Unknown

Dataset Information

0

Selective disruption of rb-raf-1 kinase interaction inhibits pancreatic adenocarcinoma growth irrespective of gemcitabine sensitivity.


ABSTRACT: 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 ?mol/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 growth in vivo accompanied 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.

SUBMITTER: Trevino JG 

PROVIDER: S-EPMC3858536 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

Selective disruption of rb-raf-1 kinase interaction inhibits pancreatic adenocarcinoma growth irrespective of gemcitabine sensitivity.

Treviño José G JG   Verma Monika M   Singh Sandeep S   Pillai Smitha S   Zhang Dongyu D   Pernazza Daniele D   Sebti Said M SM   Lawrence Nicholas J NJ   Centeno Barbara A BA   Chellappan Srikumar P SP  

Molecular cancer therapeutics 20131009 12


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 huma  ...[more]

Similar Datasets

| S-EPMC4159025 | biostudies-literature
| S-EPMC7513525 | biostudies-literature
| S-EPMC5996282 | biostudies-literature
| S-EPMC3500221 | biostudies-literature
| S-EPMC4198746 | biostudies-literature
| S-EPMC5560598 | biostudies-literature
| S-EPMC3269746 | biostudies-literature
| S-EPMC4002689 | biostudies-literature
| S-EPMC3464270 | biostudies-literature
| S-EPMC10139117 | biostudies-literature