Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer.
Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer.
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DOI：
10.1038/cddis.2014.180
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发表时间：
2014-05-08
影响因子：
9
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中科院分区：
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尽管最近批准了几种新的治疗药物，但目前还无法治愈晚期去势难治性前列腺癌（CRPC）。我们在此报告了血管抑制性色素上皮衍生因子（PEDF）在转移性LNCaP衍生CRPC CL 1模型中的抗肿瘤作用，并探讨了PEDF与低剂量化疗联合治疗的抗肿瘤疗效。检测雄激素敏感的LNCaP和CRPC PC 3细胞系作为比较。使用逆转录病毒表达系统，我们发现PEDF限制了所有测试的前列腺细胞系的增殖;这一效应归因于白细胞介素8（IL 8）-CXCR 1/IL 8 RA抑制。PEDF还减少了体外3D肿瘤球体的数量和大小，但仅诱导CRPC球体中的细胞分化。类似地，PEDF抑制CRPC细胞的迁移，表明抗增殖和抗迁移功能。在体内，PEDF使皮下（s.c.）生长减少85%和65% PC 3和CL 1肿瘤。在CL 1原位模型中，在所有动物中均发现了具有致死性转移的肿瘤摄入;然而，PEDF延长了荷瘤小鼠的中位生存期（95%置信区间：53±0.001至57±1天）。因此，PEDF延迟了胫骨内异种移植物中骨相关事件的出现。接下来，我们评估了低剂量多西他赛（DTX; 5、1、0.5 mg/kg）或环磷酰胺（CTX; 10-20 mg/kg）对建立的皮下给药的影响。条件性表达PEDF抗肿瘤表位/NT 3的PC 3肿瘤。尽管NT 3-DTX-5 mg/kg组合是无效的，但与对照相比，NT 3-DTX-lmg/kg和约0.5mg/kg分别抑制95%和87.8%的肿瘤生长并诱导肿瘤停滞。两种NT 3-CTX组合都是有利的。抑制、PEDF-DTX-5 mg/kg和PEDF-CTX-10 mg/kg延迟了大多数CL 1肿瘤生长（PEDF-DTX-5 mg/kg、PEDF-CTX-10 mg/kg和单次治疗分别为15、11和5天），细胞凋亡和血清血小板反应蛋白-1升高分别是可能的机制和标志物。同样，与单次治疗相比，PEDF-CTX-10 mg/kg和PEDF-DTX-5 mg/kg均显著延长了荷瘤小鼠的生存期。与其他治疗相比，PEDF-DTX-5 mg/kg中的转移减少，表明PEDF-DTX延迟了转移形成。我们的研究结果表明，PEDF/低剂量化疗可能是CRPC的一种新的治疗选择。
There is currently no cure for advanced castration-refractory prostate cancer (CRPC) despite the recent approval of several new therapeutic agents. We report here the anti-tumor effect of the angio-inhibitory pigment epithelium-derived factor (PEDF) in the metastatic LNCaP-derivative CRPC CL1 model and explore PEDF anti-neoplasic efficacy in combination with low-dose chemotherapy. Androgen-sensitive LNCaP and CRPC PC3 cell lines were examined as comparison. Using a retroviral expression system, we showed that PEDF limited the proliferation of all prostatic cell lines tested; an effect attributed to interleukin 8 (IL8)-CXCR1/IL8RA inhibition. PEDF also reduced the number and size of 3D tumor spheroids in vitro, but only induced cell differentiation in CRPC spheroids. Similarly, PEDF inhibited the migration of CRPC cells suggesting both anti-proliferative and anti-migratory functions. In vivo, PEDF decreased by 85% and 65% the growth of subcutaneous (s.c.) PC3 and CL1 tumors, respectively. In the CL1 orthotopic model, tumor intake with lethal metastases was found in all animals; nevertheless, PEDF prolonged the median survival of tumor-bearing mice (95% confidence interval: 53±0.001 to 57±1 days). Accordingly, PEDF delayed the emergence of skeletal-related event in intra-tibial xenografts. Next, we evaluated low-dose docetaxel (DTX; 5, 1, 0.5 mg/kg) or cyclophosphamide (CTX; 10–20 mg/kg) on established s.c. PC3 tumors that conditionally express PEDF anti-tumoral epitope/NT3. Although NT3–DTX-5 mg/kg combination was inefficient, NT3–DTX-1 mg/kg and -0.5 mg/kg inhibited by 95% and 87.8%, respectively, tumor growth compared with control and induced tumor stasis. Both NT3–CTX combinations were advantageous. Inversely, PEDF–DTX-5 mg/kg and PEDF–CTX-10 mg/kg delayed the most CL1 tumor growth (15, 11 and 5 days for PEDF–DTX-5 mg/kg, PEDF–CTX-10 mg/kg and single treatments, respectively) with elevated apoptosis and serum thrombospondin-1 as possible mechanism and marker, respectively. As well, both PEDF–CTX-10 mg/kg and PEDF–DTX-5 mg/kg prolonged significantly the survival of tumor-bearing mice compared with single treatments. Metastases were reduced in PEDF–DTX-5 mg/kg compared with other treatments, suggesting that PEDF–DTX delayed metastases formation. Our results advocate that PEDF/low-dose chemotherapy may represent a new therapeutic alternative for CRPC.
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