用都会抑制胰腺腺癌的生长。
DOI：
10.1158/1535-7163.mct-12-0719
复制
发表时间：
2013
影响因子：
5.7
通讯作者：
Chellappan,SrikumarP
中科院分区：
文献类型：
--
作者：
Treviño,JoséG;Verma,Monika;Singh,Sandeep;Pillai,Smitha;Zhang,Dongyu;Pernazza,Daniele;Sebti,SaidM;Lawrence,NicholasJ;Centeno,BarbaraA;Chellappan,SrikumarP
Inactivation of the retinoblastoma (Rb) tumor suppressor protein is widespread in human cancers. Inactivation of Rb is thought to be initiated by association with Raf-1 (C-Raf) kinase, and here we determined how RRD-251, a disruptor of the Rb–Raf-1 interaction, affects pancreatic tumor progression. Assessment of phospho-Rb levels in resected human pancreatic tumor specimens by immunohistochemistry (n= 95) showed that increased Rb phosphorylation correlated with increasing grade of resected human pancreatic adenocarcinomas (P= 0.0272), which correlated with reduced overall patient survival (P= 0.0186). To define the antitumor effects of RRD-251 (50 μmol/L), cell-cycle analyses, senescence, cell viability, cell migration, anchorage-independent growth, angiogenic tubule formation and invasion assays were conducted on gemcitabine-sensitive and -resistant pancreatic cancer cells. RRD-251 prevented S-phase entry, induced senescence and apoptosis, and inhibited anchorage-independent growth and invasion (P< 0.01). Drug efficacy on subcutaneous and orthotopic xenograft models was tested by intraperitoneal injections of RRD-251 (50 mg/kg) alone or in combination with gemcitabine (250 mg/kg). RRD-251 significantly reduced tumor growthin vivoaccompanied by reduced Rb phosphorylation and lymph node and liver metastasis (P< 0.01). Combination of RRD-251 with gemcitabine showed cooperative effect on tumor growth (P< 0.01). In conclusion, disruption of the Rb–Raf-1 interaction significantly reduces the malignant properties of pancreatic cancer cells irrespective of their gemcitabine sensitivity. Selective targeting of Rb–Raf-1 interaction might be a promising strategy targeting pancreatic cancer.Mol Cancer Ther; 12(12); 2722–34. ©2013 AACR.
