尽管采取了巨大的努力来实施新的化疗模式为肺癌,这种疾病仍然是全世界关注的主要问题。靶向Hedgehog(Hh)和丝裂原活化蛋白激酶(MAPK)的分子途径代表了肺癌治疗的新希望。这项工作是为了评估GANT61(5μM)的抗肿瘤作用,BI-847325(30μM),和GANT61(5μM)/BI-847325(30μM)组合在A549腺癌肺癌细胞系上。使用MTT进行两种药物的生长抑制50(GI50)。Caspase-3,Bcl-2相关X蛋白(Bax),髓系细胞白血病序列1(MCL-1),细胞周期蛋白D1,血管内皮生长因子(VEGF),细胞外信号调节激酶(ERK),p-Akt,和磷酸组蛋白H3(pHH3)使用ELISA测量。通过定量实时PCR评估胶质瘤相关癌基因同源物1(Gli1)基因表达。GANT61和BI-8473255的GI50分别为5µM和30µM,分别。Caspase-3和Bax蛋白水平显著升高,而MCL-1、cyclinD1、VEGF、ERK1/2,p-Akt,与对照组相比,两种药物及其组合的pHH3水平显着降低。相对于对照组,Gli1基因表达在所有组中下调。GANT61、BI-847325及其组合抑制增殖和血管生成,但激活凋亡途径。两种药物都对Hh和MAPK途径中的每一个与磷酸肌醇3-激酶(PI3K)/Akt/哺乳动物雷帕霉素靶(mTOR)之间的串扰产生了深远的负面影响。据我们所知,之前尚未测试过BI-847325/GANT61组合的抗肿瘤作用。需要进一步的体外和体内研究来支持这些发现。
Despite the huge efforts employed to implement novel chemotherapeutic paradigms for lung cancer, the disease still remains a major concern worldwide. Targeting molecular pathways as Hedgehog (Hh) and Mitogen-activated protein kinase (MAPK) represent a new hope in lung cancer treatment. This work was undertaken to evaluate the antitumor effects of
GANT61 (5 μM), BI-847325(30 μM), and
GANT61 (5 μM)/BI-847325(30 μM) combination on A549 adenocarcinoma lung cancer cell line. The growth inhibition 50 (GI50) for both drugs was performed using MTT. The protein levels of Caspase-3, Bcl-2-associated X protein (Bax), Myeloid cell leukemia sequence 1 (MCL-1), cyclin D1, vascular endothelial growth factor (VEGF), extracellular signal-regulated kinases (ERK), p-Akt, and phosphohistone H3 (pHH3) were measured using ELISA. Glioma-associated oncogene homolog 1(Gli1) gene expression was assessed by quantitative real-time PCR. The GI50 for
GANT61 and BI-8473255 were 5 µM and 30 µM, respectively. Caspase-3 and Bax protein levels were significantly elevated while MCL-1, cyclin D1, VEGF, ERK 1/2, p-Akt, and pHH3 levels were significantly reduced by both drugs and their combination relative to the control group. Gli1 gene expression was down-regulated in all groups relative to the control group.
GANT61, BI-847325 and their combination inhibited proliferation and angiogenesis but activated the apoptotic pathway. Both drugs conferred a profound negative impact on the crosstalk between each of Hh and MAPK pathways and Phosphoinositide 3 -kinases (PI3K)/Akt/Mammalian target of Rapamycin (mTOR). To the best of our knowledge, the antitumor effects of BI-847325/
GANT61 combination have not been tested before. Further in-vitro and in-vivo studies are warranted to support the findings.