Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer

• DOI: 10.1038/cddis.2014.180
• Publication Date: 2014-05-08T12:59:47Z
• Authors: T Nelius; D Martinez-Marin; J Hirsch; B Miller; K Rinard; J Lopez; W de Riese; S Filleur
• Keywords: PEDF

There is currently no cure for advanced castration-refractory prostate cancer (CRPC) despite the recent approval of several new therapeutic agents. We report here anti-tumor effect angio-inhibitory pigment epithelium-derived factor (PEDF) in metastatic LNCaP-derivative CRPC CL1 model and explore PEDF anti-neoplasic efficacy combination with low-dose chemotherapy. Androgen-sensitive LNCaP PC3 cell lines were examined as comparison. Using a retroviral expression system, we showed that limited proliferation all prostatic tested; an attributed to interleukin 8 (IL8)-CXCR1/IL8RA inhibition. also reduced number size 3D tumor spheroids vitro, but only induced differentiation spheroids. Similarly, inhibited migration cells suggesting both anti-proliferative anti-migratory functions. In vivo, decreased by 85% 65% growth subcutaneous (s.c.) tumors, respectively. orthotopic model, intake lethal metastases was found animals; nevertheless, prolonged median survival tumor-bearing mice (95% confidence interval: 53±0.001 57±1 days). Accordingly, delayed emergence skeletal-related event intra-tibial xenografts. Next, evaluated docetaxel (DTX; 5, 1, 0.5 mg/kg) or cyclophosphamide (CTX; 10–20 on established s.c. tumors conditionally express anti-tumoral epitope/NT3. Although NT3–DTX-5 mg/kg inefficient, NT3–DTX-1 -0.5 95% 87.8%, respectively, compared control stasis. Both NT3–CTX combinations advantageous. Inversely, PEDF–DTX-5 PEDF–CTX-10 most (15, 11 5 days mg/kg, single treatments, respectively) elevated apoptosis serum thrombospondin-1 possible mechanism marker, As well, significantly treatments. Metastases other PEDF–DTX formation. Our results advocate PEDF/low-dose chemotherapy may represent alternative CRPC.