Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), CP-6109, 13083-865, Campinas, SP, Brazil.
Infect Agent Cancer. 2012 Jun 18;7(1):14. doi: 10.1186/1750-9378-7-14.
Compounds that can act as agonists for toll-like receptors (TLRs) may be promising candidates for the development of drugs against infectious diseases and cancer. The present study aimed to characterize the immunomodulatory effects of P-MAPA on TLRs in vitro and in vivo, as well as to investigate its potential as adjuvant therapy in infectious diseases and cancer.
For these purposes, the activity of P-MAPA on TLRs was assayed in vitro through NF-κB activation in HEK293 cells expressing a given TLR, and using an in vivo animal model for bladder cancer (BC). The antimicrobial activity of P-MAPA was tested against Mycobacterium tuberculosis (TB) in vitro in an MIC assay, and in vivo using an aerosol infection model of murine tuberculosis. Antitumor effects of P-MAPA were tested in an animal model with experimentally induced BC. Moxifloxacin (MXF) and Bacillus Calmette-Guerin (BCG) were used as positive controls in the animal models.
The results showed that P-MAPA, administered alone or in combination with MXF, induced significant responses in vivo against TB. In contrast, the compound did not show antimicrobial activity in vitro. P-MAPA showed a significant stimulatory effect on human TLR2 and TLR4 in vitro. In BC, TLR2, TLR4 and p53 protein levels were significantly higher in the P-MAPA group than in the BCG group. The most common histopathological changes in each group were papillary carcinoma in BC group, low-grade intraepithelial neoplasia in BCG group and simple hyperplasia in P-MAPA group. Concerning the toxicological analysis performed during BC treatment, P-MAPA did not show evidence for hepatotoxicity and nephrotoxicity.
In conclusion, P-MAPA acted as TLR ligand in vitro and improved the immunological status in BC, increasing TLR2 and TLR4 protein levels. P-MAPA immunotherapy was more effective in restoring p53 and TLRs reactivities and showed significantly greater antitumor activity than BCG. The activation of TLRs and p53 may provide a hypothetical mechanism for the therapeutic effects in both cancer and infectious diseases. Taken together data obtained will encourage the further investigation of P-MAPA as a potential candidate for the treatment of cancer and infectious diseases.
能够作为 Toll 样受体 (TLR) 激动剂的化合物可能是开发用于治疗传染病和癌症的药物的有前途的候选物。本研究旨在表征 P-MAPA 在体外和体内对 TLR 的免疫调节作用，并研究其在传染病和癌症中的辅助治疗潜力。
为此，通过在表达特定 TLR 的 HEK293 细胞中测定 NF-κB 激活，以及使用膀胱癌 (BC) 的体内动物模型，在体外测定 P-MAPA 对 TLR 的活性。通过 MIC 测定法在体外和使用小鼠结核病气溶胶感染模型在体内测试 P-MAPA 对结核分枝杆菌 (TB) 的抗菌活性。在实验性诱导的 BC 动物模型中测试 P-MAPA 的抗肿瘤作用。莫西沙星 (MXF) 和卡介苗 (BCG) 被用作动物模型中的阳性对照。
结果表明，P-MAPA 单独或与 MXF 联合给药可在体内对 TB 产生显著的反应。相比之下，该化合物在体外没有显示出抗菌活性。P-MAPA 在体外对人 TLR2 和 TLR4 具有显著的刺激作用。在 BC 中，与 BCG 组相比，P-MAPA 组的 TLR2、TLR4 和 p53 蛋白水平显着升高。每个组中最常见的组织病理学变化是 BC 组的乳头状癌、BCG 组的低级别上皮内瘤变和 P-MAPA 组的单纯性增生。关于在 BC 治疗期间进行的毒理学分析，P-MAPA 没有显示出肝毒性和肾毒性的证据。
总之，P-MAPA 在体外作为 TLR 配体起作用，并改善了 BC 中的免疫状态，增加了 TLR2 和 TLR4 蛋白水平。P-MAPA 免疫疗法在恢复 p53 和 TLR 反应性方面更有效，并且显示出比 BCG 更高的抗肿瘤活性。TLR 和 p53 的激活可能为癌症和传染病的治疗效果提供一种假设机制。综合获得的数据将鼓励进一步研究 P-MAPA 作为治疗癌症和传染病的潜在候选物。
