Subaiea Gehad, Rizvi Syed Mohd Danish, Yadav Hemant Kumar Singh, Al Hagbani Turki, Abdallah Marwa Helmy, Khafagy El-Sayed, Gangadharappa Hosahalli Veerabhadrappa, Hussain Talib, Abu Lila Amr Selim
Department of Pharmacology and Toxicology, College of Pharmacy, University of Ha'il, Ha'il 81442, Saudi Arabia.
Department of Pharmaceutics, College of Pharmacy, University of Ha'il, Ha'il 81442, Saudi Arabia.
Pharmaceuticals (Basel). 2023 Feb 2;16(2):230. doi: 10.3390/ph16020230.
Among the various types of cancer, lung cancer accounts for the highest number of fatalities across the globe. A combination of different cancer chemotherapeutics is regarded as an effective strategy for clinical management of different cancers. Ganetespib (GAN) is a well-established hsp90 inhibitor with enhanced pharmacological properties in comparison with its first-generation counterparts. Previous preclinical studies have shown that GAN exerts significant effects against cancer cells; however, its therapeutic effects against non-small cell lung cancer (NSCLC) A549 cells, achieved by modulating the expression of the NF-κB/p65 signaling pathway, remains unexplored. In this study, the combinatorial effect of GAN and methotrexate (MTX) against lung carcinomas was investigated through both in silico and in vitro studies. A combinatorial treatment regimen of GAN/MTX exerted more significant cytotoxic effects ( < 0.001) against A549 cells than individual treatments. The GAN/MTX combination also instigated nuclear fragmentation followed by augmentation in intracellular ROS levels ( < 0.001). The elevated ROS in A549 cells upon exposure to GAN/MTX combinatorial regimen was concomitantly accompanied with a remarkable reduction in mitochondrial viability. In addition, it was observed that the GAN/MTX combination succeeded in elevating caspase-3 activity and downregulating the expression levels of anti-apoptotic mediators Bcl2 and survivin in NSCLC A549 cells. Most importantly, the GAN/MTX combinatorial regimen impeded the activation of the NF-kB/p65 signaling pathway via repression of the expression of E-cadherin and N-cadherin, which was confirmed by molecular docking studies. Collectively, these findings demonstrated the synergistic effect of the GAN/MTX combinatorial regimen in suppressing the growth of A549 cells by modulating the NF-κB/p65 signaling pathway.
在各类癌症中，肺癌在全球的致死人数最多。不同癌症化疗药物联合使用被认为是不同癌症临床治疗的有效策略。ganetespib（GAN）是一种成熟的热休克蛋白90抑制剂，与第一代同类药物相比，其药理特性有所增强。先前的临床前研究表明，GAN对癌细胞有显著作用；然而，其通过调节NF-κB/p65信号通路对非小细胞肺癌（NSCLC）A549细胞的治疗效果仍未得到探索。在本研究中，通过计算机模拟和体外研究，对GAN和甲氨蝶呤（MTX）联合治疗肺癌的效果进行了研究。与单独治疗相比，GAN/MTX联合治疗方案对A549细胞具有更显著的细胞毒性作用（<0.001）。GAN/MTX联合用药还引发了核碎裂，随后细胞内活性氧水平升高（<0.001）。暴露于GAN/MTX联合治疗方案后，A549细胞中升高的活性氧伴随着线粒体活力的显著降低。此外，观察到GAN/MTX联合用药成功提高了caspase-3活性，并下调了NSCLC A549细胞中抗凋亡介质Bcl2和survivin的表达水平。最重要的是，GAN/MTX联合治疗方案通过抑制E-钙黏蛋白和N-钙黏蛋白的表达，阻碍了NF-κB/p65信号通路的激活，这一点通过分子对接研究得到了证实。总的来说，这些发现证明了GAN/MTX联合治疗方案通过调节NF-κB/p65信号通路抑制A549细胞生长的协同作用。
