Delayed cancer progression in the ventral prostate of the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model has been previously reported upon celecoxib and nintedanib co-administration. Herein, we sought to further investigate the effects of these drugs association in some of their direct molecular targets (COX-2, VEGF and VEGFR-2) and in reactive stroma markers (TGF-β, αSMA, vimentin and pro-collagen 1) in the dorsolateral prostate, looking for lobe-specific responses. Male TRAMP mice were treated with celecoxib (10 mg/Kg, i.o.) and/or nintedanib (15 mg/Kg, i.o.) for 6 weeks and prostate was harvested for morphological and protein expression analyses. Results showed that combined therapy resulted in unique antitumor effects in dorsolateral prostate, especially due to the respective stromal or epithelial antiproliferative actions of these drugs, which altogether led to a complete inversion in high-grade (HGPIN) versus low-grade (LGPIN) premalignant lesion incidences in relation to controls. At the molecular level, this duality in drug action was paralleled by the differential down/upregulation of TGF-β signaling by celecoxib/nintedanib, thus leading to associated changes in stroma composition towards regression or quiescence, respectively. Additionally, combined therapy was able to promote decreased expression of inflammatory (COX-2) and angiogenesis (VEGF/VEGFR-2) mediators. Overall, celecoxib and nintedanib association provided enhanced antitumor effects in TRAMP dorsolateral as compared to former registers in ventral prostate, thus demonstrating lobe-specific responses of this combined chemoprevention approach. Among these responses, we highlight the ability in promoting TGF-β signaling and its associated stromal maturation/stabilization, thus yielding a more quiescent stromal milieu and resulting in greater epithelial proliferation impairment.

先前曾报道过塞来昔布和尼达尼布共同给药可延迟小鼠前列腺癌（TRAMP）模型腹侧前列腺的癌症进展。在此，我们试图进一步研究这些药物关联对其一些直接分子靶标（COX-2、VEGF 和 VEGFR-2）和反应性基质标志物（TGF-β、αSMA、波形蛋白和前胶原蛋白 1）的影响在前列腺背外侧，寻找叶特异性反应。用塞来昔布（10mg/Kg，io）和/或尼达尼布（15mg/Kg，io）治疗雄性TRAMP小鼠6周，并收获前列腺用于形态学和蛋白质表达分析。结果表明，联合治疗在前列腺背外侧产生了独特的抗肿瘤作用，特别是由于这些药物各自的间质或上皮抗增殖作用，这共同导致了高级别（HGPIN）与低级别（LGPIN）癌前病变的完全逆转。与对照相关的病变发生率。在分子水平上，药物作用的这种二元性与塞来昔布/尼达尼布对 TGF-β 信号传导的差异下调/上调同时存在，从而导致基质成分分别向回归或静止方向发生相关变化。此外，联合治疗能够促进炎症 (COX-2) 和血管生成 (VEGF/VEGFR-2) 介质的表达减少。总体而言，与之前在前列腺腹侧的记录相比，塞来昔布和尼达尼布联合在 TRAMP 背外侧提供了增强的抗肿瘤作用，从而证明了这种联合化学预防方法的叶特异性反应。在这些反应中，我们强调了促进 TGF-β 信号传导及其相关基质成熟/稳定的能力，从而产生更静止的基质环境并导致更大的上皮增殖损伤。