Abstract

Docetaxel (DOX) based combination therapy is a novel therapeutic strategy that attracts great interest in breast cancer treatment but its clinical utility got limited due to side effects. In contrast, noscapine, an antitussive drug showed antitumor activity against many cancers without any side effects that targets microtubules and attenuates its dynamic instability. In the quest for an increase in the anticancer activity of noscapine, we strategically designed a novel derivative, 9-vinyl phenyl noscapine (VPN), based on our in silico molecular docking and molecular dynamics simulation effort. Molecular docking of VPN and DOX onto microtubule revealed a docking score of −4.82 kcal/mol and −6.67 kcal/mol respectively, while the docking score of VPN was changed to −3.23 kcal/mol when it was docked onto the co-complex of tubulin-DOX. Further, the binding free energy (ΔG_bind,PBSA) of VPN and DOX with tubulin showed −24.04 and −18.65 kcal/mol respectively, while the binding free energy of DOX was increased further in combination with VPN (ΔG_{bind, PBSA} was reduced to −21.41 kcal/mol), denoting combination effect of both ligands. The IC₅₀ value amounted to 30.17 µM and 19.92 µM for VPN and 0.621 µM and 0.193 µM for DOX, respectively for 48 h and 72 h. The dose dependent cytotoxicity of DOX has been reduced considerably with the combination dose regimen of VPN. Further, the combine effect of both the agents improved the apoptotic cell death 28.5% compared to single agent treatment 5.71% and 10.5% for VPN and DOX, respectively. Both agents bind effectively to tubulin in single and in combination to interfere with cell cycle progression in G2/M transition. This study provides novel concept of combination treatment of DOX and VPN to amend efficiency in breast cancer treatment.

Communicated by Ramaswamy H. Sarma

摘要

基于多西紫杉醇 (DOX) 的联合疗法是一种新的治疗策略，在乳腺癌治疗中引起了极大的兴趣，但由于副作用，其临床效用受到限制。相比之下，诺斯卡品是一种镇咳药，对许多癌症显示出抗肿瘤活性，没有任何针对微管并减弱其动态不稳定性的副作用。为了提高那可丁的抗癌活性，我们战略性地设计了一种新型衍生物，9-乙烯基苯基那可丁 (VPN)，基于我们的in silico分子对接和分子动力学模拟工作。VPN 和 DOX 与微管的分子对接显示对接分数分别为 -4.82 kcal/mol 和 -6.67 kcal/mol，而当 VPN 与微管蛋白-DOX。此外，VPN和DOX与微管蛋白的结合自由能(ΔG _bind,PBSA )分别显示-24.04和-18.65 kcal/mol，而DOX与VPN结合的结合自由能进一步增加(ΔG _bind,PBSA降低)至-21.41 kcal/mol)，表示两种配体的组合效应。IC ₅₀在 48 小时和 72 小时内，VPN 的值分别为 30.17 µM 和 19.92 µM，DOX 的值为 0.621 µM 和 0.193 µM。随着 VPN 的联合给药方案，DOX 的剂量依赖性细胞毒性已大大降低。此外，与 VPN 和 DOX 的单药治疗 5.71% 和 10.5% 相比，这两种药物的联合作用使凋亡细胞死亡提高了 28.5%。两种药物都可以单独或联合有效地与微管蛋白结合，以干扰 G2/M 转换中的细胞周期进程。本研究提供了 DOX 和 VPN 联合治疗的新概念，以提高乳腺癌治疗的效率。

由 Ramaswamy H. Sarma 交流