Pascutti María Fernanda, Campodonico Gerardo, García Fabiana, Manarin Romina, Bottasso Oscar, Revelli Silvia, Serra Esteban
Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Argentina.
Int Immunopharmacol. 2009 Jun;9(6):739-45. doi: 10.1016/j.intimp.2009.02.013. Epub 2009 Mar 12.
We have shown that Benznidazole (BZL), a compound with well documented trypanocidal activity, possesses anti-inflammatory properties and inhibits the nuclear factor kappaB (NF-kappaB). Given the relationship between this transcription factor and cell growth, in this study we address the role of NF-kappaB blockade by BZL in the proliferation of different cell lines. Our studies demonstrate that this compound significantly reduced proliferation of RAW 264.7 macrophage cell line, as assessed by trypan blue exclusion, MTT reduction and [(3)H]-thymidine incorporation, at a concentration shown to inhibit NF-kappaB. Treatment with BZL also led to growth arrest in CHO, MDCK and HeLa cells. Interestingly, growth inhibition was found to be a reversible process, not accompanied by significant cell death, indicating that the drug behaves mainly as a cytostatic compound. As this effect might be related to NF-kappaB inhibition, we next evaluated whether other NF-kappaB inhibitors could induce growth arrest in RAW 264.7 and HeLa cells. We found that IKK inhibition led to growth arrest in both cell lines, indicating that NF-kappaB inhibition may be the potential mechanism by which BZL inhibits cell proliferation. To the best of our knowledge, this is the first report of an anti-proliferative activity of the trypanocidal drug against different cell lines and provides a mechanistic insight that may help understand some of the adverse effects associated with prolonged treatment.
我们已经表明，苯硝唑（BZL）是一种具有充分记载的杀锥虫活性的化合物，具有抗炎特性并能抑制核因子κB（NF-κB）。鉴于这种转录因子与细胞生长之间的关系，在本研究中我们探讨了BZL阻断NF-κB在不同细胞系增殖中的作用。我们的研究表明，在显示能抑制NF-κB的浓度下，通过台盼蓝排斥法、MTT还原法和[³H]-胸苷掺入法评估，该化合物显著降低了RAW 264.7巨噬细胞系的增殖。用BZL处理也导致CHO、MDCK和HeLa细胞生长停滞。有趣的是，发现生长抑制是一个可逆过程，且不伴有明显的细胞死亡，这表明该药物主要表现为一种细胞生长抑制剂。由于这种效应可能与NF-κB抑制有关，我们接下来评估了其他NF-κB抑制剂是否能诱导RAW 264.7和HeLa细胞生长停滞。我们发现抑制IKK会导致这两种细胞系生长停滞，表明NF-κB抑制可能是BZL抑制细胞增殖的潜在机制。据我们所知，这是关于这种杀锥虫药物对不同细胞系具有抗增殖活性的首次报道，并提供了一种机制性见解，可能有助于理解与长期治疗相关的一些不良反应。
