Purpose

Although doxorubicin is widely used to treat cancer, severe side effects limit its clinical use. Combination of standard chemotherapy with natural products can increase the efficacy and attenuate the side effects of current therapies. Here we studied the anticancer effects of a combined regimen comprising doxorubicin and [10]-gingerol against triple-negative breast cancer, which does not respond to hormonal or targeted therapies.

Methods

Cytotoxicity was evaluated by MTT assay, cell cycle progression and apoptosis were analyzed by flow cytometry and signaling pathways were analyzed by Western blotting in human and murine triple negative breast cancer cell systems. The anticancer/antimetastatic and toxic effects of the combined regimen was evaluated using syngeneic and xenograft orthotopic models.

Results

The combination of doxorubicin and [10]-gingerol significantly increased the number of apoptotic cells, compared to each compound alone. In 4T1Br4 cells, the combined regimen was the only condition able to increase the levels of active caspase 3 and γH2AX and to decrease the level of Cdk-6 cyclin. In vivo, doxorubicin (3 mg/Kg, D3) and [10]-gingerol (10 mg/Kg, G10) resulted in a significant reduction in the volume of primary tumors and a decrease in the number of circulating tumor cells (CTCs). Interestingly, only the combined regimen led to decreased tumor burdens to distant organs (i.e., metastasis) and reduced chemotherapy-induced weight loss and hepatotoxicity in tumor-bearing animals. Likewise, in a xenograft model, only the combined regimen was effective in significantly reducing the primary tumor volume and the prevalence of CTCs.

Conclusions

Our data indicate that [10]-gingerol has potential to be used as a neoadjuvant or in combined therapy with doxorubicin, to improve its anticancer activity.

中文翻译：

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[10]-姜油可改善阿霉素抗癌活性，并在三阴性乳腺癌模型中降低其副作用。

目的

尽管阿霉素被广泛用于治疗癌症，但严重的副作用限制了其临床应用。标准化学疗法与天然产品的组合可以提高疗效，并减轻当前疗法的副作用。在这里，我们研究了包含阿霉素和[10]-姜油的联合治疗方案对三阴性乳腺癌的抗癌作用，该乳腺癌对激素或靶向治疗无效。

方法

通过MTT分析评估细胞毒性，通过流式细胞术分析细胞周期进程和凋亡，并且通过蛋白质印迹分析人和鼠三阴性乳腺癌细胞系统中的信号传导途径。使用同基因和异种移植原位模型评估联合治疗方案的抗癌/抗转移和毒性作用。

结果

与单独的每种化合物相比，阿霉素和[10]-姜油醇的组合显着增加了凋亡细胞的数量。在4T1Br4细胞中，联合方案是唯一能够增加活性caspase 3和γH2AX水平并降低Cdk-6 cyclin水平的条件。体内，阿霉素（3 mg / Kg，D3）和[10]-姜醇（10 mg / Kg，G10）导致原发肿瘤体积显着减少和循环肿瘤细胞（CTC）数量减少。有趣的是，只有联合治疗方案可以减少远处器官的肿瘤负担（即转移），并减少化疗引起的荷瘤动物体重减轻和肝毒性。同样，在异种移植模型中，只有联合方案才能有效地显着减少原发肿瘤体积和CTC的发生率。

结论

我们的数据表明[10]-姜油有潜力用作新辅助药或与阿霉素联用，以提高其抗癌活性。