Noscapine, an opium alkaloid, was discovered to bind tubulin, arrest dividing cells at mitosis, and selectively induce apoptosis to cancer cells. N-3-Br-Benzyl-Noscapine (Br-Bn-Nos), one of the derivatives of noscapine, was demonstrated to have improved anticancer potential compared with noscapine. We approached to evaluate the single and combined effect of Br-Bn-Nos and docetaxel (DOX) based on molecular modeling and cellular study. The individual predicted free energy of binding (∆G_bind,pred) for Br-Bn-Nos and DOX with tubulin was found to be −28.89 and −36.07 kcal/mol based on molecular mechanics generalized Born solvation area (MM-GBSA) as well as −26.21 and −34.65 kcal/mol based on molecular mechanics Poisson Boltzmann solvation area (MM-PBSA), respectively. However, the ∆G_bind,pred of Br-Bn-Nos was significantly reduced (−33.02 and −30.24 kcal/mol using MM-GBSA and MM-PBSA) in the presence of DOX on its binding pocket. Parenthetically, the ∆G_bind,pred of DOX was significantly reduced (−37.17 and −32.80 kcal/mol using MM-GBSA and MM-PBSA) in the presence of Br-Bn-Nos on its binding pocket. The reduced ∆G_bind,pred in the presence of Br-Bn-Nos and DOX together indicated a combination effect of both the ligands. The combined interaction of both the agents onto tubulin dimmer was also determined experimentally using purified tubulin, in which a combination regimen of Br-Bn-Nos and DOX reduced the fluorescence intensity of tubulin to a higher value (68%) compared with the single regimen. Further, isobologram analysis revealed the synergistic effect of Br-Bn-Nos and DOX in antiproliferative activity using MCF-7 cell line at 48 hr (sum FIC = 0.49) and at 72 hr (sum FIC = 0.62). The combination dose regimen of Br-Bn-Nos and DOX blocks the cell cycle progression at the G2/M phase and induces apoptosis to cancer cells more effectively compared with the single regimen. Taken together, our study provides compelling evidence that the anticancer potential of noscapine derivatives may be substantially improved when it is used in a combined application with DOX for breast cancer.

中文翻译：

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N-3-Br-苄基-诺斯卡品和多西紫杉醇的协同相互作用消除了乳腺癌细胞的致癌潜力

Noscapine 是一种鸦片生物碱，被发现可以结合微管蛋白，在有丝分裂时阻止分裂细胞，并选择性地诱导癌细胞凋亡。N-3-Br-Benzyl-Noscapine (Br-Bn-Nos) 是 Noscapine 的衍生物之一，与 Noscapine 相比，已被证明具有更高的抗癌潜力。我们基于分子建模和细胞研究来评估 Br-Bn-Nos 和多西紫杉醇 (DOX) 的单一和联合作用。根据分子力学广义波恩溶剂化面积 (MM-GBSA)，发现 Br-Bn-Nos 和 DOX 与微管蛋白的个体预测结合自由能 (Δ G _bind,pred ) 分别为 -28.89 和 -36.07 kcal/mol以及分别基于分子力学泊松玻尔兹曼溶剂化面积 (MM-PBSA) 的 -26.21 和 -34.65 kcal/mol。然而，ΔG在其结合口袋上存在 DOX 的情况下，Br-Bn-Nos 的_bind,pred显着降低（-33.02 和 -30.24 kcal/mol，使用 MM-GBSA 和 MM-PBSA）。附带说明的是，在其结合口袋上存在 Br-Bn-Nos 的情况下，DOX 的∆G _bind,pred显着降低（-37.17 和 -32.80 kcal/mol，使用 MM-GBSA 和 MM-PBSA）。减少的 ∆ G _bind,pred在 Br-Bn-Nos 和 DOX 存在的情况下，这两种配体的组合效应。两种药物对微管蛋白二聚体的联合相互作用也使用纯化的微管蛋白通过实验确定，其中与单一方案相比，Br-Bn-Nos 和 DOX 的组合方案将微管蛋白的荧光强度降低到更高的值 (68%) . 此外，等值线图分析揭示了使用 MCF-7 细胞系在 48 小时（总 FIC = 0.49）和 72 小时（总 FIC = 0.62）时 Br-Bn-Nos 和 DOX 在抗增殖活性中的协同作用。与单一方案相比，Br-Bn-Nos 和 DOX 的联合给药方案在 G2/M 期阻断细胞周期进程并更有效地诱导癌细胞凋亡。综合起来，